BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.

{ "type": "p", "children": [], "text": "BRIXADI is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine." }

BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support.

{ "type": "p", "children": [], "text": "BRIXADI should be used as part of a complete treatment plan that includes counseling and psychosocial support." }

FOR SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER BRIXADI INTRAVENOUSLY, INTRAMUSCULARLY, OR INTRADERMALLY [see Warnings and Precautions (5.1), Instructions for Use (2.6)].

To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point, and the monthly dose may be administered up to 1 week before or after the monthly time point.

If a dose is missed, the next dose should be administered as soon as practically possible.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions (5.4)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu receptor [see Overdosage (10)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information (17)].

Patients Not Currently Receiving Buprenorphine Treatment

The recommended weekly dose in patients not currently receiving buprenorphine treatment is 24 mg of BRIXADI (weekly) titrated up over the first week of treatment as follows:

If needed, during this first week of treatment, administer an additional 8 mg dose of BRIXADI (weekly), waiting at least 24 hours after the previous injection, for a total weekly dose of 32 mg BRIXADI (weekly).

Administer subsequent BRIXADI (weekly) injections based on the total weekly dose that was established during Week One. Dosage adjustments can be made at weekly appointments with the maximum BRIXADI (weekly) dose being 32 mg.

A patient who misses a dose of BRIXADI (weekly) should receive the next dose as soon as possible. BRIXADI (weekly) should be administered in 7-day intervals.

Patients Switching from Transmucosal Buprenorphine-containing Products to BRIXADI

Patients currently being treated with a transmucosal buprenorphine-containing product may be switched directly to either BRIXADI (weekly) or BRIXADI (monthly).

Table 1 identifies the corresponding dose of BRIXADI when switching a patient from transmucosal buprenorphine to BRIXADI (weekly) or BRIXADI (monthly), expressing the transmucosal dose equivalents in terms of Subutex or Suboxone doses.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1: Daily doses of sublingual buprenorphine (Subutex, Suboxone, or generic product equivalents) and suggested corresponding BRIXADI (weekly) or BRIXADI (monthly) doses</span> </caption> <col align="center" valign="middle" width="34%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Daily dose of sublingual buprenorphine</th><th align="center" class="Rrule">BRIXADI (weekly)</th><th align="center" class="Rrule">BRIXADI (monthly)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3">Note: One SUBOXONE® (buprenorphine and naloxone) 8 mg/2 mg sublingual tablet provides equivalent buprenorphine exposure to one SUBUTEX® (buprenorphine HCl) 8 mg sublingual tablet or one Zubsolv® (buprenorphine and naloxone) 5.7 mg/1.4 mg sublingual tablet.</td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">≤ 6 mg</td><td align="center" class="Rrule">8 mg</td><td align="center" class="Rrule">--</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">8-10 mg</td><td align="center" class="Rrule">16 mg</td><td align="center" class="Rrule">64 mg</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">12-16 mg</td><td align="center" class="Rrule">24 mg</td><td align="center" class="Rrule">96 mg</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">18-24 mg</td><td align="center" class="Rrule">32 mg</td><td align="center" class="Rrule">128 mg</td> </tr> </tbody> </table></div>

Patients Transitioning Between BRIXADI (weekly) and BRIXADI (monthly)

Patients may be transitioned from weekly to monthly or from monthly to weekly dosing of BRIXADI based on clinical judgment (see Table 2).

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 2: Recommended dose when transitioning between BRIXADI (weekly) and BRIXADI (monthly)</span> </caption> <col align="center" valign="top" width="50%"/> <col align="center" valign="top" width="50%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">BRIXADI (weekly)</th><th align="center" class="Rrule">BRIXADI (monthly)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">16 mg</td><td align="center" class="Rrule">64 mg</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">24 mg</td><td align="center" class="Rrule">96 mg</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">32 mg</td><td align="center" class="Rrule">128 mg</td> </tr> </tbody> </table></div>

A patient who misses a dose of BRIXADI should receive the next dose as soon as possible. BRIXADI (weekly) should be administered in 7-day intervals. BRIXADI (monthly) should be administered in 28-day intervals.

Dose Adjustments of BRIXADI

An additional BRIXADI (weekly) 8 mg injection may be administered, based on clinical judgment during a dosing interval, up to a maximum dose of 32 mg per week of BRIXADI (weekly) or 128 mg per month of BRIXADI (monthly).

Patients appropriate for BRIXADI (weekly) are:

Patients appropriate for BRIXADI (monthly) are adults who are currently being treated with a transmucosal buprenorphine-containing product. BRIXADI (monthly) is not intended for patients who are not currently receiving buprenorphine treatment.

Periodic assessment is necessary to determine effectiveness of the treatment plan and overall patient progress. When evaluating the patient, examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot.

Due to the chronic nature of opioid use disorder, the need for continuing medication-assisted treatment should be re-evaluated periodically. There is no maximum recommended duration of maintenance treatment. For some patients, treatment may continue indefinitely. If considering stopping treatment, the clinical status of the patient should be considered.

If BRIXADI is discontinued, its extended-release characteristics should be considered, and the patient should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. After steady-state has been achieved, which is 4 weeks for BRIXADI (weekly) and 4 months for BRIXADI (monthly), patients discontinuing BRIXADI may have detectable plasma levels of buprenorphine for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly). The correlation between plasma concentrations of buprenorphine and those detectable in urine is not known.

Prior to injecting BRIXADI, carefully read the instructions as well as the full prescribing information.

IMPORTANT INFORMATION:

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">SAFETY SYRINGE PARTS</span> (see <a href="#Fig1">Figures 1</a>, <a href="#Fig2">2</a>, and <a href="#Fig3">3</a> below)</td><td align="left" class="Rrule"> <p class="First"> <a name="Fig1"></a>Figure 1.<br/> <img alt="Figure 1" src="/dailymed/image.cfm?name=brixadi-01.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> <br/> <p> <a name="Fig2"></a>Figure 2.<br/> <img alt="Figure 2" src="/dailymed/image.cfm?name=brixadi-02.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> <br/> <p> <a name="Fig3"></a>Figure 3.<br/> <img alt="Figure 3" src="/dailymed/image.cfm?name=brixadi-03.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">MATERIALS NEEDED FOR INJECTION</span> <br/>Illustrated in Figure 4.<ul class="Disc"> <li>Alcohol wipe</li> <li>Cotton ball</li> <li>Sharps disposal container</li> </ul> </td><td align="left" class="Rrule">Figure 4.<br/> <p class="First"> <img alt="Figure 4" src="/dailymed/image.cfm?name=brixadi-04.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">SELECTING AN INJECTION SITE</span> <br/>The areas for subcutaneous injection are highlighted in Figure 5. <span class="Bold">BRIXADI should not be administered to the same site of injection for at least 8 weeks for BRIXADI (weekly). No injection site rotation is required for BRIXADI (monthly). <br/>BRIXADI should be injected slowly, into the subcutaneous tissue of the buttock, thigh, abdomen, or upper arm.</span> <br/>In patients who are not currently receiving buprenorphine treatment, for BRIXADI (weekly), the upper arm site should only be used after steady-state has been achieved (after 4 consecutive doses) <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>].</span></td><td align="left" class="Rrule">Figure 5.<br/> <p class="First"> <img alt="Figure 5" src="/dailymed/image.cfm?name=brixadi-05.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">PREPARE THE SAFETY SYRINGE</span> <br/> <span class="Italics">Step 1: </span> <br/>Wash hands thoroughly with soap and water prior to handling the safety syringe.<br/> <span class="Italics">Step 2: </span> <br/>Remove the safety syringe components from the carton. Assemble the safety syringe. While holding the syringe guard body, insert the plunger into the body of the syringe and rotate clockwise until it is attached to the stopper inside the syringe as illustrated in Figure 6.</td><td align="left" class="Rrule">Figure 6.<br/> <p class="First"> <img alt="Figure 6" src="/dailymed/image.cfm?name=brixadi-06.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 3: </span> <br/>Inspect the safety syringe closely:<br/>Do not use the safety syringe after the expiration date shown on the carton or on the safety syringe label.<ul class="Disc"> <li>The liquid should be clear and yellowish to yellow in color.</li> <li>A small air bubble may be visible.</li> </ul>Do not use the safety syringe if the liquid contains visible particles or is cloudy.</td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">PREPARATION OF SITE</span> <br/> <span class="Italics">Step 4: </span> <ul class="Disc"> <li>Put on gloves.</li> <li>Clean the injection site with an alcohol wipe using a circular motion.</li> </ul>Do not touch the cleaned area again before injecting.</td><td align="left" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">ADMINISTERING INJECTION</span> <br/> <span class="Italics">Step 5: </span> <ul class="Disc"> <li>Grasp the safety syringe by the syringe, as shown (see <a href="#Fig7">Figure 7</a>).</li> <li>Carefully pull the needle cap straight off.</li> <li>Immediately dispose of the needle cap (Never try to recap the needle).</li> </ul>It is normal to see a small drop of liquid at the tip of the needle.</td><td align="left" class="Rrule"> <p class="First"> <a name="Fig7"></a>Figure 7.<br/> <img alt="Figure 7" src="/dailymed/image.cfm?name=brixadi-07.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 6:</span> <br/>Pinch the skin at the injection site between your thumb and index finger as shown in Figure 8.</td><td align="left" class="Rrule"> <p class="First"> <a name="Fig8"></a>Figure 8.<br/> <img alt="Figure 8" src="/dailymed/image.cfm?name=brixadi-08.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 7:</span> <br/>Hold the syringe, as shown, and insert the needle at an angle of approximately 90° (see <a href="#Fig9">Figure 9</a>). The needle is designed to inject into the subcutaneous space. It is important to fully insert the needle.</td><td align="left" class="Rrule"> <p class="First"> <a name="Fig9"></a>Figure 9.<br/> <img alt="Figure 9" src="/dailymed/image.cfm?name=brixadi-09.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 8:</span> <ul class="Disc"> <li>After the needle is completely inserted into the subcutaneous tissue, release the skin that you are grasping. Slowly press down the plunger head until it latches in the safety device 'wings' (see <a href="#Fig10">Figure 10</a>). This will ensure that all of the medication has been injected.</li> <li> <span class="Bold">Keep the plunger pressed fully down while you hold the safety syringe in place for an additional 2 seconds.</span> </li> </ul> </td><td align="left" class="Rrule"> <p class="First"> <a name="Fig10"></a>Figure 10.<br/> <img alt="Figure 10" src="/dailymed/image.cfm?name=brixadi-10.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 9:</span> <ul class="Disc"> <li>Gently pull the needle out of the skin.</li> <li>Keep the plunger fully depressed while you carefully lift the needle straight out from the injection site (see <a href="#Fig11">Figure 11</a>).</li> </ul> </td><td align="left" class="Rrule"> <p class="First"> <a name="Fig11"></a>Figure 11.<br/> <img alt="Figure 11" src="/dailymed/image.cfm?name=brixadi-11.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Step 10:</span> <ul class="Disc"> <li>As soon as you have completely removed the needle from the skin, slowly take your thumb off the plunger.</li> <li>Allow the syringe guard to automatically cover the exposed needle (see <a href="#Fig12">Figure 12</a>).</li> <li>There may be a small amount of blood at the injection site. If needed, wipe with a cotton ball or gauze.</li> </ul> </td><td align="left" class="Rrule"> <p class="First"> <a name="Fig12"></a>Figure 12.<br/> <img alt="Figure 12" src="/dailymed/image.cfm?name=brixadi-12.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">DISPOSAL OF USED SAFETY SYRINGE</span> <br/> <span class="Italics">Step 11:</span> <br/>Put the used safety syringe immediately into a sharps container (see <a href="#Fig13">Figure 13</a>).<br/> <span class="Bold">POST INJECTION CARE</span> <ul class="Disc"> <li>Examine the injection site.</li> <li>If there is blood, press a cotton ball or gauze pad on the injection site.</li> <li>Do not rub the injection site.</li> <li>Apply an adhesive bandage if needed.</li> <li>Patient should be instructed to notify you immediately if excessive swelling, redness, heat or drainage develops at the injection site.</li> </ul> </td><td align="left" class="Rrule"> <p class="First"> <a name="Fig13"></a>Figure 13.<br/> <img alt="Figure 13" src="/dailymed/image.cfm?name=brixadi-13.jpg&amp;setid=5d8a8fd0-8619-422a-a664-d1d2e8970f48"/></p> </td> </tr> </tbody> </table></div>

BRIXADI is subject to a risk evaluation and mitigation strategy (REMS) program that includes, among other elements, a restricted distribution program. The purpose of the restricted distribution program is to ensure that BRIXADI is only administered by a healthcare provider [see Warnings and Precautions (5.2)].

BRIXADI forms a biodegradable liquid crystalline gel upon injection that is not always palpable and may not be conducive to surgical removal. Therefore, removal is not recommended.

BRIXADI is a sterile, yellowish to yellow-clear liquid solution and is provided as two different formulations, one for weekly and one for monthly administration in pre-filled, single-dose, syringes, with 23 gauge ½ inch needles, available in the following dosage strengths.

{ "type": "p", "children": [], "text": "BRIXADI is a sterile, yellowish to yellow-clear liquid solution and is provided as two different formulations, one for weekly and one for monthly administration in pre-filled, single-dose, syringes, with 23 gauge ½ inch needles, available in the following dosage strengths." }

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 3: BRIXADI (weekly) Strengths</span> </caption> <col align="center" valign="top" width="50%"/> <col align="center" valign="top" width="50%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" colspan="2">BRIXADI (weekly) 50 mg/mL buprenorphine</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Dosage Strength</th><th align="center" class="Rrule">Dosage Volume</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule">8 mg</td><td align="center" class="Lrule Rrule">0.16 mL</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule">16 mg</td><td align="center" class="Lrule Rrule">0.32 mL</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule">24 mg</td><td align="center" class="Lrule Rrule">0.48 mL</td> </tr> <tr class="Last"> <td align="center" class="Lrule">32 mg</td><td align="center" class="Lrule Rrule">0.64 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"60%\">\n<caption>\n<span>Table 3: BRIXADI (weekly) Strengths</span>\n</caption>\n<col align=\"center\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"top\" width=\"50%\"/>\n<thead>\n<tr class=\"Botrule First\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">BRIXADI (weekly) 50 mg/mL buprenorphine</th>\n</tr>\n<tr class=\"Last\">\n<th align=\"center\" class=\"Lrule Rrule\">Dosage Strength</th><th align=\"center\" class=\"Rrule\">Dosage Volume</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule\">8 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.16 mL</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule\">16 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.32 mL</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule\">24 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.48 mL</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Lrule\">32 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.64 mL</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 4: BRIXADI (monthly) Strengths</span> </caption> <col align="center" valign="top" width="50%"/> <col align="center" valign="top" width="50%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" colspan="2">BRIXADI (monthly) 356 mg/mL buprenorphine</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Dosage Strength</th><th align="center" class="Rrule">Dosage Volume</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule">64 mg</td><td align="center" class="Lrule Rrule">0.18 mL</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule">96 mg</td><td align="center" class="Lrule Rrule">0.27 mL</td> </tr> <tr class="Last"> <td align="center" class="Lrule">128 mg</td><td align="center" class="Lrule Rrule">0.36 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"60%\">\n<caption>\n<span>Table 4: BRIXADI (monthly) Strengths</span>\n</caption>\n<col align=\"center\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"top\" width=\"50%\"/>\n<thead>\n<tr class=\"Botrule First\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"2\">BRIXADI (monthly) 356 mg/mL buprenorphine</th>\n</tr>\n<tr class=\"Last\">\n<th align=\"center\" class=\"Lrule Rrule\">Dosage Strength</th><th align=\"center\" class=\"Rrule\">Dosage Volume</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule\">64 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.18 mL</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule\">96 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.27 mL</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Lrule\">128 mg</td><td align=\"center\" class=\"Lrule Rrule\">0.36 mL</td>\n</tr>\n</tbody>\n</table></div>" }

BRIXADI is contraindicated in patients with hypersensitivity (e.g., anaphylactic shock) to buprenorphine, or any other ingredients in the solution for injection [see Warnings and Precautions (5.10)].

{ "type": "p", "children": [], "text": "BRIXADI is contraindicated in patients with hypersensitivity (e.g., anaphylactic shock) to buprenorphine, or any other ingredients in the solution for injection [see Warnings and Precautions (5.10)].\n" }

Intravenous injection presents significant risk of serious harm or death as BRIXADI forms a liquid crystalline gel upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life-threatening pulmonary emboli, could result if administered intravenously [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.2)]. Do not administer intravenously, intramuscularly, or intradermally.

BRIXADI is available only through a restricted program called the BRIXADI REMS because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense BRIXADI directly to a healthcare provider for administration by a healthcare provider.

Notable requirements of the BRIXADI REMS include the following:

Further information is available at www.BRIXADIREMS.com or by calling 1-833-274-9234.

BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid use disorder and addictive behaviors [see Drug Abuse and Dependence (9.2)].

Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant drugs including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with BRIXADI [see Drug Interactions (7), Warnings and Precautions (5.5), Patient Counseling Information (17)].

Use BRIXADI with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

Due to its extended-release characteristics, if BRIXADI is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for approximately 1 month for BRIXADI (weekly) and for approximately 4 months for BRIXADI (monthly).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information (17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, monitor patient during treatment and consider dose reduction using best practices for opioid taper. [see Clinical Supervision (2.6)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with BRIXADI. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration (2.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu receptor [see Overdosage (10)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information (17)].

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including respiratory depression, overdose, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use with buprenorphine. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patients' buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions (5.4)].

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions (7)].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare providers should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations (8.1)].

Advise pregnant women receiving opioid addiction treatment with BRIXADI of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1)]. This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence (9.2, 9.3)].

Patients who elect to discontinue BRIXADI treatment should be monitored for withdrawal signs and symptoms with consideration given to the product's extended-release characteristics [See Clinical Pharmacology (12.3)].

Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing BRIXADI.

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine for the treatment of opioid use disorder, both in clinical trials and through postmarketing adverse event reports.

The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases.

Liver function tests are recommended prior to initiation of treatment to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Monitor patients with declining hepatic function for side effects resulting from increased exposure to buprenorphine.

Cases of hypersensitivity to buprenorphine containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine or other components is a contraindication to the use of BRIXADI [see Contraindications (4)].

Latex Allergies: The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals.

Because of the partial agonist properties of buprenorphine, BRIXADI injection may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided.

In patients who are new entrants to treatment, administer a test dose of transmucosal buprenorphine and monitor for precipitated withdrawal and treat appropriately [see Dosage and Administration (2.3)].

While on BRIXADI, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving BRIXADI with non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a healthcare provider, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with BRIXADI [see Patient Counseling Information (17)].

Please refer to Section 2.5 for further details on duration of exposure following discontinuation for both weekly and monthly BRIXADI formulations. [see Clinical Supervision (2.5)].

There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. BRIXADI is not appropriate for use in opioid naïve patients.

In a pharmacokinetic study with transmucosal buprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of BRIXADI, has not been studied.

Because of the long-acting nature of the product, adjustments to dosages of BRIXADI are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI.

Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine and patients may require a dose adjustment [see Use in Specific Populations (8.6)].

Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT- prolonging agents is not known.

Consider these observations in clinical decisions when prescribing BRIXADI to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia. [see Clinical Pharmacology (12.2)].

BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially for the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the BRIXADI (weekly) or BRIXADI (monthly) injections, which achieves steady-state at the fourth weekly or monthly injection. Caution patients about driving or operating hazardous machinery until they are reasonably certain that BRIXADI does not adversely affect their ability to engage in such activities. [see Clinical Pharmacology (12.3)].

Buprenorphine may produce orthostatic hypotension in ambulatory patients.

Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances where cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BRIXADI was evaluated in 440 opioid-dependent patients across two, Phase 3 clinical studies: one double-blind, active-control (n=213) and one open-label (n=227). In these studies, a total of 305 patients were exposed to BRIXADI for at least 24 weeks and 132 patients were exposed for at least 48 weeks.

In the first 12-week phase of the double-blind, double-dummy, active-controlled study, patients received BRIXADI (weekly) (16, 24, 32 mg) or matching placebo injections after a one-week titration. In the second 12-week phase of the study, patients remaining in the study received BRIXADI (monthly) (64, 96, 128, or 160 mg) or matching placebo injections. The 160 mg monthly dose is not an approved dose. Those randomized to receiving placebo injections were the active control groups and received sublingual buprenorphine/naloxone tablets at corresponding doses to BRIXADI. Patients receiving active BRIXADI injections also received placebo sublingual tablets.

Adverse reactions led to premature discontinuation in 10 (4.7%) patients in the group receiving BRIXADI compared to 5 (2.3%) patients in the sublingual buprenorphine/naloxone group, during the double-blind study.

Adverse reactions commonly reported after BRIXADI administration (≥5%, regardless of dose and regimen) in the double-blind study, were injection site pain (9.9%), headache (7.5%), constipation (7.5%), nausea (7.0%), injection site erythema (6.6%), injection site pruritus (6.1%), Insomnia (5.6%), and urinary tract infection (5.2%).

Table 5 shows the adverse reactions for BRIXADI compared with the active-control group (SL BPN/NX) in the double-blind study.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Adverse Reactions in the Phase 3 Double-Blind Study: ≥ 2% of Patients Receiving BRIXADI (Excluding Injection Site Reactions).</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule">System Organ Class (SOC)</th><th align="center" class="Rrule">BRIXADI Total<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></th><th align="center" class="Rrule">SL BPN/NX<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule">  Preferred Term (PT)<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a></th><th align="center" class="Rrule">(N=213)<br/>n(%)</th><th align="center" class="Rrule">(N=215)<br/>n(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd> = This group includes all subjects exposed to varying doses of both the BRIXADI (weekly) and BRIXADI (monthly) formulations. </dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd> = SL BPN/NX denotes the active comparator: patients assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a 'booster' injection of BRIXADI (weekly), 8mg, per protocol.<br/> All patients in Study 421 received a single test dose of 4mg SL BPN/NX before randomization into either arm.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd> = report of adverse reactions that occurred in ≥ 2% of the patients randomized to BRIXADI in Study HS-11-421. Patients are represented once per PT</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Cardiac disorders</span></td><td align="center" class="Rrule"><span class="Bold">6 (2.8%)</span></td><td align="center" class="Rrule"><span class="Bold">9 (4.2%)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Tachycardia</td><td align="center" class="Rrule">5 (2.3)</td><td align="center" class="Rrule">5 (2.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Rrule"><span class="Bold">43 (20.2%)</span></td><td align="center" class="Rrule"><span class="Bold">45 (20.9%)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Constipation</td><td align="center" class="Rrule">16 (7.5)</td><td align="center" class="Rrule">16 (7.4)</td> </tr> <tr> <td align="left" class="Lrule Rrule">  Diarrhea</td><td align="center" class="Rrule">6 (2.8)</td><td align="center" class="Rrule">7 (3.3)</td> </tr> <tr> <td align="left" class="Lrule Rrule">  Nausea</td><td align="center" class="Rrule">15 (7.0)</td><td align="center" class="Rrule">17 (7.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Vomiting</td><td align="center" class="Rrule">9 (4.2)</td><td align="center" class="Rrule">8 (3.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Infections and infestations</span></td><td align="center" class="Rrule"><span class="Bold">42 (19.7%)</span></td><td align="center" class="Rrule"><span class="Bold">50 (23.3%)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Urinary tract infection</td><td align="center" class="Rrule">11 (5.2)</td><td align="center" class="Rrule">10 (4.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Upper respiratory tract infection</td><td align="center" class="Rrule">9 (4.2)</td><td align="center" class="Rrule">9 (4.2)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td><td align="center" class="Rrule"><span class="Bold">20 (9.4%)</span></td><td align="center" class="Rrule"><span class="Bold">22 (10.2%)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Arthralgia</td><td align="center" class="Rrule">7 (3.3)</td><td align="center" class="Rrule">3 (1.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Rrule"><span class="Bold">27 (12.7%)</span></td><td align="center" class="Rrule"><span class="Bold">27 (12.6%)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">16 (7.5)</td><td align="center" class="Rrule">17 (7.9)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Psychiatric disorders</span></td><td align="center" class="Rrule"><span class="Bold">20 (9.4%)</span></td><td align="center" class="Rrule"><span class="Bold">20 (9.3%)</span></td> </tr> <tr> <td align="left" class="Lrule Rrule">  Anxiety</td><td align="center" class="Rrule">6 (2.8)</td><td align="center" class="Rrule">7 (3.3)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Insomnia</td><td align="center" class="Rrule">12 (5.6)</td><td align="center" class="Rrule">6 (2.8)</td> </tr> </tbody> </table></div>

Injection site reactions in the double-blind study are presented in Table 6 below. The majority of injection site-related adverse events were mild or moderate in severity. No injection site reactions were reported as severe intensity.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6: Injection site reactions in the Double-Blind Phase 3 Study: ≥ 2% of Patients Receiving BRIXADI</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Preferred Term (PT)<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></th><th align="center" class="Rrule">BRIXADI Total<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a> <br/> (N=213)<br/>n(%)</th><th align="center" class="Rrule">SL BPN/NX<a class="Sup" href="#footnote-6" name="footnote-reference-6">‡</a> <br/> (N=215)<br/>n(%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd> = Injection site reactions (ISR) that occurred in ≥2% of patients receiving BRIXADI, in the controlled trial, HS-11-421. Patients are represented once per PT.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd> = This group includes patients exposed to varying doses of both the BRIXADI weekly and monthly formulations. </dd> <dt> <a href="#footnote-reference-6" name="footnote-6">‡</a> </dt> <dd> = SL BPN/NX denotes the active comparator: subjects assigned to daily buprenorphine with sham (placebo) injections. Patients randomized to this group could also receive a supplemental 'booster' injection of BRIXADI (weekly), 8mg, per protocol.</dd> <dt> <a href="#footnote-reference-7" name="footnote-7">§</a> </dt> <dd> = The ISRs that occurred in ≥2% of the patients randomized to BRIXADI were reported under the HGLT of Administration site reactions. However, ISRs were also identified under the Bacterial infectious disorders HGLT (of which, there were three injection site related cellulitis reactions in the BRIXADI group and one in the SL BPN/NX group, respectively) but those numbers did not rise to level of reporting. Tabulation included all events coded as treatment emergent <span class="Italics">and </span>injection site reactions, regardless of treatment emergent flags.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Administration site reactions<a class="Sup" href="#footnote-7" name="footnote-reference-7">§</a></span></td><td align="center" class="Rrule"><span class="Bold">44 (20.7%)</span></td><td align="center" class="Rrule"><span class="Bold">49 (22.8%)</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Injection site pain</td><td align="center" class="Rrule">21 (9.9%)</td><td align="center" class="Rrule">17 (7.9%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Injection site erythema</td><td align="center" class="Rrule">14 (6.6%)</td><td align="center" class="Rrule">12 (5.6%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Injection site pruritus</td><td align="center" class="Rrule">13 (6.1%)</td><td align="center" class="Rrule">13 (6.0%)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Injection site swelling</td><td align="center" class="Rrule">10 (4.7%)</td><td align="center" class="Rrule">7 (3.3%)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Injection site reaction</td><td align="center" class="Rrule">9 (4.2%)</td><td align="center" class="Rrule">7 (3.3%)</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported postmarketing adverse event observed with buprenorphine sublingual tablets, excluding drug exposure during pregnancy, was drug misuse or abuse.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with buprenorphine [see Contraindications (4)].

Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

The following adverse reactions have been identified during post-approval use of an identical buprenorphine extended-release injection for subcutaneous use outside of the United States and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Injection site mass, abscess, ulceration, and necrosis: Cases of injection site abscess, ulceration and necrosis have been reported after treatment initiation. Some cases have required debridement and antibiotic treatment. The likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration.

Insufficient dosing: Cases of drug withdrawal reactions consistent with insufficient drug dosing have been reported, often occurring at or after two weeks of treatment initiation and resolving upon dose increase.

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opiods. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

<div class="scrollingtable"><table width="100%"> <col align="right" valign="middle" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Benzodiazepines and other Central Nervous System (CNS) Depressants</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible.<br/>Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatment <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>]</span>.<br/> If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>].</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Inhibitors of CYP3A4</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">The effects on buprenorphine exposure in patients treated with BRIXADI have not been studied, and the effects may be dependent on the route of administration.<br/>Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>].</span> <br/>The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BRIXADI is achieved.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule"><span class="Underline">Patient<span class="Bold">s</span> Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inhibitors:</span> Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.<br/> <span class="Underline">Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inhibitor</span>: Monitor for signs and symptoms of over-medication. If signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, reduce the dose of BRIXADI. If available doses do not permit achievement of the desired dose, it may be necessary to discontinue treatment with BRIXADI and treat the patient with a formulation of buprenorphine that permits more precise dose adjustments.<br/> <span class="Underline">Patients Stabilized on BRIXADI in the Setting of Concomitant Medication That is a CYP3A4 Inhibitor, and the Concomitant Medication is Discontinued</span>: Monitor for withdrawal and consider a dosage adjustment of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level in the absence of the concomitant medication, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), and protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">The effects of co-administered CYP3A4 inducers on buprenorphine exposure in patients treated with BRIXADI have not been studied.<br/>Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.<br/>CYP3A4 inducers may induce metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule"><span class="Underline">Patients Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inducers:</span> Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.<br/> <span class="Underline">Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inducer</span>: Monitor for withdrawal. If the dose of BRIXADI is not adequate in the presence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, adjust the dose of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.<br/> <span class="Underline">Patients Stabilized on BRIXADI in the setting of Concomitant Medication that is a CYP3A4 Inducer, and the Concomitant Medication is Discontinued</span>: Monitor for signs and symptoms of over-medication. If the dose provided by BRIXADI is excessive in the absence of the concomitant inducer, consider reducing the dose of BRIXADI.<br/>If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Rifampin, carbamazepine, phenytoin, phenobarbital</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A4 inducers, whereas delaviridine is a CYP3A4 inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delviradine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamics effects.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">It is recommended that patients who are on BRIXADI treatment have their dose monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Efavirenz, nevirapine, etravirine, delavirdine</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Antiretrovirals: Protease Inhibitors (PIs)</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (e.g., nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics and no significant pharmacodynamics effects. Other PIs with CYP3A4 inhibitory activity (e.g., atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with BRIXADI, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to discontinue treatment with BRIXADI and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Atazanavir, ritonavir</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical impact:</td><td align="left" class="Rrule">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">None</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. Discontinue BRIXADI if serotonin syndrome is suspected.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, S-HT3 receptor antagonists, drugs that affect serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Monomaine Oxidase Inhibitors (MAOIs)</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">The use of BRIXADI is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Examples:</td><td align="left" class="Rrule">Phenelzine, tranylcypromine, linezolid</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">Monitor patients receiving muscle relaxants and BRIXADI for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see <a href="#S2.3">Dosage and Administration (2.3)</a>, <a href="#S5.4">Warnings and Precautions (5.4</a>, <a href="#S5.5">5.5)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Diuretics</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic needed.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule">Clinical Impact:</td><td align="left" class="Rrule">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr class="Last"> <td align="right" class="Lrule Rrule">Intervention:</td><td align="left" class="Rrule">Monitor patients for signs of urinary retention or reduced gastric motility when BRIXADI is used concomitantly with anticholinergic drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"right\" valign=\"middle\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"70%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines and other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible.<br/>Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatment <span class=\"Italics\">[see <a href=\"#S5.5\">Warnings and Precautions (5.5)</a>]</span>.<br/>\t\t\t\t\t\t\t\t\tIf concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder <span class=\"Italics\">[see <a href=\"#S5.4\">Warnings and Precautions (5.4)</a>].</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">The effects on buprenorphine exposure in patients treated with BRIXADI have not been studied, and the effects may be dependent on the route of administration.<br/>Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (12.3)</a>].</span>\n<br/>The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BRIXADI is achieved.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\"><span class=\"Underline\">Patient<span class=\"Bold\">s</span> Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inhibitors:</span> Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.<br/>\n<span class=\"Underline\">Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inhibitor</span>: Monitor for signs and symptoms of over-medication. If signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, reduce the dose of BRIXADI. If available doses do not permit achievement of the desired dose, it may be necessary to discontinue treatment with BRIXADI and treat the patient with a formulation of buprenorphine that permits more precise dose adjustments.<br/>\n<span class=\"Underline\">Patients Stabilized on BRIXADI in the Setting of Concomitant Medication That is a CYP3A4 Inhibitor, and the Concomitant Medication is Discontinued</span>: Monitor for withdrawal and consider a dosage adjustment of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level in the absence of the concomitant medication, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">azole antifungals (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), and protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">The effects of co-administered CYP3A4 inducers on buprenorphine exposure in patients treated with BRIXADI have not been studied.<br/>Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (12.3)</a>]</span>.<br/>CYP3A4 inducers may induce metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\"><span class=\"Underline\">Patients Converted to BRIXADI Treatment from a Regimen of Transmucosal Buprenorphine used Concomitantly with CYP3A4 Inducers:</span> Monitor to ensure that the plasma buprenorphine level provided by BRIXADI is adequate.<br/>\n<span class=\"Underline\">Patients Already on BRIXADI who Require Newly-Initiated Treatment with a CYP3A4 Inducer</span>: Monitor for withdrawal. If the dose of BRIXADI is not adequate in the presence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, adjust the dose of BRIXADI. If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments.<br/>\n<span class=\"Underline\">Patients Stabilized on BRIXADI in the setting of Concomitant Medication that is a CYP3A4 Inducer, and the Concomitant Medication is Discontinued</span>: Monitor for signs and symptoms of over-medication. If the dose provided by BRIXADI is excessive in the absence of the concomitant inducer, consider reducing the dose of BRIXADI.<br/>If the dose of BRIXADI cannot be adjusted to an adequate level, transition the patient back to a formulation of buprenorphine that permits more precise dose adjustments <span class=\"Italics\">[see <a href=\"#S12.3\">Clinical Pharmacology (12.3)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Rifampin, carbamazepine, phenytoin, phenobarbital</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A4 inducers, whereas delaviridine is a CYP3A4 inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delviradine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamics effects.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">It is recommended that patients who are on BRIXADI treatment have their dose monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Efavirenz, nevirapine, etravirine, delavirdine</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Antiretrovirals: Protease Inhibitors (PIs)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (e.g., nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetics and no significant pharmacodynamics effects. Other PIs with CYP3A4 inhibitory activity (e.g., atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with BRIXADI, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to discontinue treatment with BRIXADI and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Atazanavir, ritonavir</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical impact:</td><td align=\"left\" class=\"Rrule\">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">None</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation, and during dose adjustment of the serotonergic drug. Discontinue BRIXADI if serotonin syndrome is suspected.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, S-HT3 receptor antagonists, drugs that affect serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e. cyclobenzaprine, metaxalone), and monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Monomaine Oxidase Inhibitors (MAOIs)</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">The use of BRIXADI is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Examples:</td><td align=\"left\" class=\"Rrule\">Phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">Monitor patients receiving muscle relaxants and BRIXADI for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose <span class=\"Italics\">[see <a href=\"#S2.3\">Dosage and Administration (2.3)</a>, <a href=\"#S5.4\">Warnings and Precautions (5.4</a>, <a href=\"#S5.5\">5.5)</a>]</span>.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic needed.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\">Clinical Impact:</td><td align=\"left\" class=\"Rrule\">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Lrule Rrule\">Intervention:</td><td align=\"left\" class=\"Rrule\">Monitor patients for signs of urinary retention or reduced gastric motility when BRIXADI is used concomitantly with anticholinergic drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

The data on use of buprenorphine, the active ingredient in BRIXADI in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on sublingual buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data].

Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses 21 times and equal to, respectively, the mean daily dose of 4.6 mg buprenorphine delivered by either 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly). Pre- and post-natal development studies in rats demonstrated increased neonatal deaths at doses approximately equal to and above and dystocia at 11 times the mean daily dose of 4.6 mg buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses 4 times and greater than the mean daily dose of 4.6 mg of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses 2 and 21 times the mean daily dose of 4.6 mg of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

BRIXADI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dose Adjustment during Pregnancy and the Postpartum Period

Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely, and the dose adjusted as necessary.

Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with BRIXADI.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.6)].

Labor or Delivery

Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.

In a multicenter, double-blind, randomized, controlled trial (Maternal Opioid Treatment: Human Experimental Research [MOTHER]) designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs 10.4 mg), had shorter hospital stays (10.0 days vs 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs 9.9 days) compared to the methadone-exposed group. There were no differences between groups in other primary outcomes (neonatal head circumference) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.

Animal Data

The exposure margins below are based on the mean daily dose of 4.6 mg buprenorphine delivered by 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly) on body surface area comparisons, unless otherwise noted.

No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (64 times and 127 times, respectively, on a mg/m2 basis). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (21 times on a mg/m2 basis). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day (169 times on a mg/m2 basis). Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day (64 times and 127 times, respectively, on a mg/m2 basis).

Buprenorphine was not teratogenic in rats and rabbits after subcutaneous (SC) doses of up to 5 mg/kg/day (9 and 5 times in rat, and 12 and 7 times in rabbit the highest daily exposure from 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly), respectively, on an AUC basis), after intramuscular (IM) doses of up to 5 mg/kg/day (11 and 21 times on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (2 and 3 times on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (338 times on a mg/m2 basis) and 25 mg/kg/day in rabbits (106 times on a mg/m2 basis). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (2.4 or 1.5 times the highest daily exposure from 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly), respectively, on an AUC basis, but were not observed at oral doses up to 160 mg/kg/day (338 times on a mg/m2 basis).

Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (21 times on a mg/m2 basis) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (4 times on a mg/m2 basis) were not statistically significant. In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater (4 times on a mg/m2 basis) and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (approximately equal on a mg/m2 basis). No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (11 times on a mg/m2 basis). Fertility and pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (2 times on a mg/m2 basis), after IM doses of 0.5 mg/kg/day and up (approximately equal on a mg/m2 basis), and after SC doses of 0.1 mg/kg/day and up (0.4 or 0.3 times the highest daily exposure from 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly), respectively, on an AUC basis). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (169 times on a mg/m2 basis).

Risk Summary

Based on two studies in 13 lactating women maintained on sublingual buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk. Available data have not shown adverse reactions in breastfed infants. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for buprenorphine treatment and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties.

Data

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12% respectively, of the maternal weight-adjusted dose (relative dose/kg [%] of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median (sublingual buprenorphine) dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (Cavg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

Infertility

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)].

The safety and effectiveness of BRIXADI have not been established in pediatric patients.

Clinical studies of BRIXADI did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently to the drug than younger patients. Other reported clinical experience with buprenorphine has not identified differences in responses between the geriatric and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe BRIXADI should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

The effect of hepatic impairment on the pharmacokinetics of BRIXADI has not been studied.

The effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. While no clinically significant changes were observed in subjects with mild hepatic impairment, the plasma levels have been shown to be higher and half-life values have been shown to be longer for buprenorphine in subjects with moderate and severe hepatic impairment.

Because of the long-acting nature of the product, adjustments to dosages of BRIXADI are not rapidly reflected in plasma buprenorphine levels. Therefore, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with BRIXADI.

Patients who develop moderate to severe hepatic impairment while being treated with BRIXADI should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Warnings and Precautions (5.14), Clinical Pharmacology (12.3)].

Clinical studies of BRIXADI did not include subjects with renal impairment. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

BRIXADI contains buprenorphine, a Schedule III substance under the Controlled Substances Act.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

BRIXADI contains buprenorphine, a Schedule III controlled substance that can be abused similar to other opioids. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines [see Warnings and Precautions (5.5)].

BRIXADI is distributed through a restricted distribution program, which is intended to prevent the direct distribution to a patient. BRIXADI should only be dispensed directly to a healthcare provider for administration by a healthcare provider. It is supplied in prefilled syringes and is intended for administration only by subcutaneous injection by a healthcare provider. The entire contents of the prefilled syringe should be administered. After administration, a small amount of BRIXADI may remain in the needle and syringe should be properly disposed of [see How Supplied/Storage and Handling (16)].

Upon injection, BRIXADI spontaneously transforms from a low viscous solution to a liquid crystalline gel that encapsulates buprenorphine and releases it at a steady rate as the depot biodegrades [see Warnings and Precautions (5.1)].

Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No attempts to remove BRIXADI have been reported in clinical trials.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Monitor patients during discontinuation of BRIXADI for symptoms of withdrawal [see Warnings and Precautions (5.8)].

Due to the long-acting nature of BRIXADI, withdrawal signs and symptoms may not be evident immediately following the discontinuation of treatment.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions (5.6)].

Clinical Presentation

The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death.

Treatment of Overdose

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re‐establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be considered as indicated. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

Clinicians should consider the potential role and contribution of buprenorphine, other opioids, and other CNS depressant drugs in a patient's clinical presentation.

BRIXADI (buprenorphine) extended-release injection is a sterile, yellowish to yellow clear liquid provided in a single-dose, pre-filled syringe intended for subcutaneous injection only. BRIXADI is designed to deliver buprenorphine at a controlled rate over either one week or one month.

{ "type": "p", "children": [], "text": "BRIXADI (buprenorphine) extended-release injection is a sterile, yellowish to yellow clear liquid provided in a single-dose, pre-filled syringe intended for subcutaneous injection only. BRIXADI is designed to deliver buprenorphine at a controlled rate over either one week or one month." }

The active ingredient in BRIXADI is buprenorphine free base, a partial opioid agonist.

{ "type": "p", "children": [], "text": "The active ingredient in BRIXADI is buprenorphine free base, a partial opioid agonist." }

BRIXADI is provided in multiple doses with two durations (weekly and monthly).

{ "type": "p", "children": [], "text": "BRIXADI is provided in multiple doses with two durations (weekly and monthly)." }

{ "type": "ul", "children": [ "BRIXADI (weekly; 8, 16, 24, 32 mg) consists of 50 mg/mL buprenorphine. The inactive ingredients include dehydrated alcohol (12% v/v), glycerol dioleate (43% v/v), and soybean phosphatidylcholine (41% w/v).", "BRIXADI (monthly; 64, 96, 128 mg) consists of 356 mg/mL buprenorphine. The inactive ingredients include glycerol dioleate (24% v/v), methylpyrrolidone (31% v/v), and soybean phosphatidylcholine (15% w/v)." ], "text": "" }

Upon injection, BRIXADI spontaneously transforms from a low viscous solution to a liquid crystalline gel that encapsulates buprenorphine and releases it at a steady rate as the depot biodegrades.

{ "type": "p", "children": [], "text": "Upon injection, BRIXADI spontaneously transforms from a low viscous solution to a liquid crystalline gel that encapsulates buprenorphine and releases it at a steady rate as the depot biodegrades." }

Different drug product strengths, or doses, are accomplished by different syringe fill volumes [see Dosage Forms and Strengths (3)].

{ "type": "p", "children": [], "text": "Different drug product strengths, or doses, are accomplished by different syringe fill volumes [see Dosage Forms and Strengths (3)].\n" }

The molecular weight of buprenorphine free base is 467.65 g/mol, and its molecular formula is C29H41NO4. Chemically, buprenorphine is: (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol.

{ "type": "p", "children": [], "text": "The molecular weight of buprenorphine free base is 467.65 g/mol, and its molecular formula is C29H41NO4. Chemically, buprenorphine is: (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol. " }

The structural formula is:

{ "type": "p", "children": [], "text": "The structural formula is:" }

BRIXADI contains buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Opioid Blockade

The opioid blockade study assessed the blockade of subjective opioid drug-liking effects and pharmacokinetics (PK) of BRIXADI (weekly) in 47 patients with moderate or severe opioid dependence. The primary endpoint was the maximum rating (Emax) on the visual analogue scale (VAS) for drug-liking. After stabilization on immediate-release morphine, all patients completed a 3-day qualification/baseline hydromorphone challenge session consisting of 3 intramuscular doses of hydromorphone (0 mg, [placebo], 6 mg, and 18 mg) once daily for 3 consecutive days in a randomized, double-blind, crossover manner. Following the qualification phase, eligible patients received 2 injections of BRIXADI (weekly) for two weeks at either the 24 mg or 32 mg level. Two hydromorphone challenge sessions (3 consecutive days each) were conducted throughout the week after each weekly injection of BRIXADI (weekly).

On average, the subjective effects (e.g., drug liking [Emax]) of 6 mg or 18 mg hydromorphone was blocked following injections of BRIXADI (weekly) at the 24 mg or 32 mg levels. The variability in drug-liking scores was wider for the 18 mg than the 6 mg hydromorphone dose level. In addition, for the 18 mg hydromorphone dose challenge, the drug-liking score variability was wider towards the end of the BRIXADI (weekly) dosing interval compared to earlier in the interval (e.g. Days 4-6 versus Days 1-3; Day 11-13 versus Day 8-10). Drug-liking score variability was wider for the 24 mg BRIXADI (weekly) dose level compared to 32 mg [see Clinical Studies (14.1)].

Figure 14 illustrates the relationship between buprenorphine plasma level and drug liking after 18 mg hydromorphone where data from the 24 mg BRIXADI (weekly) arm is pooled with data from the 32 mg BRIXADI (weekly) arm. The observed plateau for maximal response of drug-liking was reached at buprenorphine concentrations of approximately 1.5-2 ng/mL plasma levels.

Figure 14: Placebo-Corrected Drug Liking VAS vs. Plasma Buprenorphine Concentration Following 18 mg Hydromorphone Challenges for Pooled 24 mg and 32 mg Arms

Androgen Deficiency

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Cardiac Electrophysiology

Thorough QT studies with buprenorphine products have demonstrated modest QT prolongation ≤15 msec. Two categorical analyses of cardiovascular-specific adverse events among patients exposed to buprenorphine demonstrated no proarrhythmic potential. One Holter monitoring study demonstrated no arrhythmia. An analysis of medical literature provided no evidence for causal association between buprenorphine and Torsades de Pointes.

Physiological Effects

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses have been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid use disorder. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.

In clinical studies conducted with BRIXADI at doses ranging from 7.5 to 32 mg for weekly BRIXADI and 64 to 192 mg for monthly BRIXADI, no incidences of temperature elevations, or clinically significant lowering of oxygen saturation were observed.

Absorption

BRIXADI is an extended-release formulation of buprenorphine designed for subcutaneous administration. BRIXADI is available in two regimens: weekly and monthly. Following single doses of BRIXADI (weekly) or BRIXADI (monthly), the buprenorphine Cmax and AUCinf increase dose-proportionally.

The steady-state PK of buprenorphine following BRIXADI (weekly), BRIXADI (monthly) and their comparison to sublingual SUBUTEX across three studies are shown in Table 7. In these studies, BRIXADI (weekly) was administered for 4 or 4 to 7 weekly doses, BRIXADI (monthly) was administered for 4 monthly doses, and SUBUTEX was administered for 7 daily doses.

After BRIXADI subcutaneous injection, the buprenorphine plasma concentration increases with a median time to maximum plasma concentration (tmax) of about 24 hours for BRIXADI (weekly) and 6-10 hours for BRIXADI (monthly). Based on trough levels after each dose, steady-state exposure is reached at administration of the fourth weekly or monthly dose.

After four repeated doses of BRIXADI (weekly) (16 mg) AUCτ (0-7d), Cmax and Ctrough values are ~40% higher exposure compared to the first dose. Based on cross-study comparisons, four repeated doses of BRIXADI (monthly) (128 mg) results in 68%, 65%, and 124% higher AUCτ (0-28d), Cmax and Ctrough values, respectively compared to the first dose.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7: Summary of steady-state PK parameters of buprenorphine after subcutaneous buttock injections of BRIXADI (weekly) and BRIXADI (monthly) and sublingual (SL) administration of SUBUTEX</span> </caption> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="9%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="9%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="9%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="8%"/> <col align="left" valign="top" width="9%"/> <col align="left" valign="top" width="8%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" colspan="3">Drug product dose</th><th align="left" class="Rrule" colspan="3">C<span class="Sub">av</span> (ng/mL)</th><th align="left" class="Rrule" colspan="3">C<span class="Sub">max</span> (ng/mL)</th><th align="left" class="Rrule" colspan="3">C<span class="Sub">trough</span><a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> (ng/mL)</th> </tr> <tr class="Botrule Last"> <th align="left" class="Lrule Rrule">SL BPN</th><th align="left" class="Rrule">Brixadi (weekly)</th><th align="left" class="Rrule">Brixadi (monthly)</th><th align="left" class="Rrule">SL BPN <a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a></th><th align="left" class="Rrule">Brixadi (weekly)</th><th align="left" class="Rrule">Brixadi (monthly)</th><th align="left" class="Rrule">SL BPN <a class="Sup" href="#footnote-9">†</a></th><th align="left" class="Rrule">Brixadi (weekly)</th><th align="left" class="Rrule">Brixadi (monthly)</th><th align="left" class="Rrule">SL BPN <a class="Sup" href="#footnote-9">†</a></th><th align="left" class="Rrule">Brixadi (weekly)</th><th align="left" class="Rrule">Brixadi (monthly)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="12"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>C<span class="Sub">168h</span> after 4<span class="Sup">th</span> dose for BRIXADI (weekly), C<span class="Sub">28d</span> after 4<span class="Sup">th</span> dose for BRIXADI (monthly) and C<span class="Sub">24h</span> after 7<span class="Sup">th</span> daily dose for Subutex</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Average value of two studies</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Simulated</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">8 mg</td><td align="left" class="Rrule">16 mg</td><td align="left" class="Rrule">64 mg</td><td align="left" class="Rrule">1.2</td><td align="left" class="Rrule">2.1</td><td align="left" class="Rrule">2.0 <a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a></td><td align="left" class="Rrule">4.7</td><td align="left" class="Rrule">4.3</td><td align="left" class="Rrule">4.0 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">0.7</td><td align="left" class="Rrule">0.8</td><td align="left" class="Rrule">1.3 <a class="Sup" href="#footnote-10">‡</a></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">16 mg</td><td align="left" class="Rrule">24 mg</td><td align="left" class="Rrule">96 mg</td><td align="left" class="Rrule">1.8</td><td align="left" class="Rrule">2.9 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">2.9 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">6.5</td><td align="left" class="Rrule">5.5 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">6.0 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">1.0</td><td align="left" class="Rrule">1.4 <a class="Sup" href="#footnote-10">‡</a></td><td align="left" class="Rrule">2.0 <a class="Sup" href="#footnote-10">‡</a></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">24 mg</td><td align="left" class="Rrule">32 mg</td><td align="left" class="Rrule">128 mg</td><td align="left" class="Rrule">2.5</td><td align="left" class="Rrule">4.2</td><td align="left" class="Rrule">3.9</td><td align="left" class="Rrule">8.2</td><td align="left" class="Rrule">6.9</td><td align="left" class="Rrule">11.1</td><td align="left" class="Rrule">1.4</td><td align="left" class="Rrule">2.6</td><td align="left" class="Rrule">2.1</td> </tr> </tbody> </table></div>

Effect of injection Site on PK of BRIXADI

After multiple dose subcutaneous injections of 32 mg BRIXADI weekly product at different injection sites (abdomen, thigh, buttock or upper arm), a comparable PK exposure was observed. However, injection in the arm site was associated with approximately 10% lower plasma levels than other sites.

Distribution:

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Elimination:

Buprenorphine is metabolized and eliminated in urine and feces. The apparent terminal plasma half-life of buprenorphine following subcutaneous injection of BRIXADI ranged between 3 to 5 days for BRIXADI (weekly) and 19 to 26 days for BRIXADI (monthly) as a result of the slow release of buprenorphine from the subcutaneous depot.

Metabolism:

Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioid-like activity.

Norbuprenorphine steady-state plasma concentrations in humans after subcutaneous injection of BRIXADI (weekly or monthly) are low compared to buprenorphine (AUC norbuprenorphine/ buprenorphine ratio of 0.35).

Excretion:

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of the buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated).

Drug Interaction Studies:

CYP3A4 Inhibitors and Inducers

The effects of co-administered CYP3A4 inhibitors and inducers on buprenorphine exposure in subjects treated with BRIXADI have not been studied; however, such interactions have been established in studies using transmucosal buprenorphine. The effects of buprenorphine may be dependent on the route of administration.

Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when BRIXADI is given concurrently with agents that affect CYP3A4 activity. The effects of co-administered CYP3A4 inducers or inhibitors have been established in studies using transmucosal buprenorphine. Patients who switch to BRIXADI treatment from a regimen for transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors (e.g., ketoconazole, macrolide antibiotics (e.g., erythromycin) or HIV protease inhibitors, or CYP3A4 inducer (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) should be monitored to ensure that the plasma buprenorphine level provided by BRIXADI is adequate and not excessive [see Drug Interactions (7)].

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic BRIXADI doses are not expected to significantly affect the metabolism (systemic exposure) of other concomitantly administered medications [see Drug Interactions (7)].

Specific Populations

Based on population pharmacokinetic analyses, age, sex and race do not have a clinically meaningful effect on PK of BRIXADI.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of BRIXADI has not been studied.

In a pharmacokinetic study, the disposition of buprenorphine was determined after administering a 2.0/0.5 mg Suboxone (buprenorphine/naloxone) sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function.

In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of buprenorphine were not clinically significant.

For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of buprenorphine were increased [see Warnings and Precautions (5.14) and Use in Specific Populations (8.6)].

Renal Impairment

The effect of renal impairment on the pharmacokinetics of BRIXADI has not been studied. Clinical studies of BRIXADI did not include subjects with severe renal impairment. Less than 1% is excreted as unchanged buprenorphine in urine following IV buprenorphine administration. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine [see Use in Specific Populations (8.7)].

Population PK analyses indicated no notable relationship between creatinine clearance and steady-state buprenorphine plasma concentrations.

HCV infection

In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean Cmax, AUC0-last, and half-life values of buprenorphine were not clinically significant in comparison to healthy subjects without HCV infection.

Carcinogenicity

Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats for 27 months at doses of 0.6, 5.5, and 56 mg/kg/day (0.3, 1.4 and 11.3 times the highest daily exposure from 32 mg BRIXADI (weekly) on an AUC basis and 0.2, 0.9 and 6.9 times the highest daily exposure from 128 mg BRIXADI (monthly) on an AUC basis). A statistically significant dose-related increase in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (7 and 4 times the highest daily exposure from 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly), respectively, on an AUC basis).

NMP, an excipient in BRIXADI (monthly) produced an increase in hepatocellular adenomas and carcinomas in male and female mice at 47 and 60 times, respectively, the maximum daily dose (MDD) of NMP via 128 mg BRIXADI (monthly) on a mg/m2 basis. The clinical significance of these findings is unclear. No tumors were noted in male or female mice at 7.4 and 9.5 times the MDD on a mg/m2 basis. In 2-year inhalation and dietary studies in rats, NMP did not result in evidence of carcinogenicity.

Mutagenicity

Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis "rec" assay; negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3 H]thymidine, and positive in unscheduled DNA synthesis test using testicular cells from mice.

Impairment of Fertility

Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg/day (169 times the mean daily dose of 4.6 mg buprenorphine as delivered by 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly) on a mg/m2 basis) or up to 5 mg/kg/day IM (11 times the mean daily dose of 4.6 mg buprenorphine as delivered by 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly) on a mg/m2 basis) or 5 mg/kg/day SC (16 or 10 times the highest daily exposure from 32 mg BRIXADI (weekly) or 128 mg BRIXADI (monthly), respectively, on an AUC basis).

The opioid blockade study assessed the blockade of subjective opioid effects, PK, and safety of BRIXADI weekly in 47 patients with moderate or severe opioid use disorder. Forty-six patients completed the study. Subjects were randomized to receive two injections of BRIXADI (weekly) once weekly for 2 weeks either at a 24 mg or 32 mg dose level.

After stabilization on immediate-release morphine, all patients completed a 3-day qualification/baseline hydromorphone (HM) challenge session, which included intramuscular administration of 3 doses of HM (0 mg [placebo], 6 mg and 18 mg) once daily for 3 consecutive days. Patients were not exposed to buprenorphine during the baseline/qualification phase.

Following the qualification phase, eligible patients were randomly assigned to receive 2 doses of either 24 mg (22 patients) or 32 mg (24 patients) BRIXADI (weekly) with each dose administered one week apart. Two HM challenge sessions (Days 1-3 and 4-6 for the first session and Days 8-10 and 11-13 for the second session, respectively) were conducted after each dose of BRIXADI (weekly).

The primary endpoint was the peak effect (Emax) on a 100-mm bipolar (i.e., 50=neutral response) "Drug Liking" Visual Analog Scale (VAS). The pre-defined upper bound of the 95% CI for complete blockade of drug liking was an 11 mm difference between VAS Emax scores obtained for HM doses compared with placebo.

During the qualification/baseline phase, mean Emax scores for placebo were neutral while intramuscular hydromorphone 6 and 18 mg produced dose-related increases in the scores. Beginning with the first injection of BRIXADI (weekly) 24 mg or 32 mg weekly, no active intramuscular hydromorphone dose resulted in a mean drug liking VAS Emax score of 11 mm or greater when compared to placebo, which demonstrated complete blockade that was sustained throughout the first and second dosing intervals (see Figure 15). Individual subject scores are shown in Figure 16.

Figure 15: Mean Difference in Placebo-Corrected Peak Drug Liking

Figure 16: Mean Difference in Placebo-Corrected Peak Drug Liking with Individual Scores

The efficacy and safety of BRIXADI for the treatment of opioid use disorder was evaluated in a Phase 3, 24-Week, randomized, double-blind, double-dummy, active controlled, multicenter study in patients who met the DSM-5 criteria for moderate or severe opioid use disorder and who were actively seeking but not currently receiving buprenorphine treatment. Patients were randomized to receive either BRIXADI injections with placebo sublingual tablets or sublingual buprenorphine/naloxone (SL BPN/NX) tablets with placebo injections. All patients received individual drug counseling for the duration of the study.

On the first day of treatment patients received an open-label 4 mg test dose of sublingual buprenorphine. Patients who tolerated the test dose (two patients did not tolerate the test dose) were randomized and given a 16 mg injection of BRIXADI (weekly) or matched placebo. During the next 6 days patients were allowed up to two further 8 mg injections as needed. Patients received an injection of 16, 24, or 32 mg on Day 8 matched to the dose they received in the previous seven days. Patients received injections weekly (every 7 days +/- 2-day window) for twelve weeks total and then transitioned to an equivalent dose of BRIXADI (monthly) (every 28 days, +/- 7-day window) for the remaining twelve weeks. Dose adjustments were permitted for the duration of the study. Supplemental 8 mg BRIXADI (weekly) injections were allowed during the second phase of the study and were also used in the active-controlled group. Overall, supplemental 8 mg injections were given to 14 patients (6.6%) in the BRIXADI arm and 17 patients (7.9%) in the SL BPN/NX arm. Table 8 shows the doses of BRIXADI (weekly) administered following the initial titration period and at the final visit before transition to BRIXADI (monthly) was allowed. Table 9 shows the first and final BRIXADI (monthly) dose administered to each patient.

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 8: Number of patients receiving each BRIXADI (weekly) dose at selected time points</span> </caption> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="34%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">BRIXADI (weekly) Dose</th><th align="center" class="Rrule">Following Titration Period</th><th align="center" class="Rrule">End of Weekly Phase</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">16 mg</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">24 mg</td><td align="center" class="Rrule">128</td><td align="center" class="Rrule">84</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">32 mg</td><td align="center" class="Rrule">54</td><td align="center" class="Rrule">64</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 9: Number of patients receiving each BRIXADI (monthly) dose at selected time points</span> </caption> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="34%"/> <col align="center" valign="middle" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">BRIXADI (monthly) Dose</th><th align="center" class="Rrule">First BRIXADI (monthly) dose</th><th align="center" class="Rrule">Final BRIXADI (monthly) dose</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>not an approved strength</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">64 mg</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">11</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">96 mg</td><td align="center" class="Rrule">84</td><td align="center" class="Rrule">83</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">128 mg</td><td align="center" class="Rrule">66</td><td align="center" class="Rrule">56</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">160 mg<a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a></td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">8</td> </tr> </tbody> </table></div>

For the first twelve weeks patients completed weekly visits. For the final twelve weeks patients were transitioned to monthly visits. Patients were also required to complete three additional randomly scheduled visits during the final twelve weeks. Efficacy was evaluated using urine drug screens combined with self-reported use of illicit opioid use. Missing urine drug screen samples and/or self-reports were counted as positive for illicit opioids.

A total of 428 patients were randomized equally (215 patients in the SL BPN/NX group and 213 in the BRIXADI group). Of the randomized patients, 69.0% (147/213) of the patients in BRIXADI treatment group and 72.6% (156/215) of the patients in the SL BPN/NX treatment group completed the 24-week period. Patient demographics and baseline characteristics are provided in Table 10.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 10: Patient Demographics and Baseline Characteristics</span> </caption> <col align="left" valign="middle" width="52%"/> <col align="center" valign="middle" width="24%"/> <col align="center" valign="middle" width="24%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">BRIXADI<br/>(N=213)</th><th align="center" class="Rrule">SL BPN/NX<br/>(N=215)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Mean Age (Years)</span></td><td align="center" class="Rrule">38.7</td><td align="center" class="Rrule">38.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Sex %</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Male</td><td align="center" class="Rrule">56.8</td><td align="center" class="Rrule">66.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Female</td><td align="center" class="Rrule">43.2</td><td align="center" class="Rrule">34.0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Race or Ethnicity %</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  White</td><td align="center" class="Rrule">74.6</td><td align="center" class="Rrule">76.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Black or African American</td><td align="center" class="Rrule">22.1</td><td align="center" class="Rrule">22.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  American Indian or Alaska Native</td><td align="center" class="Rrule">0.9</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Asian</td><td align="center" class="Rrule">0.5</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Native Hawaiian or Other Pacific Islander</td><td align="center" class="Rrule">0.5</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Other</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">0.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Primary Opioid of Use at Initiation %</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Heroin</td><td align="center" class="Rrule">71.4</td><td align="center" class="Rrule">70.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Prescription Pain Reliever</td><td align="center" class="Rrule">28.6</td><td align="center" class="Rrule">29.8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Injectable Route %</span></td><td align="center" class="Rrule">53.5</td><td align="center" class="Rrule">51.2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Substance Use by Urine Toxicology Prior to Randomization %</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Amphetamines</td><td align="center" class="Rrule">22.1</td><td align="center" class="Rrule">18.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Barbiturates</td><td align="center" class="Rrule">1.4</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Benzodiazepine</td><td align="center" class="Rrule">21.1</td><td align="center" class="Rrule">21.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Cocaine</td><td align="center" class="Rrule">30.5</td><td align="center" class="Rrule">32.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Cannabinoids</td><td align="center" class="Rrule">34.3</td><td align="center" class="Rrule">36.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Fentanyl</td><td align="center" class="Rrule">29.1</td><td align="center" class="Rrule">22.8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Phencyclidine</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">0.5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Medical History %</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Anxiety</td><td align="center" class="Rrule">14.1</td><td align="center" class="Rrule">18.6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Back Pain</td><td align="center" class="Rrule">15.5</td><td align="center" class="Rrule">18.6</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Depression</td><td align="center" class="Rrule">11.7</td><td align="center" class="Rrule">13.0</td> </tr> </tbody> </table></div>

Table 11 below illustrates the proportion of patients who were considered to be responders. A patient was a responder if they met all of the following criteria:

This responder definition was designed to identify patients who were successfully treated with both BRIXADI (weekly) (administered in the first 12 weeks of treatment) and BRIXADI (monthly) (administered in the second 12 weeks of treatment). Therefore, patients were required to have negative opioid assessments at the end of each treatment phase. Each phase also included an allowable grace period (an initial period of time when positive opioid assessments were not taken into account) and the definition also allowed for sporadic positive assessments. Based on the results of this trial, the efficacy of BRIXADI was demonstrated. Table 11 shows the response rate for each treatment arm along with the associated 95% confidence interval for their difference.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 11: Number (Percentage) of Patients who met the Responder Definition</span> </caption> <col align="center" valign="bottom" width="33%"/> <col align="center" valign="bottom" width="34%"/> <col align="center" valign="bottom" width="33%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">BRIXADI Injection with placebo sublingual tablets<br/>(N=213)</th><th align="center" class="Rrule">SL BPN/NX Tablets with Placebo Injections<br/>(N=215)</th><th align="center" class="Rrule">Treatment Difference<br/>(95% CI)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>The lower bound of the confidence interval was within the agreed upon noninferiority threshold of −10%.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First Last"> <td align="center" class="Lrule Rrule">36 (16.9%)</td><td align="center" class="Rrule">30 (14.0%)</td><td align="center" class="Rrule">2.9% (-3.9%, 9.8%)<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a></td> </tr> </tbody> </table></div>

The cumulative distribution function (CDF) of the percentage of negative opioid assessments (urine samples negative for illicit opioid use combined with self-reports negative for illicit opioid use) from Week 4 through Week 24 are shown in Figure 17 and Table 12. The figure and table are cumulative, so that a patient whose percentage of opioid-free assessments is, for example 50%, is also included at every level of negative opioid assessments below 50%. Missing values and values after premature discontinuation were considered positive. Based on the CDF of the percentage of negative opioid assessments, superiority was demonstrated with BRIXADI with statistical significance compared with SL BPN/NX. However, on the right-hand side of the curves where patients were reporting mostly negative opioid assessments (80% or greater) there was little to no difference between BRIXADI and SL BPN/NX.

Figure 17: Patients Achieving Varying Percentages of Negative Opioid Assessments (urine and self-report) in weeks 4 through 24

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 12: Patients Achieving Varying Percentage of Opioid-Negative Assessments (urine and self report) (Weeks 4-24)</span> </caption> <col align="center" valign="bottom" width="44%"/> <col align="center" valign="bottom" width="28%"/> <col align="center" valign="bottom" width="28%"/> <thead> <tr class="First"> <th align="center" class="Lrule Rrule" rowspan="2">Percentage of Opioid-Negative Assessments (Urine and Self Report)</th><th align="center" class="Botrule Rrule" colspan="2">Number (%) of Patients</th> </tr> <tr class="Botrule Last"> <th align="center" class="Rrule">BRIXADI<br/>N=213</th><th align="center" class="Rrule">SL BPN/NX<br/>N=215</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">≥ 0%</td><td align="center" class="Rrule">213 (100.0)</td><td align="center" class="Rrule">215 (100.0)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 10%</td><td align="center" class="Rrule">121 (56.8)</td><td align="center" class="Rrule">87 (40.5)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 20%</td><td align="center" class="Rrule">114 (53.5)</td><td align="center" class="Rrule">79 (36.7)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 30%</td><td align="center" class="Rrule">95 (44.6)</td><td align="center" class="Rrule">67 (31.2)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 40%</td><td align="center" class="Rrule">85 (39.9)</td><td align="center" class="Rrule">62 (28.8)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 50%</td><td align="center" class="Rrule">74 (34.7)</td><td align="center" class="Rrule">56 (26.0)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 60%</td><td align="center" class="Rrule">68 (31.9)</td><td align="center" class="Rrule">53 (24.7)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 70%</td><td align="center" class="Rrule">51 (23.9)</td><td align="center" class="Rrule">49 (22.8)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 80%</td><td align="center" class="Rrule">44 (20.7)</td><td align="center" class="Rrule">43 (20.0)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">≥ 90%</td><td align="center" class="Rrule">28 (13.1)</td><td align="center" class="Rrule">27 (12.6)</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">≥ 100%</td><td align="center" class="Rrule">23 (10.8)</td><td align="center" class="Rrule">14 (6.5)</td> </tr> </tbody> </table></div>

Store BRIXADI at room temperature at 20°C to 25°C (68°F to 77° F); with excursions permitted at 15°C to 30° C (59°F to 86°F) [see USP Controlled Room Temperature].

BRIXADI is a Schedule III drug product. Handle with adequate security and accountability. After administration, syringes should be properly disposed, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

<div class="scrollingtable"><table width="60%"> <col align="left" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="34%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="3">BRIXADI Weekly<br/>50 mg/mL buprenorphine</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Dosage </span></td><td align="center" class="Rrule"><span class="Bold">Volume</span></td><td align="center" class="Rrule"><span class="Bold">NDC </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">8 mg</td><td align="center" class="Rrule">0.16 mL</td><td align="center" class="Rrule">58284-208-01<br/>58284-208-91</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">16 mg</td><td align="center" class="Rrule">0.32 mL</td><td align="center" class="Rrule">58284-216-01<br/>58284-216-91</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">24 mg</td><td align="center" class="Rrule">0.48 mL</td><td align="center" class="Rrule">58284-224-01<br/>58284-224-91</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">32 mg</td><td align="center" class="Rrule">0.64 mL</td><td align="center" class="Rrule">58284-232-01<br/>58284-232-91</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="60%"> <col align="left" valign="middle" width="33%"/> <col align="center" valign="middle" width="33%"/> <col align="center" valign="middle" width="34%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="3">BRIXADI Monthly<br/>356 mg/mL buprenorphine</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Dosage </span></td><td align="center" class="Rrule"><span class="Bold">Volume</span></td><td align="center" class="Rrule"><span class="Bold">NDC </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">64 mg</td><td align="center" class="Rrule">0.18 mL</td><td align="center" class="Rrule">58284-264-01<br/>58284-264-91</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">96 mg</td><td align="center" class="Rrule">0.27 mL</td><td align="center" class="Rrule">58284-296-01<br/>58284-296-91</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">128 mg</td><td align="center" class="Rrule">0.36 mL</td><td align="center" class="Rrule">58284-228-01<br/>58284-228-91</td> </tr> </tbody> </table></div>

Safe Use

Before initiating treatment with BRIXADI, explain the points listed below to patients and caregivers.

BRIXADI Risk Evaluation and Mitigation Strategy (REMS)

Advise patients that because of the risk of serious harm or death due to intravenous self-administration, BRIXADI is available only through a restricted distribution program called the BRIXADI REMS. Healthcare settings and pharmacies are certified and only dispense BRIXADI directly to a healthcare provider for administration by a healthcare provider [see Warnings and Precautions (5.2)].

Life Threatening Respiratory Depression

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions 5.4)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving buprenorphine, because naloxone is often not effective at the doses available for patient access [Dosage and Administration (2.3), Warnings and Precautions (5.4), Overdosage (10)].

If naloxone is prescribed, also advise patients and caregivers:

Interaction with Benzodiazepines and other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if BRIXADI is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.5) and Drug Interactions (7)].

Serotonin Syndrome

Inform patients that BRIXADI could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)].

Adrenal Insufficiency

Inform patients that BRIXADI could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.7)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with buprenorphine. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.10)].

Latex Allergy

The BRIXADI needle cap is synthetically derived from natural rubber latex which may cause allergic reactions in latex-sensitive individuals [see Warnings and Precautions (5.10)].

Dependence and Withdrawal

Inform patients that BRIXADI can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued [see Warnings and Precautions (5.11)].

Driving or Operating Heavy Machinery

Caution patients that BRIXADI may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous machinery.

Instruct patients not to drive or operate hazardous machinery until they are reasonably certain that BRIXADI therapy does not adversely affect their ability to engage in such activities [see Warnings and Precautions (5.16)].

Orthostatic Hypotension

Inform patients that, like other opioids, BRIXADI may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.17)].

Long Duration of Action

Inform patients that they may have detectable levels of buprenorphine for a prolonged period of time after treatment with BRIXADI. Considerations of drug-drug interactions, buprenorphine effects, and analgesia may continue to be relevant for several months after the last injection [see Clinical Pharmacology (12.3)].

Drug Interactions

Instruct patients to inform their healthcare providers of any other prescription medications, over-the-counter medications, or herbal preparations that are prescribed or currently being used [see Drug Interactions (7)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Advise women that if they are pregnant while being treated with BRIXADI, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].

Embryofetal Toxicity

Advise women of childbearing potential who become pregnant or are planning to become pregnant to consult their healthcare provider regarding the possible effects of using BRIXADI during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties [see Use in Specific Populations (8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Infertility (8.3)].

Emergency Analgesia

Advise patients to instruct their family members to, in the event of emergency, inform the treating physician or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with BRIXADI [see Warnings and Precautions (5.12)].

Clinical Monitoring

Tell your patients to seek emergency attention if they have signs or symptoms of respiratory or CNS depression or overdose [see Warnings and Precautions (5.4, 5.5)].

Tell your patients not to tamper with or try to remove their depot [see Dosage and Administration (2.5)].

© 2023 Braeburn, Inc. BRIXADI® is a registered trademark of Braeburn Inc.

{ "type": "p", "children": [], "text": "© 2023 Braeburn, Inc. BRIXADI® is a registered trademark of Braeburn Inc." }

Distributed by:Braeburn Inc.Plymouth Meeting, PA 19462

{ "type": "p", "children": [], "text": "Distributed by:Braeburn Inc.Plymouth Meeting, PA 19462" }

Manufactured by:Pharmaceutics International, Inc. (Pii)Cockeysville, MD 21030

{ "type": "p", "children": [], "text": "Manufactured by:Pharmaceutics International, Inc. (Pii)Cockeysville, MD 21030" }

BRX-PI-002

{ "type": "p", "children": [], "text": "BRX-PI-002" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="60%"/> <col align="right" valign="bottom" width="40%"/> <thead> <tr class="First Last"> <th align="left" class="Botrule Lrule Rrule" colspan="2"> Medication Guide<br/>BRIXADI<span class="Sup">®</span> (brix-a-dee) (buprenorphine) extended-release injection, for subcutaneous use (CIII)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left">This Medication Guide has been approved by the U. S. Food and Drug Administration.</td><td align="right">Issued: 05/2023</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What is the most important information I should know about BRIXADI?</span> <ul> <li>Because of the serious risk of potential harm or death from self-injecting BRIXADI into a vein (intravenously), it is only available through a restricted program called the BRIXADI REMS Program.</li> <li> <ul> <li>BRIXADI is not available in retail pharmacies.</li> <li>Your BRIXADI injection will only be given to you by a healthcare provider.</li> </ul> </li> <li>BRIXADI contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life- threatening breathing problems, especially if you take or use certain other medicines or drugs.</li> <li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.</li> <li> <span class="Bold">BRIXADI can cause serious and life-threatening breathing problems. Get emergency help right away if you:</span> <ul> <li>feel faint</li> <li>feel dizzy</li> <li>are confused</li> <li>feel sleepy or uncoordinated</li> <li>have blurred vision</li> <li>have slurred speech</li> <li>are breathing slower than normal</li> <li>cannot think well or clearly</li> </ul> </li> <li> <span class="Bold">Do not take BRIXADI with certain medicines. Taking BRIXADI with other opioid medicines, benzodiazepines, alcohol, other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span> </li> <li>In an emergency, have family members tell the emergency department staff that you are physically dependent on an opioid and are being treated with BRIXADI. </li> <li>You may have detectable levels of BRIXADI in your body for several months after stopping treatment with BRIXADI.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What is BRIXADI?</span> <br/>BRIXADI is a prescription medicine used to treat moderate to severe opioid addiction (dependence) to opioid drugs (prescription or illegal) in people: <ul> <li>who have started treatment with a single dose of a buprenorphine medicine in the form of a sublingual tablet or buccal film (transmucosal), OR</li> <li>who are already being treated with buprenorphine</li> </ul>BRIXADI should be used as part of a complete treatment plan that also includes counseling and behavioral therapy. It is not known if BRIXADI is safe and effective in children. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Who should not receive BRIXADI?<br/>Do not receive BRIXADI </span> if you are allergic to buprenorphine or any ingredients in BRIXADI. See the end of this Medication Guide for a list of ingredients in BRIXADI .</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">Before receiving BRIXADI, tell your healthcare provider about all of your medical conditions, including if you have:</span> <ul> <li>trouble breathing or lung problems</li> <li>a curve in your spine that affects your breathing</li> <li>Addison's disease</li> <li>an enlarged prostate (men)</li> <li>problems urinating</li> <li>liver, kidney, or gallbladder problems</li> <li>a history of alcoholism</li> <li>a head injury or brain problem</li> <li>mental health problems</li> <li>adrenal gland or thyroid gland problems</li> <li>a latex allergy. The BRIXADI needle cap contains latex.</li> </ul> <span class="Bold">Tell your healthcare provider if you are:</span> <ul> <li> <span class="Bold">pregnant or plan to become pregnant.</span> If you receive BRIXADI while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or become pregnant.</li> <li> <span class="Bold">breastfeeding.</span> BRIXADI can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with BRIXADI. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with BRIXADI.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take, including</span> prescription and over-the-counter medicines, vitamins and herbal supplements. Talk with your healthcare provider before starting any new medicines during or after stopping treatment with BRIXADI. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">How will I receive BRIXADI?</span> <ul> <li>You will receive BRIXADI by your healthcare provider as an injection just under the skin (subcutaneous) of your buttock, thigh, stomach (abdomen), or upper arm. If you are new to buprenorphine treatment, the upper arm should only be used after 4 doses of BRIXADI.</li> <li>If you are not currently receiving buprenorphine treatment, your healthcare provider will give you a test dose of buprenorphine first to see if you are able to tolerate it, and then switch you over to BRIXADI.</li> <li>You will receive BRIXADI 1 time every week or 1 time every month.</li> <li>BRIXADI is injected as a liquid. After the injection, BRIXADI changes to a gel form called a depot. The depot is not always felt under the skin.</li> <li>Do not try to remove the depot.</li> <li>If you miss a dose of BRIXADI, see your healthcare provider to get your BRIXADI injection as soon as possible.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What should I avoid while receiving BRIXADI?</span> <ul> <li> <span class="Bold">Do not drive, operate heavy machinery or perform any other dangerous activities until you know how BRIXADI affects you.</span> BRIXADI can cause drowsiness and slow reaction times. BRIXADI can make you sleepy, dizzy, or lightheaded. This may happen more often in the first few days after your injection and when your dose is being changed.</li> <li> <span class="Bold">You should not drink alcohol</span> or use prescription or over-the-counter medicines that contain alcohol during treatment with BRIXADI, because this can lead to loss of consciousness or even death.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What are the possible side effects of BRIXADI?<br/>BRIXADI can cause serious side effects, including:</span> <ul> <li> <span class="Bold">Trouble breathing.</span> Taking BRIXADI with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.</li> <li> <span class="Bold">Sleepiness, dizziness, and problems with coordination.</span> </li> <li> <span class="Bold">Physical dependence or abuse.</span> </li> <li> <span class="Bold">Liver problems.</span> Call your healthcare provider right away if you notice any of these symptoms:<ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or "tea colored" urine</li> <li>light colored stools (bowel movements)</li> <li>loss of appetite</li> <li>ain, aching, or tenderness on the right side of your stomach-area</li> <li>nausea</li> </ul> </li> </ul>Your healthcare provider should do tests to check your liver before and during treatment with BRIXADI.<ul> <li> <span class="Bold">Allergic reaction.</span> You may have a rash, hives, swelling of your face, wheezing, light-headedness when changing positions, feeling faint, or loss of consciousness. Call your healthcare provider or get emergency help right away.</li> <li> <span class="Bold">Opioid withdrawal.</span> Call your healthcare provider right away if you get any of these symptoms: <ul> <li>shaking</li> <li>sweating more than normal</li> <li>feeling hot or cold more than normal</li> <li>runny nose</li> <li>watery eyes</li> <li>goose bumps</li> <li>diarrhea</li> <li>vomiting</li> <li>muscle aches</li> </ul> </li> </ul>These symptoms may start weeks to months after your last dose of BRIXADI. Tell your healthcare provider if you develop any of these symptoms. <ul> <li> <span class="Bold">Decrease in blood pressure.</span> You may feel dizzy if you get up too fast from sitting or lying down.</li> </ul>The most common side effects of BRIXADI include: <ul> <li>injection site pain</li> <li>headache</li> <li>constipation</li> <li>nausea</li> <li>injection site redness</li> <li>injection site itching</li> <li>trouble sleeping (insomnia)</li> <li>urinary tract infection</li> </ul>BRIXADI may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you. These are not all the of possible side effects of BRIXADI.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">General information about the safe and effective use of BRIXADI.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information that is written for healthcare professionals. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2"><span class="Bold">What are the ingredients in BRIXADI?<br/>Active ingredient:</span> buprenorphine<br/> <span class="Bold">Inactive ingredients:</span> <br/>BRIXADI weekly: anhydrous ethanol and soybean phosphatidylcholine/glycerol dioleate.<br/>BRIXADI monthly: N-methyl pyrrolidine and soybean phosphatidylcholine/glycerol dioleate.<br/> <br/> </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule">Distributed by Braeburn, Inc., Plymouth Meeting, PA 19462, USA.<br/>© 2023 Braeburn, Inc. BRIXADI<span class="Sup">®</span> is a registered trademark of Braeburn Inc.<br/>Manufactured by: Pharmaceutics International, Inc. (Pii), Cockeysville MD 21030<br/>For more information, go to www.BRIXADI.com or call 1-833-274-9234</td><td align="right" class="Botrule Rrule"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"60%\"/>\n<col align=\"right\" valign=\"bottom\" width=\"40%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\">\n Medication Guide<br/>BRIXADI<span class=\"Sup\">®</span> (brix-a-dee) (buprenorphine) extended-release injection, for subcutaneous use (CIII)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\">This Medication Guide has been approved by the U. S. Food and Drug Administration.</td><td align=\"right\">Issued: 05/2023</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is the most important information I should know about BRIXADI?</span>\n<ul>\n<li>Because of the serious risk of potential harm or death from self-injecting BRIXADI into a vein (intravenously), it is only available through a restricted program called the BRIXADI REMS Program.</li>\n<li>\n<ul>\n<li>BRIXADI is not available in retail pharmacies.</li>\n<li>Your BRIXADI injection will only be given to you by a healthcare provider.</li>\n</ul>\n</li>\n<li>BRIXADI contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life- threatening breathing problems, especially if you take or use certain other medicines or drugs.</li>\n<li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.</li>\n<li>\n<span class=\"Bold\">BRIXADI can cause serious and life-threatening breathing problems. Get emergency help right away if you:</span>\n<ul>\n<li>feel faint</li>\n<li>feel dizzy</li>\n<li>are confused</li>\n<li>feel sleepy or uncoordinated</li>\n<li>have blurred vision</li>\n<li>have slurred speech</li>\n<li>are breathing slower than normal</li>\n<li>cannot think well or clearly</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Do not take BRIXADI with certain medicines. Taking BRIXADI with other opioid medicines, benzodiazepines, alcohol, other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span>\n</li>\n<li>In an emergency, have family members tell the emergency department staff that you are physically dependent on an opioid and are being treated with BRIXADI.\n</li>\n<li>You may have detectable levels of BRIXADI in your body for several months after stopping treatment with BRIXADI.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What is BRIXADI?</span>\n<br/>BRIXADI is a prescription medicine used to treat moderate to severe opioid addiction (dependence) to opioid drugs (prescription or illegal) in people:\n <ul>\n<li>who have started treatment with a single dose of a buprenorphine medicine in the form of a sublingual tablet or buccal film (transmucosal), OR</li>\n<li>who are already being treated with buprenorphine</li>\n</ul>BRIXADI should be used as part of a complete treatment plan that also includes counseling and behavioral therapy. It is not known if BRIXADI is safe and effective in children.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Who should not receive BRIXADI?<br/>Do not receive BRIXADI </span> if you are allergic to buprenorphine or any ingredients in BRIXADI. See the end of this Medication Guide for a list of ingredients in BRIXADI .</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">Before receiving BRIXADI, tell your healthcare provider about all of your medical conditions, including if you have:</span>\n<ul>\n<li>trouble breathing or lung problems</li>\n<li>a curve in your spine that affects your breathing</li>\n<li>Addison's disease</li>\n<li>an enlarged prostate (men)</li>\n<li>problems urinating</li>\n<li>liver, kidney, or gallbladder problems</li>\n<li>a history of alcoholism</li>\n<li>a head injury or brain problem</li>\n<li>mental health problems</li>\n<li>adrenal gland or thyroid gland problems</li>\n<li>a latex allergy. The BRIXADI needle cap contains latex.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n<ul>\n<li>\n<span class=\"Bold\">pregnant or plan to become pregnant.</span> If you receive BRIXADI while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or become pregnant.</li>\n<li>\n<span class=\"Bold\">breastfeeding.</span> BRIXADI can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with BRIXADI. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with BRIXADI.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, including</span> prescription and over-the-counter medicines, vitamins and herbal supplements. Talk with your healthcare provider before starting any new medicines during or after stopping treatment with BRIXADI.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">How will I receive BRIXADI?</span>\n<ul>\n<li>You will receive BRIXADI by your healthcare provider as an injection just under the skin (subcutaneous) of your buttock, thigh, stomach (abdomen), or upper arm. If you are new to buprenorphine treatment, the upper arm should only be used after 4 doses of BRIXADI.</li>\n<li>If you are not currently receiving buprenorphine treatment, your healthcare provider will give you a test dose of buprenorphine first to see if you are able to tolerate it, and then switch you over to BRIXADI.</li>\n<li>You will receive BRIXADI 1 time every week or 1 time every month.</li>\n<li>BRIXADI is injected as a liquid. After the injection, BRIXADI changes to a gel form called a depot. The depot is not always felt under the skin.</li>\n<li>Do not try to remove the depot.</li>\n<li>If you miss a dose of BRIXADI, see your healthcare provider to get your BRIXADI injection as soon as possible.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What should I avoid while receiving BRIXADI?</span>\n<ul>\n<li>\n<span class=\"Bold\">Do not drive, operate heavy machinery or perform any other dangerous activities until you know how BRIXADI affects you.</span> BRIXADI can cause drowsiness and slow reaction times. BRIXADI can make you sleepy, dizzy, or lightheaded. This may happen more often in the first few days after your injection and when your dose is being changed.</li>\n<li>\n<span class=\"Bold\">You should not drink alcohol</span> or use prescription or over-the-counter medicines that contain alcohol during treatment with BRIXADI, because this can lead to loss of consciousness or even death.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of BRIXADI?<br/>BRIXADI can cause serious side effects, including:</span>\n<ul>\n<li>\n<span class=\"Bold\">Trouble breathing.</span> Taking BRIXADI with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.</li>\n<li>\n<span class=\"Bold\">Sleepiness, dizziness, and problems with coordination.</span>\n</li>\n<li>\n<span class=\"Bold\">Physical dependence or abuse.</span>\n</li>\n<li>\n<span class=\"Bold\">Liver problems.</span> Call your healthcare provider right away if you notice any of these symptoms:<ul>\n<li>your skin or the white part of your eyes turns yellow (jaundice)</li>\n<li>dark or \"tea colored\" urine</li>\n<li>light colored stools (bowel movements)</li>\n<li>loss of appetite</li>\n<li>ain, aching, or tenderness on the right side of your stomach-area</li>\n<li>nausea</li>\n</ul>\n</li>\n</ul>Your healthcare provider should do tests to check your liver before and during treatment with BRIXADI.<ul>\n<li>\n<span class=\"Bold\">Allergic reaction.</span> You may have a rash, hives, swelling of your face, wheezing, light-headedness when changing\npositions, feeling faint, or loss of consciousness. Call your healthcare provider or get emergency help right away.</li>\n<li>\n<span class=\"Bold\">Opioid withdrawal.</span> Call your healthcare provider right away if you get any of these symptoms:\n <ul>\n<li>shaking</li>\n<li>sweating more than normal</li>\n<li>feeling hot or cold more than normal</li>\n<li>runny nose</li>\n<li>watery eyes</li>\n<li>goose bumps</li>\n<li>diarrhea</li>\n<li>vomiting</li>\n<li>muscle aches</li>\n</ul>\n</li>\n</ul>These symptoms may start weeks to months after your last dose of BRIXADI. Tell your healthcare provider if you develop any of these symptoms.\n <ul>\n<li>\n<span class=\"Bold\">Decrease in blood pressure.</span> You may feel dizzy if you get up too fast from sitting or lying down.</li>\n</ul>The most common side effects of BRIXADI include:\n <ul>\n<li>injection site pain</li>\n<li>headache</li>\n<li>constipation</li>\n<li>nausea</li>\n<li>injection site redness</li>\n<li>injection site itching</li>\n<li>trouble sleeping (insomnia)</li>\n<li>urinary tract infection</li>\n</ul>BRIXADI may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you. These are not all the of possible side effects of BRIXADI.<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">General information about the safe and effective use of BRIXADI.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information that is written for healthcare professionals.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in BRIXADI?<br/>Active ingredient:</span> buprenorphine<br/>\n<span class=\"Bold\">Inactive ingredients:</span>\n<br/>BRIXADI weekly: anhydrous ethanol and soybean phosphatidylcholine/glycerol dioleate.<br/>BRIXADI monthly: N-methyl pyrrolidine and soybean phosphatidylcholine/glycerol dioleate.<br/>\n<br/>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule\">Distributed by Braeburn, Inc., Plymouth Meeting, PA 19462, USA.<br/>© 2023 Braeburn, Inc. BRIXADI<span class=\"Sup\">®</span> is a registered trademark of Braeburn Inc.<br/>Manufactured by: Pharmaceutics International, Inc. (Pii), Cockeysville MD 21030<br/>For more information, go to www.BRIXADI.com or call 1-833-274-9234</td><td align=\"right\" class=\"Botrule Rrule\"></td>\n</tr>\n</tbody>\n</table></div>" }

Carton - Single-dose Prefilled Syringe Kit - 8 mg Weekly Dose - BRIXADI

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PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIWEEKLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIWEEKLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

8 mg0.16 mLof a 50 mg/mL solutionper syringe (Weekly)

{ "type": "p", "children": [], "text": "\n8 mg0.16 mLof a 50 mg/mL solutionper syringe (Weekly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 8 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-208-01

{ "type": "p", "children": [], "text": "NDC 58284-208-01" }

Carton - Single-dose Prefilled Syringe Kit - 16 mg Weekly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 16 mg Weekly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIWEEKLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIWEEKLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

16 mg0.32 mLof a 50 mg/mL solutionper syringe (Weekly)

{ "type": "p", "children": [], "text": "\n16 mg0.32 mLof a 50 mg/mL solutionper syringe (Weekly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 16 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-216-01

{ "type": "p", "children": [], "text": "NDC 58284-216-01" }

Carton - Single-dose Prefilled Syringe Kit - 24 mg Weekly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 24 mg Weekly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIWEEKLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIWEEKLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

24 mg0.48 mLof a 50 mg/mL solutionper syringe (Weekly)

{ "type": "p", "children": [], "text": "\n24 mg0.48 mLof a 50 mg/mL solutionper syringe (Weekly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 24 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-224-01

{ "type": "p", "children": [], "text": "NDC 58284-224-01" }

Carton - Single-dose Prefilled Syringe Kit - 32 mg Weekly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 32 mg Weekly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIWEEKLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIWEEKLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

32 mg0.64 mLof a 50 mg/mL solutionper syringe (Weekly)

{ "type": "p", "children": [], "text": "\n32 mg0.64 mLof a 50 mg/mL solutionper syringe (Weekly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 32 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-weekly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-232-01

{ "type": "p", "children": [], "text": "NDC 58284-232-01" }

Carton - Single-dose Prefilled Syringe Kit - 64 mg Monthly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 64 mg Monthly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIMONTHLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIMONTHLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

64 mg0.18 mLof a 356 mg/mL solutionper syringe (Monthly)

{ "type": "p", "children": [], "text": "\n64 mg0.18 mLof a 356 mg/mL solutionper syringe (Monthly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 64 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-264-01

{ "type": "p", "children": [], "text": "NDC 58284-264-01" }

Carton - Single-dose Prefilled Syringe Kit - 96 mg Monthly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 96 mg Monthly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIMONTHLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIMONTHLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

96 mg0.27 mLof a 356 mg/mL solutionper syringe (Monthly)

{ "type": "p", "children": [], "text": "\n96 mg0.27 mLof a 356 mg/mL solutionper syringe (Monthly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 96 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-296-01

{ "type": "p", "children": [], "text": "NDC 58284-296-01" }

Carton - Single-dose Prefilled Syringe Kit - 128 mg Monthly Dose - BRIXADI

{ "type": "p", "children": [], "text": "\n\nCarton - Single-dose Prefilled Syringe Kit - 128 mg Monthly Dose - BRIXADI\n" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Brixadi® (buprenorphine) extended-releaseinjection for subcutaneous use CIIIMONTHLY

{ "type": "p", "children": [], "text": "\nBrixadi®\n(buprenorphine) extended-releaseinjection for subcutaneous use\nCIIIMONTHLY\n" }

For Subcutaneous Use Only

{ "type": "p", "children": [], "text": "\nFor Subcutaneous Use Only\n" }

128 mg0.36 mLof a 356 mg/mL solutionper syringe (Monthly)

{ "type": "p", "children": [], "text": "\n128 mg0.36 mLof a 356 mg/mL solutionper syringe (Monthly)" }

WARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.

{ "type": "p", "children": [], "text": "\nWARNING: SERIOUS HARM OR DEATH COULDRESULT IF INJECTED INTRAVENOUSLY.\n" }

SINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:

{ "type": "p", "children": [], "text": "\nSINGLE-DOSE PREFILLED SYRINGE KITCONTENTS:\n" }

{ "type": "ul", "children": [ "One (1) sterile prefilled syring with needle shield. 128 mg (buprenorphine) per syringe", "One (1) plunger rod", "Prescribing Information", "Instructions for Use", "Medication Guide" ], "text": "" }

For Healthcare ProviderAdministration Only.Do Not Dispense to Patient.

{ "type": "p", "children": [], "text": "\nFor Healthcare ProviderAdministration Only.Do Not Dispense to Patient.\n" }

Attention: Dispense the enclosedMedication Giude to each patient.Rx ONLY Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.

{ "type": "p", "children": [], "text": "\nAttention: Dispense the enclosedMedication Giude to each patient.Rx ONLY\n\n Distributed by: Braeburn Inc.Plymouth Meeting, PA 19462Properly dispose of BRIXADI® syringes per facilityprocedure for a Schedule III drug product, and perapplicable federal, state, and local regulations.Once-monthly subcutaneous injection fortreatment of opiod use disorder. For questions,call 1-833-274-9234.\n " }

05/23

{ "type": "p", "children": [], "text": "\n 05/23\n " }

NDC 58284-228-01

{ "type": "p", "children": [], "text": "NDC 58284-228-01" }

Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and are preferred for induction. Buprenorphine Sublingual Tablets should be used as part of a complete treatment plan to include counseling and psychosocial support.

{ "type": "p", "children": [], "text": "Buprenorphine Sublingual Tablets are indicated for the treatment of opioid dependence and are preferred for induction. Buprenorphine Sublingual Tablets should be used as part of a complete treatment plan to include counseling and psychosocial support." }

Buprenorphine Sublingual Tablets are administered sublingually as a single daily dose.

Buprenorphine Sublingual Tablets do not contain naloxone and is preferred for use only during induction. Following induction, buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets are preferred due to the presence of naloxone when clinical use includes unsupervised administration. The use of Buprenorphine Sublingual Tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone sublingual film or buprenorphine and naloxone sublingual tablets; for example, those patients who have been shown to be hypersensitive to naloxone.

Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Buprenorphine Sublingual Tablets. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with Buprenorphine Sublingual Tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of Buprenorphine Sublingual Tablets and its affinity for the mu-opioid receptor [see Overdosage ( 10)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information ( 17)].

Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.

Patients Dependent on Heroin or Other Short-acting Opioid Products:

At treatment initiation, the first dose of Buprenorphine Sublingual Tablets should be administered only when objective and clear signs of moderate opioid withdrawal appear, and not less than 4 hours after the patient last used an opioid.

It is recommended that an adequate treatment dose, titrated to clinical effectiveness, should be achieved as rapidly as possible. The dosing on the initial day of treatment may be given in 2 mg to 4 mg increments if preferred. In some studies, gradual induction over several days led to a high rate of drop-out of buprenorphine patients during the induction period.

In a one-month study, patients received 8 mg of Buprenorphine Sublingual Tablets on Day 1 and 16 mg Buprenorphine Sublingual Tablets on Day 2. From Day 3 onward, patients received either buprenorphine and naloxone sublingual tablets or Buprenorphine Sublingual Tablets at the same buprenorphine dose as Day 2 based on their assigned treatment. Induction in the studies of buprenorphine solution was accomplished over 3-4 days, depending on the target dose.

Patients Dependent on Methadone or Other Long-acting Opioid Products:

Patients dependent upon methadone or other long-acting opioid products may be more susceptible to precipitated and prolonged withdrawal during induction than those on short-acting opioid products; therefore, the first dose of Buprenorphine Sublingual Tablets should only be administered when objective and clear signs of moderate opioid withdrawal appear, and generally not less than 24 hours after the patient last used a long-acting opioid product.

There is little controlled experience with the transfer of methadone-maintained patients to buprenorphine. Available evidence suggests that withdrawal signs and symptoms are possible during induction onto buprenorphine. Withdrawal appears more likely in patients maintained on higher doses of methadone (>30 mg) and when the first buprenorphine dose is administered shortly after the last methadone dose.

Buprenorphine Sublingual Tablets must be administered whole. Do not cut, chew, or swallow Buprenorphine Sublingual Tablets. Advise patients not to eat or drink anything until the tablet is completely dissolved.

Buprenorphine Sublingual Tablets should be placed under the tongue until it is dissolved. For doses requiring the use of more than two tablets, patients are advised to either place all the tablets at once or alternatively (if they cannot fit in more than two tablets comfortably), place two tablets at a time under the tongue. Either way, the patients should continue to hold the tablets under the tongue until they dissolve; swallowing the tablets reduces the bioavailability of the drug. To ensure consistency in bioavailability, patients should follow the same manner of dosing with continued use of the product.

Proper administration technique should be demonstrated to the patient.

Advise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow. Advise patients to wait for at least one hour after taking Buprenorphine Sublingual Tablets before brushing teeth [see Warnings and Precautions ( 5.13), Postmarketing Experience ( 6.2), Information for Patients ( 17), and the Medication Guide].

Treatment should be initiated with supervised administration, progressing to unsupervised administration as the patient’s clinical stability permits. The use of Buprenorphine Sublingual Tablets for unsupervised administration should be limited to those patients who cannot tolerate buprenorphine and naloxone, for example those patients with known hypersensitivity to naloxone. Buprenorphine and naloxone and buprenorphine are both subject to diversion and abuse. When determining the prescription quantity for unsupervised administration, consider the patient’s level of stability, the security of his or her home situation, and other factors likely to affect the ability of the patient to manage supplies of take-home medication.

Ideally, patients should be seen at reasonable intervals (e.g., at least weekly during the first month of treatment) based upon the individual circumstances of the patient. Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or without appropriate patient follow-up visits. Periodic assessment is necessary to determine compliance with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.

Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule may be reasonable for patients on a stable dosage of medication who are making progress toward their treatment objectives. Continuation or modification of pharmacotherapy should be based on the healthcare provider’s evaluation of treatment outcomes and objectives such as:

If treatment goals are not being achieved, the healthcare provider should re-evaluate the appropriateness of continuing the current treatment.

Consider reducing the starting and titration incremental dose by half and monitor for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Healthcare providers will need to decide when they cannot appropriately provide further management for particular patients. For example, some patients may be abusing or dependent on various drugs, or unresponsive to psychosocial intervention such that the healthcare provider does not feel that he/she has the expertise to manage the patient. In such cases, the healthcare provider may want to assess whether to refer the patient to a specialist or more intensive behavioral treatment environment. Decisions should be based on a treatment plan established and agreed upon with the patient at the beginning of treatment.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with, or referred to, more intensive and structured treatment.

The decision to discontinue therapy with buprenorphine and naloxone or Buprenorphine Sublingual Tablets after a period of maintenance should be made as part of a comprehensive treatment plan. Advise patients of the potential to relapse to illicit drug use following discontinuation of opioid agonist/partial agonist medication-assisted treatment. Taper patients to reduce the occurrence of withdrawal signs and symptoms [see Warnings and Precautions ( 5.7)].

Buprenorphine Sublingual Tablets are supplied as white, sublingual tablets available in two dosage strengths:

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Buprenorphine Sublingual Tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported [see Warnings and Precautions ( 5.9)] .

{ "type": "p", "children": [], "text": "Buprenorphine Sublingual Tablets are contraindicated in patients with a history of hypersensitivity to buprenorphine, as serious adverse reactions, including anaphylactic shock, have been reported\n \n [see Warnings and Precautions (\n \n 5.9)]\n \n .\n\n " }

Buprenorphine Sublingual Tablets contain buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure appropriate protection from theft, including in the home. Clinical monitoring appropriate to the patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or without appropriate patient follow-up visits [see Drug Abuse and Dependence ( 9.2)].

Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Buprenorphine Sublingual Tablets [see Warnings and Precautions ( 5.3), Drug Interactions ( 7)].

Use Buprenorphine Sublingual Tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17)].

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.9)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Buprenorphine Sublingual Tablets. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration ( 2.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with Buprenorphine Sublingual Tablets itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of Buprenorphine Sublingual Tablets and its affinity for the mu-opioid receptor [see Overdosage ( 10)].

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17)].

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient’s buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions ( 5.2)].

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions ( 7)].

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it. Store buprenorphine-containing medications safely out of the sight and reach of children and destroy any unused medication appropriately [see Patient Counseling ( 17)].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations ( 8.1)].

Advise pregnant women receiving opioid addiction treatment with Buprenorphine Sublingual Tablets of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1)] . This risk must be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of management of opioid addiction throughout pregnancy.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence ( 9.3)]. When discontinuing Buprenorphine Sublingual Tablets, gradually taper the dosage [see Dosage and Administration ( 2.9)].

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, Buprenorphine Sublingual Tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated.

Cases of hypersensitivity to buprenorphine products have been reported both in clinical trials and in the post-marketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine is a contraindication to the use of Buprenorphine Sublingual Tablets.

Because of the partial agonist properties of buprenorphine, Buprenorphine Sublingual Tablets may precipitate opioid withdrawal signs and symptoms in individuals physically dependent on full opioid agonists if administered sublingually or parenterally before the agonist effects of other opioids have subsided.

There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine Sublingual Tablets are not appropriate as an analgesic.

In a pharmacokinetic study, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration ( 2.7), Use in Specific Populations ( 8.6)].

Cases of dental caries, some severe (i.e., tooth fracture, tooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.

Refer patients to dental care services and encourage them to have regular dental checkups while taking Buprenorphine Sublingual Tablets. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing the teeth and gums with water and then swallowing after Buprenorphine Sublingual Tablets have been completely dissolved in the oral mucosa. Advise patients to wait for at least one hour after taking Buprenorphine Sublingual Tablets before brushing teeth [see Dosing and Administration (2.5), Information for Patients ( 17), Medication Guide].

Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing Buprenorphine Sublingual Tablets to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

Buprenorphine Sublingual Tablets may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery, especially during treatment induction and dose adjustment. Caution patients about driving or operating hazardous machinery until they are reasonably certain that buprenorphine therapy does not adversely affect his or her ability to engage in such activities.

Like other opioids, Buprenorphine Sublingual Tablets may produce orthostatic hypotension in ambulatory patients.

Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Buprenorphine Sublingual Tablets was supported by clinical trials using buprenorphine sublingual tablets, buprenorphine and naloxone sublingual tablets and other trials using buprenorphine sublingual solutions. In total, safety data were available from 3214 opioid-dependent subjects exposed to buprenorphine at doses in the range used in treatment of opioid addiction.

Few differences in adverse event profile were noted between buprenorphine sublingual tablets or buprenorphine administered as a sublingual solution.

The following adverse events were reported to occur by at least 5% of patients in a 4-week study (Table 1).

<div class="scrollingtable"><table width="91.66%"> <caption> <span>Table 1. Adverse Events ≥5% by Body System and Treatment Group in a 4-week Study</span> </caption> <col width="32%"/> <col width="37%"/> <col width="31%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td align="center" class="Botrule Lrule Toprule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Body System / Adverse Event</span> </p> <p> <span class="Bold">(COSTART Terminology)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Buprenorphine Sublingual Tablets</span> </p> <p> <span class="Bold">16 mg/day</span> </p> <p> <span class="Bold">N=103</span> </p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=107</span> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (4.9%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">7 (6.5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Chills</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (7.8%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">8 (7.5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">30 (29.1%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">24 (22.4%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Infection</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (11.7%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">7 (6.5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (18.4%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">20 (18.7%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pain Abdomen</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (11.7%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">7 (6.5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pain Back</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (7.8%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">12 (11.2%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Withdrawal Syndrome</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (18.4%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">40 (37.4%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Cardiovascular System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Vasodilation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (3.9%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">7 (6.5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Digestive System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (7.8%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">3 (2.8%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (4.9%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">16 (15.0%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (13.6%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">12 (11.2%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (7.8%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">5 (4.7%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">22 (21.4%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">17 (15.9%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (9.7%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">14 (13.1%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and Appendages</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> <p class="First">Sweating</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (12.6%)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">11 (10.3%)</p> </td> </tr> </tbody> </table></div>

The adverse event profile of buprenorphine was also characterized in the dose-controlled study of buprenorphine solution, over a range of doses in four months of treatment. Table 2 shows adverse events reported by at least 5% of subjects in any dose group in the dose-controlled study.

<div class="scrollingtable"><table width="100.12%"> <caption> <span>Table 2. Adverse Events (≥5%) by Body System and Treatment Group in a 16-week Study</span> </caption> <col width="20%"/> <col width="20%"/> <col width="15%"/> <col width="16%"/> <col width="15%"/> <col width="15%"/> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Sublingual solution. Doses in this table cannot necessarily be delivered in tablet form, but for comparison purposes: "Very low" dose (1 mg solution) would be less than a tablet dose of 2 mg "Low" dose (4 mg solution) approximates a 6 mg tablet dose "Moderate" dose (8 mg solution) approximates a 12 mg tablet dose "High" dose (16 mg solution) approximates a 24 mg tablet dose </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" rowspan="3" valign="top"> <p class="First"> <span class="Bold">Body System / <br/> Adverse Event (COSTART Terminology) </span> </p> </td><td align="center" class="Botrule Lrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Buprenorphine Dose</span><a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Very Low</span><a class="Sup" href="#footnote-1">*</a><span class="Bold">(N=184)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Low</span><a class="Sup" href="#footnote-1">*</a> <br/> <span class="Bold">(N=180)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Moderate</span><a class="Sup" href="#footnote-1">*</a> <br/> <span class="Bold">(N=186)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">High</span><a class="Sup" href="#footnote-1">*</a> <br/> <span class="Bold">(N=181)</span> </p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">Total</span><a class="Sup" href="#footnote-1">*</a> <br/> <span class="Bold">(N=731)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First"> <span class="Bold">N (%)</span> </p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Body as a Whole</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Abscess</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (1%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">3 (2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (1%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">16 (2%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Asthenia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26 (14%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (16%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26 (14%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (13%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">104 (14%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Chills</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (6%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">42 (6%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Fever</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (1%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">2 (1%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (6%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">21 (3%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Flu Syndrome</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (10%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (4%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">44 (6%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Headache</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">51 (28%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">62 (34%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">54 (29%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">53 (29%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">220 (30%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Infection</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">32 (17%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">39 (22%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">38 (20%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">40 (22%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">149 (20%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Injury Accidental</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (3%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">25 (3%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pain</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">47 (26%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">37 (21%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">49 (26%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">44 (24%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">177 (24%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pain Back</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (10%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">29 (16%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">28 (15%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (15%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">102 (14%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Withdrawal Syndrome</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">45 (24%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">40 (22%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">41 (22%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">36 (20%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">162 (22%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Digestive System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Constipation</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">26 (14%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">82 (11%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">19 (10%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">40 (5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Dyspepsia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">24 (3%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">22 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (10%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">75 (10%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">8 (4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">14 (8%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">38 (5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Nervous System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Anxiety</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">22 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (11%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25 (14%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">91 (12%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Depression</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">24 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (9%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">25 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">18 (10%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">83 (11%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Dizziness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (6%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">31 (4%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Insomnia</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">42 (23%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">50 (28%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">43 (23%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">51 (28%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">186 (25%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Nervousness</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">12 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">10 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (7%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">46 (6%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Somnolence</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (6%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">38 (5%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Respiratory System</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Cough Increase</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">5 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">11 (6%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">4 (2%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">26 (4%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">7 (4%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">28 (4%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Rhinitis</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">27 (15%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">16 (9%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">15 (8%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (12%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">79 (11%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Skin and Appendages</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First">Sweat</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (13%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">21 (12%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">20 (11%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">23 (13%)</p> </td><td align="center" class="Botrule Lrule" valign="top"> <p class="First">87 (12%)</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> <p class="First"> <span class="Bold">Special Senses</span> </p> </td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> <p class="First">Runny Eyes</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">13 (7%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">9 (5%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td align="center" class="Botrule Rrule" valign="top"> <p class="First">6 (3%)</p> </td><td class="Botrule" valign="top"> <ul> <li>34 (5%)</li> </ul> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequently reported postmarketing adverse events with buprenorphine not observed in clinical trials, excluding drug exposure during pregnancy, was drug misuse or abuse.

Serotonin Syndrome:Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal Insufficiency:Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis:Anaphylaxis has been reported with ingredients contained in Buprenorphine Sublingual Tablets.

Androgen Deficiency:Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)].

Local Reactions:Dental decay (including caries, tooth fracture, and tooth loss), glossodynia, glossitis, oral mucosal erythema, oral hypoesthesia, and stomatitis.

Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 3 includes clinically significant drug interactions with Buprenorphine Sublingual Tablets.

{ "type": "p", "children": [], "text": "Table 3 includes clinically significant drug interactions with Buprenorphine Sublingual Tablets." }

Table 3. Clinically Significant Drug Interactions

{ "type": "p", "children": [], "text": "\nTable 3. Clinically Significant Drug Interactions\n" }

<div class="scrollingtable"><table width="100%"> <col width="22%"/> <col width="78%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Benzodiazepines or other Central Nervous System (CNS) Depressants</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate.</p> <p>Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments <span class="Italics">[see Warnings and Precautions ( <a href="#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f">5.2</a>, <a href="#ID_da3cdd6e-dd67-4839-b675-62215a78c0ff">5.3</a>)]. </span> </p> <p>If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder <span class="Italics">[see Warnings and Precautions ( <a href="#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f">5.2</a>)]. </span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Inhibitors of CYP3A4</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine Sublingual Tablets is achieved.</p> <p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology ( <a href="#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91">12.3</a>)], </span>potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider dosage reduction of Buprenorphine Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.</p> <p>If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">CYP3A4 Inducers</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine <span class="Italics">[see Clinical Pharmacology ( <a href="#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91">12.3</a>)], </span>potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. </p> <p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase <span class="Italics">[see Clinical Pharmacology ( <a href="#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91">12.3</a>)], </span>which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If concomitant use is necessary, consider increasing the Buprenorphine Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p> <p>If a CYP3A4 inducer is discontinued, consider Buprenorphine Sublingual Tablets dosage reduction and monitor for signs of respiratory depression.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Rifampin, carbamazepine, phenytoin</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Patients who are on chronic Buprenorphine Sublingual Tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">efavirenz, nevirapine, etravirine, delavirdine</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Antiretrovirals: Protease inhibitors (PIs)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor patients taking Buprenorphine Sublingual Tablets and atazanavir with and without ritonavir, and reduce dose of Buprenorphine Sublingual Tablets if warranted.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">atazanavir, ritonavir</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">None</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Serotonergic Drugs</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Buprenorphine Sublingual Tablets if serotonin syndrome is suspected.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">The use of Buprenorphine Sublingual Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Examples:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">phenelzine, tranylcypromine, linezolid</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Muscle Relaxants</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor patients receiving muscle relaxants and Buprenorphine Sublingual Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Buprenorphine Sublingual Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#ID_97924142-8453-4d27-99f3-7c0308b7314d">2.2</a>), Warnings and Precautions ( <a href="#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f">5.2</a>, <a href="#ID_da3cdd6e-dd67-4839-b675-62215a78c0ff">5.3</a>)]. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Diuretics</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Anticholinergic Drugs</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Clinical Impact:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Italics">Intervention:</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Monitor patients for signs of urinary retention or reduced gastric motility when Buprenorphine Sublingual Tablets are used concomitantly with anticholinergic drugs.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"22%\"/>\n<col width=\"78%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Benzodiazepines or other Central Nervous System (CNS) Depressants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or CNS depressant or decreasing to the lowest effective dose may be appropriate.</p>\n<p>Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f\">5.2</a>,\n \n <a href=\"#ID_da3cdd6e-dd67-4839-b675-62215a78c0ff\">5.3</a>)].\n \n </span>\n</p>\n<p>If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f\">5.2</a>)].\n \n </span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Inhibitors of CYP3A4</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine Sublingual Tablets is achieved.</p>\n<p>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91\">12.3</a>)],\n \n </span>potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider dosage reduction of Buprenorphine Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.</p>\n<p>If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">CYP3A4 Inducers</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91\">12.3</a>)],\n \n </span>potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine.\n \n </p>\n<p>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#ID_1fb6d68f-9e14-4181-87ca-442e41ac3f91\">12.3</a>)],\n \n </span>which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.\n \n </p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is necessary, consider increasing the Buprenorphine Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.</p>\n<p>If a CYP3A4 inducer is discontinued, consider Buprenorphine Sublingual Tablets dosage reduction and monitor for signs of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Rifampin, carbamazepine, phenytoin</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Patients who are on chronic Buprenorphine Sublingual Tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">efavirenz, nevirapine, etravirine, delavirdine</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antiretrovirals: Protease inhibitors (PIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients taking Buprenorphine Sublingual Tablets and atazanavir with and without ritonavir, and reduce dose of Buprenorphine Sublingual Tablets if warranted.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">atazanavir, ritonavir</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">None</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Serotonergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Buprenorphine Sublingual Tablets if serotonin syndrome is suspected.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">The use of Buprenorphine Sublingual Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Examples:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">phenelzine, tranylcypromine, linezolid</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Muscle Relaxants</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients receiving muscle relaxants and Buprenorphine Sublingual Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Buprenorphine Sublingual Tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#ID_97924142-8453-4d27-99f3-7c0308b7314d\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#ID_a9a488a3-5966-4a53-8f22-d8518ca7282f\">5.2</a>,\n \n <a href=\"#ID_da3cdd6e-dd67-4839-b675-62215a78c0ff\">5.3</a>)].\n \n </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Diuretics</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Anticholinergic Drugs</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Clinical Impact:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Italics\">Intervention:</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Monitor patients for signs of urinary retention or reduced gastric motility when Buprenorphine Sublingual Tablets are used concomitantly with anticholinergic drugs.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary:

The data on use of buprenorphine, the active ingredient in Buprenorphine Sublingual Tablets, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Data].Observational studies have reported on congenital malformations among buprenorphine-exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Data].

Reproductive and developmental studies in rats and rabbits identified adverse events at clinically relevant and higher doses. Embryofetal death was observed in both rats and rabbits administered buprenorphine during the period of organogenesis at doses approximately 6 and 0.3 times, respectively, the human sublingual dose of 16 mg/day of buprenorphine. Pre- and post-natal development studies in rats demonstrated increased neonatal deaths at 0.3 times and above and dystocia at approximately 3 times the human sublingual dose of 16 mg/day of buprenorphine. No clear teratogenic effects were seen when buprenorphine was administered during organogenesis with a range of doses equivalent to or greater than the human sublingual dose of 16 mg/day of buprenorphine. However, increases in skeletal abnormalities were noted in rats and rabbits administered buprenorphine daily during organogenesis at doses approximately 0.6 times and approximately equal to the human sublingual dose of 16 mg/day of buprenorphine, respectively. In a few studies, some events such as acephalus and omphalocele were also observed but these findings were not clearly treatment-related [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations:

Disease-associated maternal and embryo-fetal risk: Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Dose adjustment during pregnancy and the postpartum period:Dosage adjustments of buprenorphine may be required during pregnancy, even if the patient was maintained on a stable dose prior to pregnancy. Withdrawal signs and symptoms should be monitored closely and the dose adjusted as necessary.

Fetal/neonatal adverse reactions: Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with Buprenorphine Sublingual Tablets.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5)] .

Labor or delivery: Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor.

Data:

Human Data: Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Several factors may complicate the interpretation of investigations of the children of women who take buprenorphine during pregnancy, including maternal use of illicit drugs, late presentation for prenatal care, infection, poor compliance, poor nutrition, and psychosocial circumstances. Interpretation of data is complicated further by the lack of information on untreated opioid-dependent pregnant women, who would be the most appropriate group for comparison. Rather, women on another form of opioid medication-assisted treatment, or women in the general population are generally used as the comparison group. However, women in these comparison groups may be different from women prescribed buprenorphine-containing products with respect to maternal factors that may lead to poor pregnancy outcomes.

In a multicenter, double-blind, randomized, controlled trial [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] designed primarily to assess neonatal opioid withdrawal effects, opioid-dependent pregnant women were randomized to buprenorphine (n=86) or methadone (n=89) treatment, with enrollment at an average gestational age of 18.7 weeks in both groups. A total of 28 of the 86 women in the buprenorphine group (33%) and 16 of the 89 women in the methadone group (18%) discontinued treatment before the end of pregnancy.

Among women who remained in treatment until delivery, there was no difference between buprenorphine-treated and methadone-treated groups in the number of neonates requiring NOWS treatment or in the peak severity of NOWS. Buprenorphine-exposed neonates required less morphine (mean total dose, 1.1 mg vs. 10.4 mg), had shorter hospital stays (10.0 days vs. 17.5 days), and shorter duration of treatment for NOWS (4.1 days vs. 9.9 days) compared to the methadone-exposed group.

There were no differences between groups in other primary outcomes (neonatal head circumference,) or secondary outcomes (weight and length at birth, preterm birth, gestational age at delivery, and 1-minute and 5-minute Apgar scores), or in the rates of maternal or neonatal adverse events. The outcomes among mothers who discontinued treatment before delivery and may have relapsed to illicit opioid use are not known. Because of the imbalance in discontinuation rates between the buprenorphine and methadone groups, the study findings are difficult to interpret.

Animal Data: The exposure margins listed below are based on body surface area comparisons (mg/m 2) to the human sublingual dose of 16 mg buprenorphine via Buprenorphine Sublingual Tablets.

No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the human sublingual dose of 16 mg). Maternal toxicity resulting in mortality was noted in these studies in both rats and rabbits. Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Maternal toxicity was seen in the high-dose group but not at the lower doses where the findings were observed. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the human sublingual dose of 16 mg). In the rabbit, increased post-implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.

Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the human sublingual dose of 16 mg), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the human sublingual dose of 16 mg), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the human sublingual dose of 16 mg) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the human sublingual dose of 16 mg). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the human sublingual dose of 16 mg), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the human sublingual dose of 16 mg) in the absence of maternal toxicity or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the human sublingual dose of 16 mg) were not statistically significant.

In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the human sublingual dose of 16 mg). No maternal toxicity was noted at doses causing post-implantation loss in this study.

Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine from Gestation Day 14 through Lactation Day 21 at 5 mg/kg/day (approximately 3 times the human sublingual dose of 16 mg). Fertility, and pre- and post-natal development studies with buprenorphine in rats indicated increases in neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the human sublingual dose of 16 mg), after IM doses of 0.5 mg/kg/day and up (approximately 0.3 times the human sublingual dose of 16 mg), and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the human sublingual dose of 16 mg). An apparent lack of milk production during these studies likely contributed to the decreased pup viability and lactation indices. Delays in the occurrence of righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day (approximately 50 times the human sublingual dose of 16 mg).

Risk Summary:

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine were present in low levels in human milk and available data have not shown adverse reactions in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Buprenorphine Sublingual Tablets and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations:

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

Data:

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (C avg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

Infertility:

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Clinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)].

The safety and effectiveness of Buprenorphine Sublingual Tablets have not been established in pediatric patients.

Clinical studies of buprenorphine sublingual tablets, buprenorphine and naloxone sublingual film, or buprenorphine and naloxone sublingual tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe Buprenorphine Sublingual Tablets should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a pharmacokinetic study. Buprenorphine is extensively metabolized in the liver and buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment.

For patients with severe hepatic impairment, a dose adjustment is recommended, and patients with moderate or severe hepatic impairment should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.12), Clinical Pharmacology ( 12.3)].

No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

Buprenorphine Sublingual Tablets contain buprenorphine, a Schedule III controlled substance under the Controlled Substances Act.

Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion. Healthcare professionals should contact their state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Patients who continue to misuse, abuse, or divert, buprenorphine products or other opioids should be provided or referred for more intensive and structured treatment.

Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

The healthcare provider may be able to more easily detect misuse or diversion by maintaining records of medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of medication prescribed.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper handling and storage of the medication are appropriate measures that help to limit abuse of opioid drugs.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Warnings and Precautions ( 5.7)].

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.5)].

Clinical Presentation:

{ "type": "p", "children": [], "text": "\nClinical Presentation:\n" }

The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death.

{ "type": "p", "children": [], "text": "The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death." }

Treatment of Overdose:

{ "type": "p", "children": [], "text": "\nTreatment of Overdose:\n" }

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated.

{ "type": "p", "children": [], "text": "In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be employed as indicated." }

In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of Buprenorphine Sublingual Tablets should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk.

{ "type": "p", "children": [], "text": "In the case of overdose, the primary management should be the re-establishment of adequate ventilation with mechanical assistance of respiration, if required. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary. The long duration of action of Buprenorphine Sublingual Tablets should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Insufficient duration of monitoring may put patients at risk." }

Buprenorphine Sublingual Tablets are supplied as white, sublingual tablets available in two dosage strengths, 2 mg buprenorphine free base and 8 mg buprenorphine free base. Each tablet also contains citric acid anhydrous, corn starch, crospovidone, lactose monohydrate, magnesium stearate, mannitol, povidone, purified water and sodium citrate.

{ "type": "p", "children": [], "text": "Buprenorphine Sublingual Tablets are supplied as white, sublingual tablets available in two dosage strengths, 2 mg buprenorphine free base and 8 mg buprenorphine free base. Each tablet also contains citric acid anhydrous, corn starch, crospovidone, lactose monohydrate, magnesium stearate, mannitol, povidone, purified water and sodium citrate." }

Chemically, buprenorphine hydrochloride, USP is (6R, 7R, 14S)-17-Cyclopropylmethyl-7,8-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-O-methyl-6,14-ethano-17-normorphine hydrochloride. It has the following chemical structure:

{ "type": "p", "children": [], "text": "Chemically, buprenorphine hydrochloride, USP is (6R, 7R, 14S)-17-Cyclopropylmethyl-7,8-dihydro-7-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6-O-methyl-6,14-ethano-17-normorphine hydrochloride. It has the following chemical structure:" }

Buprenorphine hydrochloride, USP has the molecular formula C 29H 41NO 4• HCl and the molecular weight is 504.10. It is a white or almost white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane, acetone, and ethylacetate.

{ "type": "p", "children": [], "text": "Buprenorphine hydrochloride, USP has the molecular formula C\n \n 29H\n \n 41NO\n \n 4• HCl and the molecular weight is 504.10. It is a white or almost white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane, acetone, and ethylacetate.\n\n " }

Buprenorphine Sublingual Tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

Subjective Effects:

Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.

Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8 to 32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.

Physiologic Effects:

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses have been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O 2saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O 2saturation to the same degree.

Effects on the Endocrine System:

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Cardiac Electrophysiology

Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤15 msec.

Absorption:

Plasma levels of buprenorphine increased with the sublingual dose of Buprenorphine Sublingual Tablets (Table 4). There was wide inter-patient variability in the sublingual absorption of buprenorphine, but within subjects the variability was low. Both C maxand AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 mg to 16 mg), although the increase was not directly dose-proportional.

<div class="scrollingtable"><table width="90.84%"> <caption> <span>Table 4. Pharmacokinetic Parameters of Buprenorphine and Norbuprenorphine after the Sublingual Administration of Buprenorphine Sublingual Tablets</span> </caption> <col width="8%"/> <col width="21%"/> <col width="13%"/> <col width="14%"/> <col width="13%"/> <col width="14%"/> <col width="16%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Dose</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Analyte</span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Mean <br/> SD </span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">C <span class="Sub">max</span> <br/> (ng/mL) </span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">T <span class="Sub">max</span> <br/> (h) </span> </p> </td><td class="Botrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">AUC <span class="Sub">inf</span> <br/> (h•ng/mL) </span> </p> </td><td class="Botrule Lrule Toprule" valign="top"> <p class="First"> <span class="Bold">t <span class="Sub">1/2</span>(h) </span> </p> </td> </tr> <tr> <td class="Botrule Rrule" rowspan="2" valign="middle"> <p class="First">2 mg</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">Buprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.25</p> <p>0.584</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.84</p> <p>0.62</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">10.93</p> <p>3.945</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">31.66</p> <p>12.66</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="middle"> <p class="First">Norbuprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">0.301</p> <p>0.127</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2.36</p> <p>2.75</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">12.39</p> <p>4.526</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">39.28</p> <p>20.85</p> </td> </tr> <tr> <td class="Botrule Rrule" rowspan="2" valign="middle"> <p class="First">8 mg</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">Buprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2.88</p> <p>1.14</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.28</p> <p>0.46</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">28.39</p> <p>10.22</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">35.01</p> <p>14.7</p> </td> </tr> <tr> <td class="Botrule Rrule" valign="middle"> <p class="First">Norbuprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.38</p> <p>0.752</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.75</p> <p>2.11</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">50.18</p> <p>22.61</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">44.33</p> <p>19.27</p> </td> </tr> <tr> <td class="Botrule Rrule" rowspan="2" valign="middle"> <p class="First">16 mg</p> </td><td class="Botrule Rrule" valign="middle"> <p class="First">Buprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">4.70</p> <p>2.16</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.42</p> <p>0.50</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">47.09</p> <p>20.03</p> </td><td class="Botrule Lrule" valign="top"> <p class="First">36.51</p> <p>13.99</p> </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="middle"> <p class="First">Norbuprenorphine</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">Mean</p> <p>SD</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">2.65</p> <p>1.62</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">1.52</p> <p>1.34</p> </td><td class="Botrule Rrule" valign="top"> <p class="First">92.31</p> <p>34.74</p> </td><td class="Botrule" valign="top"> <p class="First">40.35</p> <p>12.07</p> </td> </tr> </tbody> </table></div>

Distribution:

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Elimination:

Metabolism:Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro;however, it is not known whether norbuprenorphine contributes to the overall effect of Buprenorphine Sublingual Tablets.

Excretion:A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated).

When Buprenorphine Sublingual Tablets are administered sublingually, buprenorphine has a mean elimination half-life from plasma ranging from 31 to 35 hours.

Drug Interactions Studies:

CYP3A4 Inhibitors and Inducers: Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine has been found to be a moderate CYP2D6 inhibitor in in vitrostudies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns [see Drug Interactions ( 7)] .

Specific Populations:

Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine was determined after administering a 2.0 mg/0.5 mg buprenorphine and naloxone sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function.

In subjects with mild hepatic impairment, the changes in mean C max, AUC 0-last, and half-life values of buprenorphine were not clinically significant.

For subjects with moderate and severe hepatic impairment, mean C max, AUC 0-last, and half-life values of buprenorphine were increased (Table 5) [see Warnings and Precautions ( 5.12), Use in Specific Populations ( 8.6)].

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5. Changes in Buprenorphine Pharmacokinetic Parameters in Subjects with Moderate and Severe Hepatic Impairment</span> </caption> <col width="33%"/> <col width="35%"/> <col width="32%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Hepatic Impairment</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">PK Parameters</span> </p> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Increase in buprenorphine compared to healthy subjects</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Moderate</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">C <span class="Sub">max</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">8%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">AUC <span class="Sub">0-last</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">64%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Half-life</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">35%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Severe</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">C <span class="Sub">max</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">72%</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">AUC <span class="Sub">0-last</span> </p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">181%</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">Half-life</p> </td><td class="Botrule Lrule Rrule" valign="top"> <p class="First">57%</p> </td> </tr> </tbody> </table></div>

HCV Infection:In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean C max, AUC 0-last, and half-life values of buprenorphine were not clinically significant in comparison to healthy subjects without HCV infection.

Carcinogenicity:

Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated exposure was approximately 0.4, 3 and 35 times the recommended human daily sublingual dose of 16 mg on a mg/m 2basis) for 27 months. As in the buprenorphine/naloxone carcinogenicity study in rat, statistically significant dose-related increases in Leydig cell tumors occurred. In an 86-week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a mg/m 2basis).

Mutagenicity:

Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast (S. cerevisiae)for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets (E. coli)survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivoand in vitroincorporation of [ 3H]thymidine, and positive in unscheduled DNA synthesis (UDS) test using testicular cells from mice.

Impairment of Fertility:

Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily oral doses up to 80 mg/kg/day (estimated exposure was approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m 2basis) or up to 5 mg/kg/day IM or SC (estimated exposure was approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m 2basis).

Clinical data on the safety and efficacy of Buprenorphine Sublingual Tablets were derived from studies of buprenorphine sublingual tablet formulations, with and without naloxone, and from studies of sublingual administration of a more bioavailable ethanolic solution of buprenorphine.

{ "type": "p", "children": [], "text": "Clinical data on the safety and efficacy of Buprenorphine Sublingual Tablets were derived from studies of buprenorphine sublingual tablet formulations, with and without naloxone, and from studies of sublingual administration of a more bioavailable ethanolic solution of buprenorphine." }

Buprenorphine sublingual tablets were studied in 1834 patients; buprenorphine and naloxone sublingual tablets in 575 patients, and buprenorphine sublingual solutions in 2470 patients. A total of 1270 women received buprenorphine in those clinical trials. Dosing recommendations are based on data from one trial of both tablet formulations and two trials of the ethanolic solution. All trials used buprenorphine in conjunction with psychosocial counseling as part of a comprehensive addiction treatment program. There were no clinical studies conducted to assess the efficacy of buprenorphine as the only component of treatment.

{ "type": "p", "children": [], "text": "Buprenorphine sublingual tablets were studied in 1834 patients; buprenorphine and naloxone sublingual tablets in 575 patients, and buprenorphine sublingual solutions in 2470 patients. A total of 1270 women received buprenorphine in those clinical trials. Dosing recommendations are based on data from one trial of both tablet formulations and two trials of the ethanolic solution. All trials used buprenorphine in conjunction with psychosocial counseling as part of a comprehensive addiction treatment program. There were no clinical studies conducted to assess the efficacy of buprenorphine as the only component of treatment." }

In a double-blind placebo- and active-controlled study, 326 heroin-addicted subjects were randomly assigned to either buprenorphine and naloxone sublingual tablets, 16/4 mg per day; buprenorphine sublingual tablets, 16 mg per day; or placebo sublingual tablets. For subjects randomized to either active treatment, dosing began with one 8 mg of buprenorphine sublingual tablet on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine sublingual tablets on Day 2. On Day 3, those randomized to receive buprenorphine and naloxone sublingual tablets were switched to the combination tablet. Subjects randomized to placebo received one placebo tablet on Day 1 and two placebo tablets per day thereafter for four weeks. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. Subjects were instructed to hold the medication under the tongue for approximately 5 to 10 minutes until completely dissolved. Subjects received counseling regarding HIV infection and up to one hour of individualized counseling per week. The primary study comparison was to assess the efficacy of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets individually against placebo sublingual tablet. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets than for placebo sublingual tablets.

{ "type": "p", "children": [], "text": "In a double-blind placebo- and active-controlled study, 326 heroin-addicted subjects were randomly assigned to either buprenorphine and naloxone sublingual tablets, 16/4 mg per day; buprenorphine sublingual tablets, 16 mg per day; or placebo sublingual tablets. For subjects randomized to either active treatment, dosing began with one 8 mg of buprenorphine sublingual tablet on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine sublingual tablets on Day 2. On Day 3, those randomized to receive buprenorphine and naloxone sublingual tablets were switched to the combination tablet. Subjects randomized to placebo received one placebo tablet on Day 1 and two placebo tablets per day thereafter for four weeks. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. Subjects were instructed to hold the medication under the tongue for approximately 5 to 10 minutes until completely dissolved. Subjects received counseling regarding HIV infection and up to one hour of individualized counseling per week. The primary study comparison was to assess the efficacy of buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets individually against placebo sublingual tablet. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine and naloxone sublingual tablets and buprenorphine sublingual tablets than for placebo sublingual tablets." }

In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg per day of buprenorphine sublingual tablets), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to 10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually.

{ "type": "p", "children": [], "text": "In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg per day of buprenorphine sublingual tablets), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to 10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually." }

Maintenance dosing continued through Week 17, and then medications were tapered by approximately 20% to 30% per week over Weeks 18 to 24, with placebo dosing for the last two weeks. Subjects received individual and/or group counseling weekly.

{ "type": "p", "children": [], "text": "Maintenance dosing continued through Week 17, and then medications were tapered by approximately 20% to 30% per week over Weeks 18 to 24, with placebo dosing for the last two weeks. Subjects received individual and/or group counseling weekly." }

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

{ "type": "p", "children": [], "text": "Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated." }

In a dose-controlled, double-blind, parallel-group, 16-week study, 731 subjects were randomized to receive one of four doses of buprenorphine ethanolic solution: 1 mg, 4 mg, 8 mg, and 16 mg. Buprenorphine was titrated to maintenance doses over 1 to 4 days and continued for 16 weeks. Subjects received at least one session of AIDS education and additional counseling ranging from one hour per month to one hour per week, depending on site.

{ "type": "p", "children": [], "text": "In a dose-controlled, double-blind, parallel-group, 16-week study, 731 subjects were randomized to receive one of four doses of buprenorphine ethanolic solution: 1 mg, 4 mg, 8 mg, and 16 mg. Buprenorphine was titrated to maintenance doses over 1 to 4 days and continued for 16 weeks. Subjects received at least one session of AIDS education and additional counseling ranging from one hour per month to one hour per week, depending on site." }

Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, the three highest tested doses were superior to the 1 mg dose. Therefore, this study showed that a range of buprenorphine doses may be effective. The 1 mg dose of buprenorphine sublingual solution can be considered to be somewhat lower than a 2 mg tablet dose. The other doses used in the study encompass a range of tablet doses from approximately 6 mg to approximately 24 mg.

{ "type": "p", "children": [], "text": "Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, the three highest tested doses were superior to the 1 mg dose. Therefore, this study showed that a range of buprenorphine doses may be effective. The 1 mg dose of buprenorphine sublingual solution can be considered to be somewhat lower than a 2 mg tablet dose. The other doses used in the study encompass a range of tablet doses from approximately 6 mg to approximately 24 mg." }

Buprenorphine Sublingual Tablets

{ "type": "p", "children": [], "text": "\nBuprenorphine Sublingual Tablets\n" }

2 mg, supplied as white, flat faced, beveled-edge tablets with product identification "54” over “775" on one side and plain on the other side.

{ "type": "p", "children": [], "text": "\n2 mg, supplied as white, flat faced, beveled-edge tablets with product identification \"54” over “775\" on one side and plain on the other side.\n" }

NDC 0054-0176-13: Bottle of 30 Sublingual Tablets

{ "type": "p", "children": [], "text": "NDC 0054-0176-13: Bottle of 30 Sublingual Tablets" }

8 mg, supplied as white, flat faced, beveled-edge tablets with product identification "54” over “411" on one side and plain on the other side.

{ "type": "p", "children": [], "text": "\n8 mg, supplied as white, flat faced, beveled-edge tablets with product identification \"54” over “411\" on one side and plain on the other side.\n" }

NDC 0054-0177-13: Bottle of 30 Sublingual Tablets

{ "type": "p", "children": [], "text": "NDC 0054-0177-13: Bottle of 30 Sublingual Tablets" }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]" }

Dispense in a tight, light-resistant container as defined in USP.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in USP." }

Store Buprenorphine Sublingual Tablets securely and dispose of properly [see Patient Counseling Information ( 17)].

{ "type": "p", "children": [], "text": "Store Buprenorphine Sublingual Tablets securely and dispose of properly\n \n [see Patient Counseling Information (\n \n 17)].\n \n \n" }

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Buprenorphine Sublingual Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home [see Warnings and Precautions ( 5.1, 5.4), Abuse ( 9.2)] . Inform patients that leaving Buprenorphine Sublingual Tablets unsecured can pose a deadly risk to others in the home.

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Buprenorphine Sublingual Tablets should be disposed of by flushing the unused medication down the toilet, if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposalfor a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

Before initiating treatment with Buprenorphine Sublingual Tablets, explain the points listed below to caregivers and patients. Instruct patients to read the Medication Guide each time Buprenorphine Sublingual Tablets are dispensed because new information may be available.

Distributed by: Hikma Pharmaceuticals USA Inc.

Berkeley Heights, NJ 07922

C50000231/13

Revised January 2025

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">MEDICATION GUIDE</span> </p> <p> <span class="Bold">Buprenorphine (bue” pre nor’ feen) Sublingual Tablets CIII</span> </p> <p> <span class="Bold">Rx only</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">IMPORTANT:</span>Keep Buprenorphine Sublingual Tablets in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses Buprenorphine Sublingual Tablets, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is the most important information I should know about Buprenorphine Sublingual Tablets?</span> </p> <ul> <li>Buprenorphine Sublingual Tablets contain a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.</li> <li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of Buprenorphine Sublingual Tablets by a child. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.</li> <li>Buprenorphine Sublingual Tablets may cause serious and life-threatening breathing problems. Get emergency help right away if you: <ul> <li>feel faint</li> <li>feel dizzy</li> <li>are confused</li> <li>feel sleepy or uncoordinated</li> <li>have blurred vision</li> <li>have slurred speech</li> <li>are breathing slower than normal</li> <li>cannot think well or clearly</li> </ul> </li> <li> <span class="Bold">Do not take Buprenorphine Sublingual Tablets with certain medicines. Taking Buprenorphine Sublingual Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span> </li> <li> <span class="Bold">Do not inject (“shoot-up”) Buprenorphine Sublingual Tablets.</span>Injecting Buprenorphine Sublingual Tablets may cause life-threatening infections and other serious health problems. </li> <li> <span class="Bold">Do not switch from Buprenorphine Sublingual Tablets to other medicines that contain buprenorphine</span>without talking with your healthcare provider. The amount of buprenorphine in a dose of Buprenorphine Sublingual Tablets is not the same as in other medicines that contain buprenorphine. Your healthcare provider will prescribe a starting dose of Buprenorphine Sublingual Tablets that may be different than other buprenorphine containing medicines you may have been taking. </li> <li>Do not stop taking Buprenorphine Sublingual Tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine (physical dependence). Physical dependence is not the same as drug addiction.</li> <li>In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with Buprenorphine Sublingual Tablets.</li> <li>Never give anyone else your Buprenorphine Sublingual Tablets. They could die from taking them. Selling or giving away Buprenorphine Sublingual Tablets is against the law.</li> <li>Store Buprenorphine Sublingual Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are Buprenorphine Sublingual Tablets?</span> </p> <ul> <li>Buprenorphine Sublingual Tablets are a prescription medicine used to treat opioid addiction in adults and is part of a complete treatment program that also includes counseling and behavioral therapy.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Who should not take Buprenorphine Sublingual Tablets?</span> </p> <p> <span class="Bold">Do not take Buprenorphine Sublingual Tablets</span>if you are allergic to buprenorphine. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Before taking Buprenorphine Sublingual Tablets, tell your healthcare provider about all of your medical conditions, including if you have:</span> </p> <ul> <li> <ul> <li>tooth problems, including a history of cavities</li> <li>trouble breathing or lung problems</li> <li>a curve in your spine that affects your breathing</li> <li>Addison’s disease</li> <li>an enlarged prostate (men)</li> <li>problems urinating</li> <li>liver, kidney, or gallbladder problems</li> <li>alcoholism</li> <li>a head injury or brain problem</li> <li>mental health problems</li> <li>adrenal gland or thyroid gland problems</li> </ul> </li> </ul> <p> <span class="Bold">Tell your healthcare provider if you are:</span> </p> <ul> <li> <span class="Bold">pregnant or plan to become pregnant.</span>If you take Buprenorphine Sublingual Tablets while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life‐threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant. </li> <li> <span class="Bold">breastfeeding or plan to breastfeed.</span>Buprenorphine can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Buprenorphine Sublingual Tablets. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with Buprenorphine Sublingual Tablets. </li> </ul> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take, including</span>prescription and over‐the‐counter medicines, vitamins, or herbal supplements. </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I take Buprenorphine Sublingual Tablets?</span> </p> <ul> <li>After Buprenorphine Sublingual Tablets are completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.</li> <li>Report any problems with your teeth immediately to your provider and schedule an appointment with a dentist. Tell your dentist that you have started taking Buprenorphine Sublingual Tablets.</li> </ul> <p> <span class="Bold">Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to take Buprenorphine Sublingual Tablets.</span> </p> <ul> <li>Take Buprenorphine Sublingual Tablets exactly as prescribed by your healthcare provider. Your healthcare provider may change your dose after seeing how it affects you. Do not change your dose unless your healthcare provider tells you to change it.</li> <li>Do not take Buprenorphine Sublingual Tablets more often than prescribed by your healthcare provider.</li> <li> <span class="Bold">Buprenorphine Sublingual Tablets are not for occasional or “as needed” use.</span> </li> <li>If you are prescribed a dose of 2 or more Buprenorphine Sublingual Tablets at the same time: <ul> <li>Ask your healthcare provider for instructions on the right way to take Buprenorphine Sublingual Tablets.</li> </ul> </li> <li>Follow the same instructions every time you take a dose of Buprenorphine Sublingual Tablets.</li> <li>Take the entire Buprenorphine Sublingual Tablet. Do not cut, chew, or swallow Buprenorphine Sublingual Tablet because the medicine will not work as well.</li> <li>If you miss a dose of Buprenorphine Sublingual Tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.</li> <li>Dispose of expired, unwanted, or unused Buprenorphine Sublingual Tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li> <li> <span class="Bold">If you take too many Buprenorphine Sublingual Tablets or overdose, call Poison Control or get emergency medical help right away.</span> </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking Buprenorphine Sublingual Tablets?</span> </p> <ul> <li> <span class="Bold">Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how Buprenorphine Sublingual Tablets affect you.</span>Buprenorphine can cause drowsiness and slow reaction times. Buprenorphine Sublingual Tablets can make you sleepy, dizzy, or lightheaded. </li> <li> <span class="Bold">You should not drink alcohol</span>or take prescription or over‐the‐counter medicines that contain alcohol while taking Buprenorphine Sublingual Tablets, because this can lead to loss of consciousness or even death. </li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of Buprenorphine Sublingual Tablets?</span> </p> <p> <span class="Bold">Buprenorphine Sublingual Tablets can cause serious side effects, including:</span> </p> <ul> <li> <span class="Bold">Trouble breathing.</span>Taking Buprenorphine Sublingual Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death. </li> <li> <span class="Bold">Sleepiness, dizziness, and problems with coordination.</span> </li> <li> <span class="Bold">Physical dependence or abuse.</span> </li> <li> <span class="Bold">Liver problems.</span>Call your healthcare provider right away if you notice any of these symptoms: <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light colored stools (bowel movements)</li> <li>loss of appetite</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> <li>nausea</li> </ul> </li> <li>Your healthcare provider should do blood tests to check your liver before you start taking and while you take Buprenorphine Sublingual Tablets.</li> <li> <span class="Bold">Allergic reaction.</span>You may have a rash, hives, swelling of your face, wheezing, low blood pressure, or loss of consciousness. Call your healthcare provider or get emergency help right away. </li> <li> <span class="Bold">Opioid withdrawal.</span>Call your healthcare provider right away if you get any of these symptoms: <ul> <li>shaking</li> <li>sweating more than normal</li> <li>feeling hot or cold more than normal</li> <li>runny nose</li> <li>watery eyes</li> <li>goose bumps</li> <li>diarrhea</li> <li>vomiting</li> <li>muscle aches</li> </ul> </li> <li> <span class="Bold">Decrease in blood pressure.</span>You may feel dizzy if you get up too fast from sitting or lying down. </li> <li> <span class="Bold">The most common side effects of Buprenorphine Sublingual Tablets include:</span> <ul> <li>headache</li> <li>nausea</li> <li>vomiting</li> <li>constipation</li> <li>pain</li> <li>increased sweating</li> <li>decrease in sleep (insomnia)</li> </ul> </li> <li>Buprenorphine Sublingual Tablets may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.</li> </ul> <p>These are not all the possible side effects of Buprenorphine Sublingual Tablets.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of Buprenorphine Sublingual Tablets.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Buprenorphine Sublingual Tablets for a condition for which they were not prescribed. Do not give Buprenorphine Sublingual Tablets to other people, even if they have the same symptoms you have. They may harm them and it <span class="Bold">is against the law.</span> </p> <p> <span class="Bold">What are the ingredients in Buprenorphine Sublingual Tablets?</span> </p> <p> <span class="Bold">Active ingredient:</span>buprenorphine hydrochloride, USP </p> <p> <span class="Bold">Inactive ingredients:</span>citric acid anhydrous, corn starch, crospovidone, lactose monohydrate, magnesium stearate, mannitol, povidone, purified water and sodium citrate. </p> <p>You can ask your doctor or pharmacist for information that is written for healthcare professionals.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">For more information, call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364.</p> <p>Distributed by: <span class="Bold"></span> </p> <p> <span class="Bold">Hikma Pharmaceuticals USA Inc.</span> </p> <p>Berkeley Heights, NJ 07922</p> <p> <span class="Bold">C50000231/13</span> </p> <p> <span class="Bold">Revised January 2025</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">MEDICATION GUIDE</span>\n</p>\n<p>\n<span class=\"Bold\">Buprenorphine (bue” pre nor’ feen) Sublingual Tablets CIII</span>\n</p>\n<p>\n<span class=\"Bold\">Rx only</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">IMPORTANT:</span>Keep Buprenorphine Sublingual Tablets in a secure place away from children. Accidental use by a child is a medical emergency and can result in death. If a child accidentally uses Buprenorphine Sublingual Tablets, get emergency help or call 911 right away. Tell your healthcare provider if you are living in a household where there are small children.\n \n </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is the most important information I should know about Buprenorphine Sublingual Tablets?</span>\n</p>\n<ul>\n<li>Buprenorphine Sublingual Tablets contain a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.</li>\n<li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to patients for the emergency treatment of an opioid overdose, including accidental use of Buprenorphine Sublingual Tablets by a child. If naloxone is given, you must call 911 or get emergency medical help right away to treat an overdose or accidental use of an opioid.</li>\n<li>Buprenorphine Sublingual Tablets may cause serious and life-threatening breathing problems. Get emergency help right away if you:\n \n <ul>\n<li>feel faint</li>\n<li>feel dizzy</li>\n<li>are confused</li>\n<li>feel sleepy or uncoordinated</li>\n<li>have blurred vision</li>\n<li>have slurred speech</li>\n<li>are breathing slower than normal</li>\n<li>cannot think well or clearly</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Do not take Buprenorphine Sublingual Tablets with certain medicines. Taking Buprenorphine Sublingual Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span>\n</li>\n<li>\n<span class=\"Bold\">Do not inject (“shoot-up”) Buprenorphine Sublingual Tablets.</span>Injecting Buprenorphine Sublingual Tablets may cause life-threatening infections and other serious health problems.\n \n </li>\n<li>\n<span class=\"Bold\">Do not switch from Buprenorphine Sublingual Tablets to other medicines that contain buprenorphine</span>without talking with your healthcare provider. The amount of buprenorphine in a dose of Buprenorphine Sublingual Tablets is not the same as in other medicines that contain buprenorphine. Your healthcare provider will prescribe a starting dose of Buprenorphine Sublingual Tablets that may be different than other buprenorphine containing medicines you may have been taking.\n \n </li>\n<li>Do not stop taking Buprenorphine Sublingual Tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine (physical dependence). Physical dependence is not the same as drug addiction.</li>\n<li>In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with Buprenorphine Sublingual Tablets.</li>\n<li>Never give anyone else your Buprenorphine Sublingual Tablets. They could die from taking them. Selling or giving away Buprenorphine Sublingual Tablets is against the law.</li>\n<li>Store Buprenorphine Sublingual Tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are Buprenorphine Sublingual Tablets?</span>\n</p>\n<ul>\n<li>Buprenorphine Sublingual Tablets are a prescription medicine used to treat opioid addiction in adults and is part of a complete treatment program that also includes counseling and behavioral therapy.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take Buprenorphine Sublingual Tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take Buprenorphine Sublingual Tablets</span>if you are allergic to buprenorphine.\n \n </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Before taking Buprenorphine Sublingual Tablets, tell your healthcare provider about all of your medical conditions, including if you have:</span>\n</p>\n<ul>\n<li>\n<ul>\n<li>tooth problems, including a history of cavities</li>\n<li>trouble breathing or lung problems</li>\n<li>a curve in your spine that affects your breathing</li>\n<li>Addison’s disease</li>\n<li>an enlarged prostate (men)</li>\n<li>problems urinating</li>\n<li>liver, kidney, or gallbladder problems</li>\n<li>alcoholism</li>\n<li>a head injury or brain problem</li>\n<li>mental health problems</li>\n<li>adrenal gland or thyroid gland problems</li>\n</ul>\n</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider if you are:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">pregnant or plan to become pregnant.</span>If you take Buprenorphine Sublingual Tablets while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life‐threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant.\n \n </li>\n<li>\n<span class=\"Bold\">breastfeeding or plan to breastfeed.</span>Buprenorphine can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Buprenorphine Sublingual Tablets. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with Buprenorphine Sublingual Tablets.\n \n </li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, including</span>prescription and over‐the‐counter medicines, vitamins, or herbal supplements.\n \n </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take Buprenorphine Sublingual Tablets?</span>\n</p>\n<ul>\n<li>After Buprenorphine Sublingual Tablets are completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.</li>\n<li>Report any problems with your teeth immediately to your provider and schedule an appointment with a dentist. Tell your dentist that you have started taking Buprenorphine Sublingual Tablets.</li>\n</ul>\n<p>\n<span class=\"Bold\">Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to take Buprenorphine Sublingual Tablets.</span>\n</p>\n<ul>\n<li>Take Buprenorphine Sublingual Tablets exactly as prescribed by your healthcare provider. Your healthcare provider may change your dose after seeing how it affects you. Do not change your dose unless your healthcare provider tells you to change it.</li>\n<li>Do not take Buprenorphine Sublingual Tablets more often than prescribed by your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Buprenorphine Sublingual Tablets are not for occasional or “as needed” use.</span>\n</li>\n<li>If you are prescribed a dose of 2 or more Buprenorphine Sublingual Tablets at the same time:\n \n <ul>\n<li>Ask your healthcare provider for instructions on the right way to take Buprenorphine Sublingual Tablets.</li>\n</ul>\n</li>\n<li>Follow the same instructions every time you take a dose of Buprenorphine Sublingual Tablets.</li>\n<li>Take the entire Buprenorphine Sublingual Tablet. Do not cut, chew, or swallow Buprenorphine Sublingual Tablet because the medicine will not work as well.</li>\n<li>If you miss a dose of Buprenorphine Sublingual Tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.</li>\n<li>Dispose of expired, unwanted, or unused Buprenorphine Sublingual Tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</li>\n<li>\n<span class=\"Bold\">If you take too many Buprenorphine Sublingual Tablets or overdose, call Poison Control or get emergency medical help right away.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking Buprenorphine Sublingual Tablets?</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how Buprenorphine Sublingual Tablets affect you.</span>Buprenorphine can cause drowsiness and slow reaction times. Buprenorphine Sublingual Tablets can make you sleepy, dizzy, or lightheaded.\n \n </li>\n<li>\n<span class=\"Bold\">You should not drink alcohol</span>or take prescription or over‐the‐counter medicines that contain alcohol while taking Buprenorphine Sublingual Tablets, because this can lead to loss of consciousness or even death.\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of Buprenorphine Sublingual Tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Buprenorphine Sublingual Tablets can cause serious side effects, including:</span>\n</p>\n<ul>\n<li>\n<span class=\"Bold\">Trouble breathing.</span>Taking Buprenorphine Sublingual Tablets with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.\n \n </li>\n<li>\n<span class=\"Bold\">Sleepiness, dizziness, and problems with coordination.</span>\n</li>\n<li>\n<span class=\"Bold\">Physical dependence or abuse.</span>\n</li>\n<li>\n<span class=\"Bold\">Liver problems.</span>Call your healthcare provider right away if you notice any of these symptoms:\n \n <ul>\n<li>your skin or the white part of your eyes turns yellow (jaundice)</li>\n<li>dark or “tea-colored” urine</li>\n<li>light colored stools (bowel movements)</li>\n<li>loss of appetite</li>\n<li>pain, aching, or tenderness on the right side of your stomach area</li>\n<li>nausea</li>\n</ul>\n</li>\n<li>Your healthcare provider should do blood tests to check your liver before you start taking and while you take Buprenorphine Sublingual Tablets.</li>\n<li>\n<span class=\"Bold\">Allergic reaction.</span>You may have a rash, hives, swelling of your face, wheezing, low blood pressure, or loss of consciousness. Call your healthcare provider or get emergency help right away.\n \n </li>\n<li>\n<span class=\"Bold\">Opioid withdrawal.</span>Call your healthcare provider right away if you get any of these symptoms:\n \n <ul>\n<li>shaking</li>\n<li>sweating more than normal</li>\n<li>feeling hot or cold more than normal</li>\n<li>runny nose</li>\n<li>watery eyes</li>\n<li>goose bumps</li>\n<li>diarrhea</li>\n<li>vomiting</li>\n<li>muscle aches</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Decrease in blood pressure.</span>You may feel dizzy if you get up too fast from sitting or lying down.\n \n </li>\n<li>\n<span class=\"Bold\">The most common side effects of Buprenorphine Sublingual Tablets include:</span>\n<ul>\n<li>headache</li>\n<li>nausea</li>\n<li>vomiting</li>\n<li>constipation</li>\n<li>pain</li>\n<li>increased sweating</li>\n<li>decrease in sleep (insomnia)</li>\n</ul>\n</li>\n<li>Buprenorphine Sublingual Tablets may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you.</li>\n</ul>\n<p>These are not all the possible side effects of Buprenorphine Sublingual Tablets.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of Buprenorphine Sublingual Tablets.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Buprenorphine Sublingual Tablets for a condition for which they were not prescribed. Do not give Buprenorphine Sublingual Tablets to other people, even if they have the same symptoms you have. They may harm them and it\n \n <span class=\"Bold\">is against the law.</span>\n</p>\n<p>\n<span class=\"Bold\">What are the ingredients in Buprenorphine Sublingual Tablets?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span>buprenorphine hydrochloride, USP\n \n </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span>citric acid anhydrous, corn starch, crospovidone, lactose monohydrate, magnesium stearate, mannitol, povidone, purified water and sodium citrate.\n \n </p>\n<p>You can ask your doctor or pharmacist for information that is written for healthcare professionals.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">For more information, call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364.</p>\n<p>Distributed by:\n \n <span class=\"Bold\"></span>\n</p>\n<p>\n<span class=\"Bold\">Hikma Pharmaceuticals USA Inc.</span>\n</p>\n<p>Berkeley Heights, NJ 07922</p>\n<p>\n<span class=\"Bold\">C50000231/13</span>\n</p>\n<p>\n<span class=\"Bold\">Revised January 2025</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Medication Guide has been approved by the U.S. Food and Drug Administration." }

INSTRUCTIONS FOR USE Buprenorphine (bue” pre nor’ feen) Sublingual Tablets CIII Rx only

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n\nBuprenorphine (bue” pre nor’ feen) Sublingual Tablets CIII\n\nRx only\n" }

This “Instructions for Use” contains information on how to correctly take Buprenorphine Sublingual Tablets.

{ "type": "p", "children": [], "text": "\nThis “Instructions for Use” contains information on how to correctly take Buprenorphine Sublingual Tablets.\n" }

Important Information You Need to Know Before Taking Buprenorphine Sublingual Tablets:

{ "type": "p", "children": [], "text": "\nImportant Information You Need to Know Before Taking Buprenorphine Sublingual Tablets:\n" }

{ "type": "ul", "children": [ "Your healthcare provider should show you how to take Buprenorphine Sublingual Tablets the right way." ], "text": "" }

Preparing to take Buprenorphine Sublingual Tablets:

{ "type": "p", "children": [], "text": "\nPreparing to take Buprenorphine Sublingual Tablets:\n" }

{ "type": "ul", "children": [ "Put the tablets under your tongue. Let them dissolve completely." ], "text": "" }

{ "type": "ul", "children": [ "While Buprenorphine Sublingual Tablet is dissolving, do not chew or swallow the tablet because the medicine will not work as well.", "Talking while the tablet is dissolving can affect how well the medicine in Buprenorphine Sublingual Tablets is absorbed.", "After Buprenorphine Sublingual Tablet is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.", "If you miss a dose of Buprenorphine Sublingual Tablets, take your medicine when you remember. If it is almost time for your next dose, skip the missed dose and take the next dose at your regular time. Do not take 2 doses at the same time unless your healthcare provider tells you to. If you are not sure about your dosing, call your healthcare provider.", "Do not stop taking Buprenorphine Sublingual Tablets suddenly. You could become sick and have withdrawal symptoms because your body has become used to the medicine. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. To have fewer withdrawal symptoms, ask your healthcare provider how to stop using Buprenorphine Sublingual Tablets the right way." ], "text": "" }

If you take too many Buprenorphine Sublingual Tablets or overdose, call Poison Control or get emergency medical help right away.

{ "type": "p", "children": [], "text": "\nIf you take too many Buprenorphine Sublingual Tablets or overdose, call Poison Control or get emergency medical help right away.\n" }

Storing Buprenorphine Sublingual Tablets:

{ "type": "p", "children": [], "text": "\nStoring Buprenorphine Sublingual Tablets:\n" }

{ "type": "ul", "children": [ "Store Buprenorphine Sublingual Tablets at room temperature between 68° to 77°F (20° to 25°C).", "\nKeep Buprenorphine Sublingual Tablets in a safe place, out of the sight and reach of children.\n" ], "text": "" }

Disposing of Buprenorphine Sublingual Tablets:

{ "type": "p", "children": [], "text": "\nDisposing of Buprenorphine Sublingual Tablets:\n" }

{ "type": "ul", "children": [ "Dispose of unused Buprenorphine Sublingual Tablets as soon as you no longer need them." ], "text": "" }

Dispose of expired, unwanted or unused Buprenorphine Sublingual Tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.

{ "type": "p", "children": [], "text": "Dispose of expired, unwanted or unused Buprenorphine Sublingual Tablets by promptly flushing down the toilet (if a drug take‐back option is not readily available). Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines." }

If you need help with disposal of Buprenorphine Sublingual Tablets, call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364.

{ "type": "p", "children": [], "text": "If you need help with disposal of Buprenorphine Sublingual Tablets, call Hikma Pharmaceuticals USA Inc. at 1-800-962-8364." }

Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922

{ "type": "p", "children": [], "text": "Distributed by: \n \nHikma Pharmaceuticals USA Inc.\n Berkeley Heights, NJ 07922\n\n " }

C50000231/13 Revised January 2025

{ "type": "p", "children": [], "text": "\nC50000231/13\n\nRevised January 2025\n" }

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This “Instructions for Use” has been approved by the U.S. Food and Drug Administration." }

NDC 0054-0176-13

{ "type": "p", "children": [], "text": "NDC 0054-0176-13" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

NDC 0054-0177-13

{ "type": "p", "children": [], "text": "NDC 0054-0177-13" }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.

{ "type": "p", "children": [], "text": "\nSUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine.\n" }

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

{ "type": "p", "children": [], "text": "SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support." }

FOR SUBCUTANEOUS INJECTION ONLY. DO NOT ADMINISTER SUBLOCADE INTRAVENOUSLY, INTRAMUSCULARLY OR INTRADERMALLY [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1, 5.6)] .

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver. Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBLOCADE. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Warnings and Precautions ( 5.4)] .

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage ( 10)] .

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Patient Counseling Information ( 17)] .

Induction in patients not already receiving buprenorphine

Treatment with buprenorphine should be initiated when objective and clear signs of opioid withdrawal are evident in order to minimize the risk of precipitating withdrawal [see Warnings and Precautions ( 5.12)] .

Patients should receive an initial dose (e.g. 4 mg) of transmucosal buprenorphine and be observed for one hour to confirm tolerability before administering the first injection of SUBLOCADE. The recommended starting dose of SUBLOCADE is 300 mg. Monitor patients in a healthcare setting after injection with SUBLOCADE to assess for symptoms of worsening withdrawal or sedation. Patients' symptoms should be stable or improving prior to release from the healthcare setting. On induction day, up to an additional 8 mg of transmucosal buprenorphine could be administered to manage withdrawal symptoms.

The recommended dose for the second injection is 300 mg. The second injection may be administered as early as 1 week and up to 1 month after the initial injection, based on patient need [ seeTable 1].

Transition of patients already receiving transmucosal buprenorphine

Patients who have been on 8 mg to 24 mg daily of transmucosal buprenorphine may be transitioned directly to the recommended starting dose of 300 mg of SUBLOCADE. The recommended dose for the second injection is 300 mg. The second injection may be administered as early as 1 week and up to 1 month after the initial injection, based on patient need [ seeTable 1].

Patients established on long-term treatment and whose symptoms are controlled with 8 mg to 18 mg daily of transmucosal buprenorphine may receive 100 mg of SUBLOCADE as their second dose if symptoms remain controlled following the initial dose of 300 mg [ seeTable 1].

Maintenance dosage

After the first two injections, the recommended maintenance dosage of SUBLOCADE is 100 mg monthly. A monthly maintenance dosage of 300 mg may be considered in patients who tolerate 100 mg of SUBLOCADE monthly, but do not demonstrate a satisfactory clinical response. Maintenance doses should be administered with at least 26 days between injections.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1 Recommended Dosing Schedule</span> </caption> <col align="left" width="29.540%"/> <col align="left" width="17.040%"/> <col align="left" width="17.040%"/> <col align="left" width="19.120%"/> <col align="left" width="17.260%"/> <tfoot> <tr class="First"> <td align="left" colspan="5" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange">TM BUP, transmucosal buprenorphine; NA, not applicable</span> </p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Sup">a</span>The second injection may be administered as early as 1 week and up to 1 month after the initial injection based on patient need. </span> </p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Sup">b</span>A monthly maintenance dosage of 300 mg may be considered in patients who tolerate SUBLOCADE, but do not demonstrate a satisfactory clinical response. </span> </p> </td> </tr> <tr> <td align="left" colspan="5" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Sup">c</span>On induction day, additional transmucosal buprenorphine may be administered as needed to manage withdrawal symptoms. Monitor patients for 1 hour to confirm tolerability before administering the first injection of SUBLOCADE. </span> </p> </td> </tr> <tr class="Last"> <td align="left" colspan="5" valign="top"> <p class="First" style="border-left:1px solid;"> <span class="XmChange"><span class="Sup">d</span>Patients established on long-term treatment and whose symptoms are controlled with 8 mg to 18 mg daily of transmucosal buprenorphine may receive 100 mg of SUBLOCADE as their second dose if symptoms remain controlled following the initial dose of 300 mg. </span> </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span></span><span class="Bold">Previous Dose of TM BUP</span></td><td align="center" class="Botrule Rrule Toprule" valign="middle"><span class="Bold">TM BUP</span></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="middle"><span class="Bold">SUBLOCADE</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="middle"><span></span><span class="Bold">Initial Dose</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Injection #1</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Injection #2</span><span class="Bold"><span class="Sup">a</span></span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">Maintenance Dose</span><span class="Bold"><span class="Sup">b</span></span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="middle"><span></span>Initiation in patients not already receiving buprenorphine </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"><span></span>NA </td><td align="center" class="Botrule Rrule" valign="middle">4 mg <span class="Sup">c</span></td><td align="center" class="Botrule Rrule" valign="middle">300 mg</td><td align="center" class="Botrule Rrule" valign="middle">300 mg</td><td align="center" class="Botrule Rrule" valign="middle">100 mg</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="5" valign="middle"><span></span>Transition of patients already receiving transmucosal buprenorphine </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle"><span></span>8 – 24 mg/day </td><td align="center" class="Botrule Rrule" valign="middle">NA</td><td align="center" class="Botrule Rrule" valign="middle">300 mg</td><td align="center" class="Botrule Rrule" valign="middle">300 mg <span class="Sup">d</span></td><td align="center" class="Botrule Rrule" valign="middle">100 mg</td> </tr> </tbody> </table></div>

Missed doses

A patient who misses a maintenance dose should receive the next dose as soon as possible, with the following dose given at least 26 days later. Occasional delays in dosing up to 2 weeks are not expected to have a clinically significant impact on treatment effect.

For patients in established treatment of 100 mg monthly, there may be instances when allowance for a two-month dosing interval may be appropriate (e.g., extended travel); in those instances, a single 300 mg dose may be given to cover a two-month period. Thereafter, the 100 mg monthly regimen would resume. Patients should be cautioned that the peak plasma level after injection of a 300 mg dose will be higher than their usual monthly dose and that they may experience sedation or other buprenorphine- related effects.

Periodic assessment is necessary to determine effectiveness of the treatment plan and overall patient progress. When evaluating the patient, examine the injection site for signs of infection or evidence of tampering or attempts to remove the depot.

Due to the chronic nature of opioid use disorder, the need for continuing medication-assisted treatment should be re-evaluated periodically. There is no maximum recommended duration of maintenance treatment. For some patients, treatment may continue indefinitely. If considering stopping treatment, the clinical status of the patient should be considered.

If SUBLOCADE is discontinued, its extended-release characteristics should be considered and the patient should be monitored for several months for signs and symptoms of withdrawal and treated appropriately. After steady-state has been achieved (4-6 months), patients discontinuing SUBLOCADE may have detectable plasma and urine levels of buprenorphine for twelve months or longer [see Clinical Pharmacology ( 12.3)] .

IMPORTANT INFORMATION:

STEP 1: GETTING READY

Remove the foil pouch and safety needle from the carton. Open the pouch and remove the syringe.

Discard the oxygen absorber pack. It is not needed.

Figure 1

STEP 2: CHECK THE LIQUID CLARITY

Check that the medication does not contain contaminants or particles. SUBLOCADE ranges from colorless to yellow to amber. Variations of color within this range do not affect the potency of the product.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Figure 2

STEP 3: ATTACH THE SAFETY NEEDLE

Remove the cap from the syringe and the safety needle supplied in the carton from its sterile package.

Gently twist the needle clockwise until it is tight and firmly attached.

Do not remove the plastic cover from the needle.

Figure 3

STEP 4: PREPARE THE INJECTION SITE

Choose one of the following body regions for subcutaneous injection (see Figure 4):

Ensure that the selected injection site has adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment).

Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred in any way.

To avoid irritation, rotate injection sites.

Clean the injection site well with an alcohol swab.

Figure 4

STEP 5: REMOVE EXCESS AIR FROM SYRINGE

Hold the syringe upright for several seconds to allow air bubbles to rise. Due to the viscous nature of the medication, bubbles will not rise as quickly as those in an aqueous solution.

Remove needle cover and slowly depress the plunger to push out the excess air from the syringe.

If medication is seen at the needle tip, pull back slightly on the plunger to prevent medication spillage.

Figure 5

STEP 6: PINCH THE INJECTION SITE

Pinch the skin around the injection area. Be sure to pinch enough skin to accommodate the size of the needle. Lift the adipose tissue from the underlying muscle to prevent accidental intramuscular injection.

Figure 6

STEP 7: INJECT THE MEDICATION

SUBLOCADE is for subcutaneous injection only.Do not inject intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.1, 5.6)] .

Insert needle fully into the subcutaneous tissue. Actual angle of injection will depend on the amount of subcutaneous tissue.

Use a slow, steady push to inject the medication. Continue pushing until all of the medication is given.

Figure 7

STEP 8: WITHDRAW THE NEEDLE

Withdraw the needle at the same angle used for insertion and release the pinched skin.

Do not rub the injection area after the injection. There may be a small amount of blood or fluid at the injection site; wipe with a cotton ball or gauze before applying a gauze pad or bandage using minimal pressure.

Figure 8

STEP 9: LOCK THE NEEDLE GUARD AND DISCARD THE SYRINGE

Lock the needle guard into place by pushing it against a hard surface such as a table ( Figure 9).

Dispose of all syringe components in a secure sharps disposal container.

Figure 9

STEP 10: INSTRUCT THE PATIENT

Advise the patient that they may have a lump for several weeks that will decrease in size over time. Instruct the patient not to rub or massage the injection site and to be aware of the placement of any restrictive clothing, such as belts, waistbands, or sleeves.

SUBLOCADE is subject to a risk evaluation and mitigation strategy (REMS) program that includes, among other elements, a restricted distribution system. The purpose of the restricted distribution system is to ensure that SUBLOCADE is only administered by a health care provider [see Warnings and Precautions ( 5.2)] .

In the event the depot must be removed, it can be surgically excised under local anesthesia within 14 days of injection. Only the most recently-injected depot can be removed.

The removed depot should be handled with adequate security, accountability, and proper disposal, per facility procedure for a Schedule III drug product and pharmaceutical biohazardous waste, and per applicable federal, state, and local regulations.

The residual plasma concentrations from previous injections will decrease gradually over subsequent months [see Clinical Pharmacology ( 12.3)] .

Patients who have the depot removed should be monitored for signs and symptoms of withdrawal and treated appropriately [see Warnings and Precautions ( 5.9)] .

SUBLOCADE injection is available in dosage strengths of 100 mg/0.5 mL and 300 mg/1.5 mL buprenorphine. Each injection is a sterile, clear, colorless to yellow to amber solution provided in a single-dose, prefilled syringe with a 19 gauge 5/8-inch needle.

{ "type": "p", "children": [], "text": "SUBLOCADE injection is available in dosage strengths of 100 mg/0.5 mL and 300 mg/1.5 mL buprenorphine. Each injection is a sterile, clear, colorless to yellow to amber solution provided in a single-dose, prefilled syringe with a 19 gauge 5/8-inch needle." }

SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of the ATRIGEL ®delivery system [see Warnings and Precautions ( 5.11)] .

{ "type": "p", "children": [], "text": "SUBLOCADE should not be administered to patients who have been shown to be hypersensitive to buprenorphine or any component of the ATRIGEL\n \n ®delivery system\n \n [see Warnings and Precautions (\n \n 5.11)]\n \n .\n\n " }

Intravenous injection presents significant risk of serious harm or death as SUBLOCADE forms a solid mass upon contact with body fluids. Occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, could result if administered intravenously [see Warnings and Precautions ( 5.2), Drug Abuse and Dependence ( 9.2)] . Do not administer intravenously, intramuscularly, or intradermally [see Warnings and Precautions ( 5.6)] .

SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program because of the risk of serious harm or death that could result from intravenous self-administration. The goal of the REMS is to mitigate serious harm or death that could result from intravenous self-administration by ensuring that healthcare settings and pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider for administration by a healthcare provider.

Notable requirements of the SUBLOCADE REMS Program include the following:

Further information is available at www.SublocadeREMS.com or call 1-866-258-3905.

SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor all patients for progression of opioid use disorder and addictive behaviors [see Drug Abuse and Dependence ( 9.2)] .

Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, postmarketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with SUBLOCADE [see Warnings and Precautions ( 5.5), Drug Interactions ( 7), Patient Counseling Information ( 17)].

Use SUBLOCADE with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression).

Due to its extended-release characteristics, if SUBLOCADE is discontinued as a result of compromised respiratory function, monitor patients for ongoing buprenorphine effects for several months.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Patient Counseling Information ( 17)] .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.7)] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver.

Because patients being treated for opioid use disorder have the potential for relapse, putting them at risk for opioid overdose, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with SUBLOCADE. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose [see Dosage and Administration ( 2.2)].

Advise patients and caregivers that naloxone may also be administered for a known or suspected overdose with buprenorphine itself. Higher than normal doses and repeated administration of naloxone may be necessary due to the long duration of action of buprenorphine and its affinity for the mu-opioid receptor [see Overdosage ( 10)] .

Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize respiratory depression and, if naloxone is prescribed, how to treat with naloxone. Emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered [see Patient Counseling Information ( 17)].

Concomitant use of buprenorphine and benzodiazepines or other CNS depressants increases the risk of adverse reactions including overdose, respiratory depression, and death. Medication-assisted treatment of opioid use disorder, however, should not be categorically denied to patients taking these drugs. Prohibiting or creating barriers to treatment can pose an even greater risk of morbidity and mortality due to the opioid use disorder alone.

As a routine part of orientation to buprenorphine treatment, educate patients about the risks of concomitant use of benzodiazepines, sedatives, opioid analgesics, and alcohol.

Develop strategies to manage use of prescribed or illicit benzodiazepines or other CNS depressants at initiation of buprenorphine treatment, or if it emerges as a concern during treatment. Adjustments to induction procedures and additional monitoring may be required. There is no evidence to support dose limitations or arbitrary caps of buprenorphine as a strategy to address benzodiazepine use in buprenorphine-treated patients. However, if a patient is sedated at the time of buprenorphine dosing, delay or omit the buprenorphine dose if appropriate.

Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use with buprenorphine.  In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate.

For patients in buprenorphine treatment, benzodiazepines are not the treatment of choice for anxiety or insomnia. Before co-prescribing benzodiazepines, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments to address anxiety or insomnia. Ensure that other healthcare providers prescribing benzodiazepines or other CNS depressants are aware of the patient's buprenorphine treatment and coordinate care to minimize the risks associated with concomitant use.

If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in buprenorphine treatment for opioid use disorder [see Warnings and Precautions ( 5.4)].

In addition, take measures to confirm that patients are taking their medications as prescribed and are not diverting or supplementing with illicit drugs. Toxicology screening should test for prescribed and illicit benzodiazepines [see Drug Interactions ( 7)] .

Injection site reactions are most commonly manifested by pain, erythema and pruritus. In some post-marketing case reports injection site reactions have involved abscess, ulceration, and necrosis. Some cases resulted in surgical depot removal, debridement, antibiotic administration, and SUBLOCADE discontinuation. The likelihood of serious injection site reactions may be increased with inadvertent intramuscular or intradermal administration. Carefully review injection technique [see Instructions for Use ( 2.5)] . Evaluate and treat serious injection site reactions as appropriate.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see Use in Specific Populations ( 8.1)] .

Advise pregnant women receiving opioid addiction treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1)] . This risk should be balanced against the risk of untreated opioid addiction which often results in continued or relapsing illicit opioid use and is associated with poor pregnancy outcomes. Therefore, prescribers should discuss the importance of management of opioid addiction throughout pregnancy.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation. The withdrawal syndrome is milder than that seen with full agonists and may be delayed in onset [see Drug Abuse and Dependence ( 9.3)] .

Withdrawal signs and symptoms were not observed in the month following discontinuation of SUBLOCADE. Considering the long half-life, any withdrawal signs and symptoms that may occur would be expected to be delayed [see Clinical Pharmacology ( 12.2)] . Model simulations indicate that steady-state buprenorphine plasma concentrations decreased slowly over time following the last injection and remained at therapeutic levels for 2 to 5 months on average, depending on the dosage administered (100 or 300 mg, respectively).

Patients who elect to discontinue treatment with SUBLOCADE should be monitored for withdrawal signs and symptoms. Consider transmucosal buprenorphine if needed to treat withdrawal after discontinuing SUBLOCADE.

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through postmarketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases, however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. In one subject in the SUBLOCADE clinical program, surgical removal was followed by improvement in liver enzymes.

Liver function tests, prior to initiation of treatment, are recommended to establish a baseline. Monthly monitoring of liver function during treatment, particularly with 300 mg maintenance dose, is also recommended. An etiological evaluation is recommended when a hepatic adverse event is suspected.

Cases of hypersensitivity to buprenorphine-containing products have been reported both in clinical trials and in the postmarketing experience. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. The most common signs and symptoms include rashes, hives, and pruritus. A history of hypersensitivity to buprenorphine is a contraindication to the use of SUBLOCADE [see Contraindications ( 4)] .

Because of the partial opioid agonist properties of buprenorphine, buprenorphine may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists if administered before the effects of the full opioid agonist have subsided, at least 6 hours for short-acting opioids (e.g., heroin, morphine) and 24 hours for long-acting opioids (e.g., methadone). Verify that patients have tolerated transmucosal buprenorphine before administering the first injection of SUBLOCADE.

While on SUBLOCADE, situations may arise where patients need acute pain management, or may require anesthesia. Treat patients receiving SUBLOCADE with a non-opioid analgesic whenever possible. Patients requiring opioid therapy for analgesia may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function. Higher doses may be required for analgesic effect. Therefore, a higher potential for toxicity exists with opioid administration. If opioid therapy is required as part of anesthesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure. The opioid therapy should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.

Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with SUBLOCADE [see Patient Counseling Information ( 17)] .

The above guidance should also be considered for any patient who has been treated with SUBLOCADE within the last 6 months.

There have been reported deaths of opioid naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet. SUBLOCADE is not appropriate for use in opioid naïve patients.

In a pharmacokinetic study with transmucosal buprenorphine, buprenorphine plasma levels were found to be higher and the half-life was found to be longer in subjects with moderate and severe hepatic impairment, but not in subjects with mild hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of SUBLOCADE has not been studied.

Because of the long-acting nature of the product, adjustments to dosages of SUBLOCADE are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly decreased, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with SUBLOCADE.

Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3)] .

Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing SUBLOCADE to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery especially during the first few days following treatment and dose adjustment. Buprenorphine plasma levels accumulate during the first two months and are maintained with the 100 mg maintenance dose; further accumulation occurs with the 300 mg maintenance dose, which achieves steady-state after the fourth monthly injection. Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities.

Buprenorphine may produce orthostatic hypotension in ambulatory patients.

Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of SUBLOCADE was evaluated in 848 opioid-dependent subjects (see Table 2). In these studies, there was a total of 557 subjects who received at least 6 monthly SC injections of SUBLOCADE and 138 subjects who received 12 monthly SC injections. Adverse events led to premature discontinuation in 4% of the group receiving SUBLOCADE compared with 2% in the placebo group (13-0001, NCT02357901).

In the Phase 3 open-label study (13-0003, NCT02510014), adverse events leading to drug dose reductions were reported in 7.3% of subjects receiving SUBLOCADE.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2 Total Subjects Exposed to SUBLOCADE</span> </caption> <col align="left" width="12.986%"/> <col align="left" width="12.998%"/> <col align="left" width="9.911%"/> <col align="left" width="12.823%"/> <col align="left" width="12.998%"/> <col align="left" width="11.774%"/> <col align="left" width="13.161%"/> <col align="left" width="13.348%"/> <tfoot> <tr class="First"> <td align="left" colspan="8" valign="top"> <p class="First Footnote">*Not included in total subjects exposed to SUBLOCADE</p> </td> </tr> <tr> <td align="left" colspan="8" valign="top"> <p class="First Footnote">† FLEX = 300 mg initial dose with an option to receive either 100 mg or 300 mg for subsequent dosing per clinician's discretion</p> </td> </tr> <tr class="Last"> <td align="left" colspan="8" valign="top"> <p class="First Footnote">‡ = Not included in total unique subjects exposed to SUBLOCADE, already accounted for in Study 13-0001 section of table</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" rowspan="2" valign="top"><span class="Bold">Study 13-0001 (NCT02357901)</span> <br/> <span class="Bold">Up to 6 Injections</span></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">Study 13-0003 (NCT02510014)</span></td><td align="center" class="Botrule Rrule Toprule" rowspan="3" valign="top"><span class="Bold">Total Subjects Exposed To</span> <br/> <span class="Bold">SUBLOCADE</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" colspan="3" valign="top"><span class="Bold">Roll-Over</span><span class="Bold"> <br/> </span><span class="Bold">Up to 6 Injections</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">De-Novo</span><span class="Bold"> <br/> </span><span class="Bold">Up to 12 Injections</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"><span class="Bold">SUBLOCADE 300/100 mg</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">SUBLOCADE 300/300 mg</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">Placebo</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">From SUBLOCADE 300/100 mg To</span><span class="Bold"> <br/> </span><span class="Bold">SUBLOCADE 300/Flex†</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">From SUBLOCADE 300/300 mg To</span><span class="Bold"> <br/> </span><span class="Bold">SUBLOCADE 300/Flex†</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">From Placebo</span><span class="Bold"> <br/> </span><span class="Bold">To</span><span class="Bold"> <br/> </span><span class="Bold">SUBLOCADE 300/Flex†</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">SUBLOCADE 300/Flex</span></td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="top">N = 203</td><td align="center" class="Botrule Rrule" valign="top">N = 201</td><td align="center" class="Botrule Rrule" valign="top">N = 100*</td><td align="center" class="Botrule Rrule" valign="top">N = 112‡</td><td align="center" class="Botrule Rrule" valign="top">N = 113‡</td><td align="center" class="Botrule Rrule" valign="top">N = 32</td><td align="center" class="Botrule Rrule" valign="top">N = 412</td><td align="center" class="Botrule Rrule" valign="top">N = 848</td> </tr> </tbody> </table></div>

Table 3shows the non-injection site-related adverse reactions (ADRs) for the groups receiving SUBLOCADE 300/300 mg (6 doses of 300 mg SC injections) 300/100 mg (300 mg SC injections for the first two doses followed by 4 doses of 100 mg SC injections) and placebo (volume-matched ATRIGEL ®delivery system subcutaneous injections) reported following administration in the 6 month, double-blind, placebo-controlled study. The systemic safety profile for SUBLOCADE, given by a healthcare provider in clinical trials, was consistent with the known safety profile of transmucosal buprenorphine. Common adverse reactions associated with buprenorphine included constipation, nausea, vomiting, abnormal liver enzymes, headache, sedation and somnolence. Dose dependent hepatic effects observed in the Phase 3, double-blind study (13-0001, NCT02357901) included the incidence of ALT more than 3 times the upper limit of normal (> 3 × ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300/300-mg, SUBLOCADE 300/100-mg, and placebo groups, respectively. The incidence of AST > 3 × ULN was 11.4%, 7.9%, and 1.0%, respectively. Adverse drug reactions [by MedDRA Preferred Terms (PT)] reported in at least 2% of subjects receiving SUBLOCADE are grouped by System Organ Class (SOC).

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 3 Adverse Reactions for Phase 3 Double-Blind Study: ≥ 2% of Subjects Receiving SUBLOCADE</span> </caption> <col align="left" width="60.875%"/> <col align="left" width="11.625%"/> <col align="left" width="13.750%"/> <col align="left" width="13.750%"/> <thead> <tr class="First"> <th align="center" class="Lrule Rrule Toprule" valign="bottom"><span class="Bold">System Organ Class</span> <br/> <span class="Bold">Preferred Term</span></th><th align="center" class="Rrule Toprule" valign="bottom"><span class="Bold">PLACEBO</span></th><th align="center" class="Rrule Toprule" valign="bottom"><span class="Bold">SUBLOCADE</span> <br/> <span class="Bold">300/100 mg</span></th><th align="center" class="Rrule Toprule" valign="bottom"><span class="Bold">SUBLOCADE</span> <br/> <span class="Bold">300/300 mg</span></th> </tr> <tr class="Last"> <th align="center" class="Botrule Lrule Rrule" valign="bottom"></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Count (%)</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Count (%)</span></th><th align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Count (%)</span></th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top"> <p class="First Footnote">*There were no cases of serious liver injury attributed to study drug.</p> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Total</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">N = 100</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">N = 203</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">N = 201</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Gastrointestinal disorders</span></td><td align="center" class="Botrule Rrule" valign="top">12 (12%)</td><td align="center" class="Botrule Rrule" valign="top">51 (25.1%)</td><td align="center" class="Botrule Rrule" valign="top">45 (22.4%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Constipation</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">19 (9.4)</td><td align="center" class="Botrule Rrule" valign="top">16 (8)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Nausea</td><td align="center" class="Botrule Rrule" valign="top">5 (5)</td><td align="center" class="Botrule Rrule" valign="top">18 (8.9)</td><td align="center" class="Botrule Rrule" valign="top">16 (8)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Vomiting</td><td align="center" class="Botrule Rrule" valign="top">4 (4)</td><td align="center" class="Botrule Rrule" valign="top">19 (9.4)</td><td align="center" class="Botrule Rrule" valign="top">11 (5.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">General disorders and administration site conditions</span></td><td align="center" class="Botrule Rrule" valign="top">17 (17%)</td><td align="center" class="Botrule Rrule" valign="top">40 (19.7%)</td><td align="center" class="Botrule Rrule" valign="top">49 (24.4%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Fatigue</td><td align="center" class="Botrule Rrule" valign="top">3 (3)</td><td align="center" class="Botrule Rrule" valign="top">8 (3.9)</td><td align="center" class="Botrule Rrule" valign="top">12 (6)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Investigations*</span></td><td align="center" class="Botrule Rrule" valign="top">2 (2%)</td><td align="center" class="Botrule Rrule" valign="top">21 (10.3%)</td><td align="center" class="Botrule Rrule" valign="top">19 (9.5%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Alanine aminotransferase increased (ALT)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">2 (1)</td><td align="center" class="Botrule Rrule" valign="top">10 (5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Aspartate aminotransferase increased (AST)</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">7 (3.4)</td><td align="center" class="Botrule Rrule" valign="top">9 (4.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Blood creatine phosphokinase increased (CPK)</td><td align="center" class="Botrule Rrule" valign="top">1 (1)</td><td align="center" class="Botrule Rrule" valign="top">11 (5.4)</td><td align="center" class="Botrule Rrule" valign="top">5 (2.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Gamma-glutamyl transferase increased (GGT)</td><td align="center" class="Botrule Rrule" valign="top">1 (1)</td><td align="center" class="Botrule Rrule" valign="top">6 (3)</td><td align="center" class="Botrule Rrule" valign="top">8 (4)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Nervous system disorders</span></td><td align="center" class="Botrule Rrule" valign="top">7 (7%)</td><td align="center" class="Botrule Rrule" valign="top">35 (17.2%)</td><td align="center" class="Botrule Rrule" valign="top">25 (12.4%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Headache</td><td align="center" class="Botrule Rrule" valign="top">6 (6)</td><td align="center" class="Botrule Rrule" valign="top">19 (9.4)</td><td align="center" class="Botrule Rrule" valign="top">17 (8.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Sedation</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">7 (3.4)</td><td align="center" class="Botrule Rrule" valign="top">3 (1.5)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Dizziness</td><td align="center" class="Botrule Rrule" valign="top">2 (2)</td><td align="center" class="Botrule Rrule" valign="top">5 (2.5)</td><td align="center" class="Botrule Rrule" valign="top">3 (1.5)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">     Somnolence</td><td align="center" class="Botrule Rrule" valign="top">0</td><td align="center" class="Botrule Rrule" valign="top">10 (4.9)</td><td align="center" class="Botrule Rrule" valign="top">4 (2)</td> </tr> </tbody> </table></div>

Table 4shows the injection site-related adverse events reported by ≥ 2 subjects in the Phase 3 studies. Most injection site adverse drug reactions (ADRs) were of mild to moderate severity, with one report of severe injection site pruritus. None of the injection site reactions were serious. One reaction, an injection site ulcer, led to study treatment discontinuation.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 4 Injection Site Adverse Drug Reactions Reported by ≥ 2 Subjects in the Phase 3 Studies</span> </caption> <col align="left" width="13.711%"/> <col align="left" width="10.933%"/> <col align="left" width="10.889%"/> <col align="left" width="9.744%"/> <col align="left" width="10.944%"/> <col align="left" width="10.944%"/> <col align="left" width="10.944%"/> <col align="left" width="10.944%"/> <col align="left" width="10.944%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="9" valign="top"> <p class="First Footnote">*Patients received SUBOXONE film for a run-in period before they switched to SUBLOCADE injection.</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" rowspan="3" valign="bottom"><span class="Bold">Preferred term, n (%)</span></td><td align="center" class="Botrule Rrule Toprule" colspan="3" rowspan="2" valign="middle"><span class="Bold">13-0001 (Ph3DB)</span></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">13-0003 (Ph3OL)</span></td><td align="center" class="Botrule Rrule Toprule" rowspan="2" valign="top"><span class="Bold">All <br/> Phase 3* </span></td> </tr> <tr> <td align="center" class="Botrule Rrule" colspan="3" valign="middle"><span class="Bold">Roll–over</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">De-novo</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">SUBLOCADE</span> <br/> <span class="Bold">300/300</span> <br/> <span class="Bold">(N = 201)</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">SUBLOCADE 300/100</span> <br/> <span class="Bold">(N = 203)</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo</span> <br/> <span class="Bold">(N = 100)</span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">SUBLOCADE 300 →</span> <br/> <span class="Bold">SUBLOCADE</span> <br/> <span class="Bold">300/Flex <br/> (N = 113) </span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">SUBLOCADE 100 →</span> <br/> <span class="Bold">SUBLOCADE</span> <br/> <span class="Bold">300/Flex <br/> (N = 112) </span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Placebo →</span> <br/> <span class="Bold">SUBLOCADE 300/Flex <br/> (N = 32) </span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">SUBLOCADE 300/Flex <br/> (N = 412) </span></td><td align="center" class="Botrule Rrule" valign="bottom"><span class="Bold">Total <br/> SUBLOCADE <br/> (N = 848) </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Subjects with any injection site reactions</td><td align="center" class="Botrule Rrule" valign="middle">38 (18.9%)</td><td align="center" class="Botrule Rrule" valign="middle">28 (13.8%)</td><td align="center" class="Botrule Rrule" valign="middle">9 (9.0%)</td><td align="center" class="Botrule Rrule" valign="middle">6 (5.3%)</td><td align="center" class="Botrule Rrule" valign="middle">13 (11.6%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (6.3%)</td><td align="center" class="Botrule Rrule" valign="middle">61 (14.8%)</td><td align="center" class="Botrule Rrule" valign="middle">140 (16.5%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site pain</td><td align="center" class="Botrule Rrule" valign="middle">12 (6.0%)</td><td align="center" class="Botrule Rrule" valign="middle">10 (4.9%)</td><td align="center" class="Botrule Rrule" valign="middle">3 (3.0%)</td><td align="center" class="Botrule Rrule" valign="middle">4 (3.5%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.8%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (6.3%)</td><td align="center" class="Botrule Rrule" valign="middle">33 (8.0%)</td><td align="center" class="Botrule Rrule" valign="middle">61 (7.2%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site pruritus</td><td align="center" class="Botrule Rrule" valign="middle">19 (9.5%)</td><td align="center" class="Botrule Rrule" valign="middle">13 (6.4%)</td><td align="center" class="Botrule Rrule" valign="middle">4 (4.0%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.8%)</td><td align="center" class="Botrule Rrule" valign="middle">6 (5.4%)</td><td align="center" class="Botrule Rrule" valign="middle">1 (3.1%)</td><td align="center" class="Botrule Rrule" valign="middle">17 (4.1%)</td><td align="center" class="Botrule Rrule" valign="middle">56 (6.6%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site erythema</td><td align="center" class="Botrule Rrule" valign="middle">6 (3.0%)</td><td align="center" class="Botrule Rrule" valign="middle">9 (4.4%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.9%)</td><td align="center" class="Botrule Rrule" valign="middle">4 (3.6%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">21 (5.1%)</td><td align="center" class="Botrule Rrule" valign="middle">40 (4.7%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site induration</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.9%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">7 (1.7%)</td><td align="center" class="Botrule Rrule" valign="middle">12 (1.4%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site bruising</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">2 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">6 (0.7%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site swelling</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">2 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.9%)</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.9%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.2%)</td><td align="center" class="Botrule Rrule" valign="middle">6 (0.7%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site discomfort</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">3 (0.7%)</td><td align="center" class="Botrule Rrule" valign="middle">5 (0.6%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site reaction</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">3 (2.7%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.2%)</td><td align="center" class="Botrule Rrule" valign="middle">5 (0.6%)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site cellulitis</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">2 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">3 (0.4%)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Injection site infection</td><td align="center" class="Botrule Rrule" valign="middle">1 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">1 (1.0%)</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">0</td><td align="center" class="Botrule Rrule" valign="middle">2 (0.5%)</td><td align="center" class="Botrule Rrule" valign="middle">3 (0.4%)</td> </tr> </tbody> </table></div>

Longer-term experience

In an interim analysis of the ongoing open-label long-term safety study (13-0003), safety was evaluated for up to 12 injections over the course of a year (see Table 2). Adverse events were reported for 432 of 669 subjects during the treatment period. The overall adverse event profile was similar to the double-blind trial described above.

Rapid Induction study

The proportion of patients who experienced an adverse event associated with opioid withdrawal was 31.4% in patients who received SUBLOCADE injection after an initial dose of transmucosal buprenorphine (rapid induction) and 25.1% in those who first received transmucosal buprenorphine for at least 7 days (standard induction). Three fentanyl positive patients in the rapid induction arm had serious adverse events associated with opioid withdrawal, and none in the standard induction arm.

The most frequently reported systemic postmarketing adverse event observed with buprenorphine sublingual tablets was drug misuse or abuse. The most frequently reported systemic postmarketing adverse event with buprenorphine/naloxone sublingual tablets and film was peripheral edema.

The following adverse reactions have been identified during post-approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome:Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency:Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis:Anaphylaxis has been reported with ingredients contained in SUBLOCADE.

Androgen deficiency:Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology ( 12.2)] .

Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 5includes clinically significant drug interactions with SUBLOCADE.

{ "type": "p", "children": [], "text": "\nTable 5includes clinically significant drug interactions with SUBLOCADE.\n\n " }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 5 Clinically Significant Drug Interactions</span> </caption> <col align="left" width="22.700%"/> <col align="left" width="77.300%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible. <br/> Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments <span class="Italics">[see Warnings and Precautions ( <a href="#s20">5.4</a>, <a href="#s22">5.5</a>)] </span>. <br/> If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder <span class="Italics">[see Warnings and Precautions ( <a href="#s20">5.4</a>)]. </span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Inhibitors of CYP3A4</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">The effects of co-administered CYP3A4 inhibitors on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. <br/> The concomitant use of sublingual buprenorphine and CYP3A4 inhibitors (e.g., ketoconazole) can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors [e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)] should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inhibitors, the patients should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, it may be necessary to remove the depot and treat the patient with a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inhibitor, and the concomitant medication is discontinued, the patient should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">The effects of co-administered CYP3A4 inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied. <br/> Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. <br/> CYP3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inducers, the patients should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inducer, and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if the dose provided by SUBLOCADE is excessive in the absence of the concomitant inducer, it may be necessary to remove the SUBLOCADE and treat the patient with a formulation of buprenorphine that permits dose adjustments <span class="Italics">[see Clinical Pharmacology ( <a href="#s83">12.3</a>)] </span>. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Rifampin, carbamazepine, phenytoin, phenobarbital</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and sublingual buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Patients who are on chronic treatment with SUBLOCADE should be monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Efavirenz, nevirapine, etravirine, delavirdine</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Antiretrovirals: Protease inhibitors (PIs)</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on sublingual buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine after sublingual administration, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with SUBLOCADE, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to remove the depot and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Atazanavir, ritonavir</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">None</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">If concomitant use is warranted, carefully monitor the patient for signs and symptoms of serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">The use of SUBLOCADE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Examples:</span></td><td align="left" class="Botrule Rrule" valign="top">Phenelzine, tranylcypromine, linezolid</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Monitor patients receiving muscle relaxants and SUBLOCADE for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#s7">2.2</a>), Warnings and Precautions ( <a href="#s20">5.4</a>, <a href="#s22">5.5</a>)] </span>. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Diuretics</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="2" valign="top"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Botrule Rrule" valign="top">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule" valign="top"><span class="Italics">Intervention:</span></td><td align="left" class="Botrule Rrule" valign="top">Monitor patients for signs of urinary retention or reduced gastric motility when SUBLOCADE is used concomitantly with anticholinergic drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 5 Clinically Significant Drug Interactions</span>\n</caption>\n<col align=\"left\" width=\"22.700%\"/>\n<col align=\"left\" width=\"77.300%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Similarly, cessation of other CNS depressants is preferred when possible. \n <br/> Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#s20\">5.4</a>,\n \n <a href=\"#s22\">5.5</a>)]\n \n </span>. \n <br/> If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder\n \n <span class=\"Italics\">[see Warnings and Precautions (\n \n <a href=\"#s20\">5.4</a>)].\n \n </span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The effects of co-administered CYP3A4 inhibitors on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied and the effects may be dependent on the route of administration; however, such interactions have been established in studies using transmucosal buprenorphine. Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. \n <br/> The concomitant use of sublingual buprenorphine and CYP3A4 inhibitors (e.g., ketoconazole) can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects.\n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors [e.g., azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease inhibitors (e.g., ritonavir, indinavir, and saquinavir)] should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inhibitors, the patients should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if signs and symptoms of buprenorphine toxicity or overdose occur but the concomitant medication cannot be reduced or discontinued, it may be necessary to remove the depot and treat the patient with a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inhibitor, and the concomitant medication is discontinued, the patient should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The effects of co-administered CYP3A4 inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied. \n <br/> Buprenorphine is metabolized to norbuprenorphine primarily by CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. \n <br/> CYP3A4 inducers may induce the metabolism of buprenorphine and, therefore, may cause increased clearance of the drug which could lead to a decrease in buprenorphine plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome.\n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inducers should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate. If patients already on SUBLOCADE require newly-initiated treatment with CYP3A4 inducers, the patients should be monitored for withdrawal. If the dose of SUBLOCADE is not adequate in the absence of the concomitant medication, and the concomitant medication cannot be reduced or discontinued, that patient should be transitioned back to a formulation of buprenorphine that permits dose adjustments. Conversely, if a patient has been stabilized on SUBLOCADE in the setting of concomitant medication that is a CYP3A4 inducer, and the concomitant medication is discontinued, the patient should be monitored for signs and symptoms of over-medication. Within 2 weeks of SUBLOCADE administration, if the dose provided by SUBLOCADE is excessive in the absence of the concomitant inducer, it may be necessary to remove the SUBLOCADE and treat the patient with a formulation of buprenorphine that permits dose adjustments\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#s83\">12.3</a>)]\n \n </span>.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Rifampin, carbamazepine, phenytoin, phenobarbital</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and sublingual buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Patients who are on chronic treatment with SUBLOCADE should be monitored for increase or decrease in therapeutic effects if NNRTIs are added to their treatment regimen.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Efavirenz, nevirapine, etravirine, delavirdine</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Antiretrovirals: Protease inhibitors (PIs)</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on sublingual buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine after sublingual administration, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving sublingual buprenorphine and atazanavir with and without ritonavir concomitantly.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">If treatment with atazanavir with and without ritonavir must be initiated in a patient already treated with SUBLOCADE, the patient should be monitored for signs and symptoms of over-medication. It may be necessary to remove the depot and treat the patient with a sublingual buprenorphine product that permits rapid dose adjustments.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Atazanavir, ritonavir</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">None</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">If concomitant use is warranted, carefully monitor the patient for signs and symptoms of serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The use of SUBLOCADE is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Monitor patients receiving muscle relaxants and SUBLOCADE for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, strongly consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#s7\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#s20\">5.4</a>,\n \n <a href=\"#s22\">5.5</a>)]\n \n </span>.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Botrule Rrule\" valign=\"top\">Monitor patients for signs of urinary retention or reduced gastric motility when SUBLOCADE is used concomitantly with anticholinergic drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

The data on use of buprenorphine, the active ingredient in SUBLOCADE, in pregnancy, are limited; however, these data do not indicate an increased risk of major malformations specifically due to buprenorphine exposure. There are limited data from randomized clinical trials in women maintained on buprenorphine that were not designed appropriately to assess the risk of major malformations [see Human Data] .

Observational studies have reported congenital malformations among buprenorphine‐exposed pregnancies, but were also not designed appropriately to assess the risk of congenital malformations specifically due to buprenorphine exposure [see Human Data] .

In animal reproduction studies with SUBLOCADE, SUBLOCADE administered subcutaneously to pregnant rats and rabbits during the period of organogenesis at a buprenorphine dose equivalent to 38 and 15 times, respectively, the maximum recommended human dose (MRHD) of 300 mg caused embryolethality, which appeared to be attributable primarily to the SUBLOCADE vehicle (ATRIGEL ®delivery system). In addition, reduced fetal body weights, increased visceral malformations and skeletal malformations were observed in rats and rabbits at buprenorphine doses equivalent to 38 and 15 times, respectively, the MRHD. These effects were also observed with the ATRIGEL ®delivery system alone, but the skeletal and visceral malformations in rat appear at least partially attributable to buprenorphine [see Animal Data] . Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

SUBLOCADE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Disease-associated maternal and embryo-fetal risk

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use.

Fetal/neonatal adverse reactions

Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving treatment with SUBLOCADE.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.7)] .

Labor or Delivery

Opioid-dependent women on buprenorphine maintenance therapy may require additional analgesia during labor. As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as naloxone should be available for reversal of opioid induced respiratory depression in the neonate.

Data

Human Data

Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine during pregnancy. Limited data on malformations from trials, observational studies, case series, and case reports on buprenorphine use in pregnancy do not indicate an increased risk of major malformations specifically due to buprenorphine. Pregnancy in an opioid dependent woman poses challenges to treating physicians and potential hazards for the fetus including control of illicit drug, nicotine and alcohol use, infections, premature birth, abortion, low birth weight, toxaemia, third trimester bleeding, malpresentation, puerperal morbidity, fetal distress, meconium aspiration, narcotic withdrawal, postnatal growth deficiency, microcephaly, (neuro-) developmental disorders and increased neonatal mortality.

A multicenter, double-blind, double-dummy, flexible-dose study in 175 pregnant women [Maternal Opioid Treatment: Human Experimental Research (MOTHER)] was conducted to study outcomes in neonates born to mothers using methadone or buprenorphine, including the number of neonates requiring treatment for NOWS, the Peak NOWS score, the total amount of morphine needed to treat NOWS, the length of hospital stay for neonates, and neonatal head circumference. The authors found that 18% of pregnant women in the methadone group and 33% in the buprenorphine group discontinued treatment over the course of the pregnancy. They reported no significant difference in the incidence of NOWS, but in the prenatally buprenorphine-exposed condition, the duration of treatment for NOWS was shorter, duration of hospital stays were shorter and the amount of morphine required was significantly less; however, methodological concerns limit the conclusions that may be made.

Animal Data

In an embryofetal development study in rats, SUBLOCADE administered subcutaneously to pregnant animals before mating and again on Gestation Day (GD) 7 during the period of organogenesis resulted in increased post-implantation loss, which correlated with higher mean number of resorptions and decreased number of viable fetuses per litter, and decreased mean fetal body weights at 900 mg/kg (approximately 38 times the maximum recommended human dose [MRHD] of 300 mg of SUBLOCADE on an AUC basis); however, similar effects were observed with an equivalent level of ATRIGEL ®delivery system alone, indicating they may be attributable to the vehicle. Dose-related increases in incidences of skeletal malformations of the head and visceral malformations were observed with SUBLOCADE with significant changes at 900 mg/kg (approximately 38 times the MRHD on an AUC basis). Although similar effects were observed with equivalent levels of ATRIGEL ®delivery system, the incidence of skeletal malformations, primarily skull malformations, was higher in the SUBLOCADE groups suggesting that buprenorphine contributed to the increased incidence. Based on these results, the NOAEL for developmental toxicity was approximately 15 times the MRHD on an AUC basis.

In an embryofetal development study in rabbits, administration of a single subcutaneous injection of SUBLOCADE to pregnant animals on GD 7 during the period of organogenesis resulted an increased litter incidence of skeletal malformations at 155 mg/kg (approximately 7 times the MRHD on an AUC basis), which appear to be buprenorphine-related adverse effects. There was also an increased litter incidence of external malformations, visceral, and skeletal malformations and variations at 390 mg/kg SUBLOCADE (approximately 15 times the MRHD on an AUC basis); however, similar effects were observed with an equivalent level of the ATRIGEL ®delivery system, indicating they may be attributable to the vehicle. In addition, increased post-implantation loss, which correlated with increased mean number of resorptions and decreased mean number of viable fetuses, and decreased fetal body weights were observed at 390 mg/kg (approximately 15 times the MRHD on an AUC basis); however, similar findings were also observed with an equivalent level of the ATRIGEL ®delivery system alone. Based on these results, the NOAEL for developmental toxicity for SUBLOCADE was 78 mg/kg (approximately 2 times the MRHD on an AUC basis).

In a pre- and postnatal development study in rats, SUBLOCADE was administered subcutaneously to pregnant animals once during implantation (on GD 7) and once during weaning (on Lactation Day 7). There were no adverse effects on offspring survival, sexual maturation, behavioral assessment, or reproductive performance at up to 300 mg/kg (approximately 15 times the MRHD on an AUC basis).

Risk Summary

Based on two studies in 13 lactating women maintained on buprenorphine treatment, buprenorphine and its metabolite norbuprenorphine are present in low levels in human milk and infant urine. Available data have not shown adverse reactions in breastfed infants. Caution should be exercised when SUBLOCADE is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SUBLOCADE and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

Clinical Considerations

Advise breastfeeding women taking buprenorphine products to monitor the infant for increased drowsiness and breathing difficulties.

Data

Data were consistent from two studies (N=13) of breastfeeding infants whose mothers were maintained on sublingual doses of buprenorphine ranging from 2.4 to 24 mg/day, showing that the infants were exposed to less than 1% of the maternal daily dose.

In a study of six lactating women who were taking a median sublingual buprenorphine dose of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk provided a median infant dose of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, equal to 0.2% and 0.12%, respectively, of the maternal weight-adjusted dose (relative dose/kg (%) of norbuprenorphine was calculated from the assumption that buprenorphine and norbuprenorphine are equipotent).

Data from a study of seven lactating women who were taking a median sublingual buprenorphine dose of 7 mg/day an average of 1.12 months after delivery indicated that the mean milk concentrations (C avg) of buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the study data, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed infant would receive an estimated mean absolute infant dose (AID) of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of norbuprenorphine, or a mean relative infant dose (RID) of 0.38% and 0.18%, respectively, of the maternal weight-adjusted dose.

Human Data

Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2)] .

Animal Data

Infertility

Male

Male fertility may be reduced based on animal data demonstrating adverse effects of SUBLOCADE on sperm parameters [see Nonclinical Toxicology ( 13.1)].

The safety and effectiveness of SUBLOCADE have not been established in pediatric patients.

Clinical studies of SUBLOCADE did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently than younger subjects. Other reported clinical experience with buprenorphine has not identified differences in responses between geriatric and younger patients.

Due to possible decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in geriatric patients, the decision to prescribe SUBLOCADE should be made cautiously in individuals 65 years of age or older and these patients should be monitored for signs and symptoms of toxicity or overdose.

The effect of hepatic impairment on the pharmacokinetics of SUBLOCADE has not been studied.

The effect of hepatic impairment on the pharmacokinetics of sublingual buprenorphine has been evaluated in a pharmacokinetic study. While no clinically significant changes have been observed in subjects with mild hepatic impairment, the plasma levels have been shown to be higher and half-life values have been shown to be longer for buprenorphine in subjects with moderate and severe hepatic impairment.

Because of the long-acting nature of the product, adjustments to dosages of SUBLOCADE are not rapidly reflected in plasma buprenorphine levels. Because buprenorphine levels cannot be rapidly adjusted, patients with pre-existing moderate to severe hepatic impairment are not candidates for treatment with SUBLOCADE.

Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine. If signs and symptoms of toxicity or overdose occur within 2 weeks of SUBLOCADE administration, removal of the depot may be required [see Dosage and Administration ( 2.7), Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.3)] .

Clinical studies of SUBLOCADE did not include subjects with renal impairment. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine.

SUBLOCADE contains buprenorphine, a Schedule III substance under the Controlled Substances Act.

SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused similar to other opioids. Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be provided with or referred for more intensive and structured treatment. Abuse of buprenorphine poses a risk of overdose and death. This risk is increased with the abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

SUBLOCADE is distributed through a restricted distribution system, which is intended to prevent the direct distribution to a patient. SUBLOCADE should only be dispensed directly to a healthcare provider for administration by a healthcare provider. It is supplied in prefilled syringes and is intended for administration only by subcutaneous injection by a healthcare provider. The entire contents of the prefilled syringe should be administered. After administration, a small amount (approximately 0.1 mL) of SUBLOCADE will remain in the needle and syringe and should be properly disposed of [see How Supplied/Storage and Handling ( 16)] .

SUBLOCADE is injected as a liquid, and the subsequent precipitation of the poly (DL-lactide-co-glycolide) polymer creates a solid depot which contains buprenorphine. After initial formation of the depot, buprenorphine is released via diffusion from, and the biodegradation of, the depot. Clinical monitoring for evidence at the injection site of tampering or attempting to remove the depot should be ongoing throughout treatment. No accounts of subjects removing or attempting to remove the depot after administration of SUBLOCADE were reported in premarketing studies.

Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms upon abrupt discontinuation. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset [see Warnings and Precautions ( 5.12)] .

Due to the long-acting nature of SUBLOCADE, withdrawal signs and symptoms may not be evident immediately following the discontinuation of treatment.

Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy [see Warnings and Precautions ( 5.7)] .

Clinical Presentation

The manifestations of acute buprenorphine overdose include pinpoint pupils, sedation, hypotension, hypoglycemia, respiratory depression, and death.

Treatment of Overdose

In the event of overdose, the respiratory and cardiac status of the patient should be monitored carefully. When respiratory or cardiac functions are depressed, primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Oxygen, IV fluids, vasopressors, and other supportive measures should be considered as indicated. Naloxone may be of value for the management of buprenorphine overdose. Higher than normal doses and repeated administration may be necessary.

Clinicians should consider the potential role and contribution of buprenorphine, other opioids, and other CNS depressant drugs in a patient's clinical presentation. Clinical data are limited with regards to the possible surgical removal of the depot. Two cases of surgical removal were reported in premarketing clinical studies.

SUBLOCADE (buprenorphine extended-release) injection is a clear, viscous, colorless to yellow to amber, sterile solution for subcutaneous injection only. It is designed to deliver buprenorphine at a controlled rate over a one month period.

{ "type": "p", "children": [], "text": "SUBLOCADE (buprenorphine extended-release) injection is a clear, viscous, colorless to yellow to amber, sterile solution\n \n for subcutaneous injection only. It is designed to deliver buprenorphine at a controlled rate over a one month period.\n\n " }

The active ingredient in SUBLOCADE is buprenorphine free base, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist.

{ "type": "p", "children": [], "text": "The active ingredient in SUBLOCADE is buprenorphine free base, a mu-opioid receptor partial agonist and a kappa-opioid receptor antagonist." }

Buprenorphine is dissolved in the ATRIGEL ®delivery system at 18% by weight.

{ "type": "p", "children": [], "text": "Buprenorphine is dissolved in the ATRIGEL\n \n ®delivery system at 18% by weight.\n\n " }

The ATRIGEL ®delivery system is a biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent, N-methyl-2-pyrrolidone (NMP).

{ "type": "p", "children": [], "text": "The ATRIGEL\n \n ®delivery system is a biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent,\n \n N-methyl-2-pyrrolidone (NMP).\n\n " }

SUBLOCADE is provided in dosage strengths of 100 mg and 300 mg. Table 6presents the delivered amounts of the raw materials and the approximate delivered volume for the two dosage strengths.

{ "type": "p", "children": [], "text": "SUBLOCADE is provided in dosage strengths of 100 mg and 300 mg.\n \n Table 6presents the delivered amounts of the raw materials and the approximate delivered volume for the two dosage strengths.\n\n " }

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 6 Amounts of Raw Materials and Delivered Volume for the Dosage Strengths</span> </caption> <col align="left" width="44.733%"/> <col align="left" width="27.633%"/> <col align="left" width="27.633%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">Raw Materials in SUBLOCADE</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">100 mg Dosage</span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">300 mg Dosage</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Buprenorphine</td><td align="center" class="Botrule Rrule" valign="top">100 mg</td><td align="center" class="Botrule Rrule" valign="top">300 mg</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">Poly(DL-lactide-co-glycolide)</td><td align="center" class="Botrule Rrule" valign="top">178 mg</td><td align="center" class="Botrule Rrule" valign="top">533 mg</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Italics">N</span>-methyl-2-pyrrolidone </td><td align="center" class="Botrule Rrule" valign="top">278 mg</td><td align="center" class="Botrule Rrule" valign="top">833 mg</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">Approximate Delivered Volume</td><td align="center" class="Botrule Rrule" valign="top">0.5 mL</td><td align="center" class="Botrule Rrule" valign="top">1.5 mL</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n<span>Table 6 Amounts of Raw Materials and Delivered Volume for the Dosage Strengths</span>\n</caption>\n<col align=\"left\" width=\"44.733%\"/>\n<col align=\"left\" width=\"27.633%\"/>\n<col align=\"left\" width=\"27.633%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">Raw Materials in SUBLOCADE</span></td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">100 mg Dosage</span></td><td align=\"center\" class=\"Botrule Rrule Toprule\" valign=\"top\"><span class=\"Bold\">300 mg Dosage</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Buprenorphine</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">100 mg</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">300 mg</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Poly(DL-lactide-co-glycolide)</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">178 mg</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">533 mg</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\"><span class=\"Italics\">N</span>-methyl-2-pyrrolidone\n \n </td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">278 mg</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">833 mg</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" valign=\"top\">Approximate Delivered Volume</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">0.5 mL</td><td align=\"center\" class=\"Botrule Rrule\" valign=\"top\">1.5 mL</td>\n</tr>\n</tbody>\n</table></div>" }

The molecular weight of buprenorphine free base is 467.6, and its molecular formula is C 29H 41NO 4. Chemically, buprenorphine is (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol. The structural formula is:

{ "type": "p", "children": [], "text": "The molecular weight of buprenorphine free base is 467.6, and its molecular formula is C\n \n 29H\n \n 41NO\n \n 4. Chemically, buprenorphine is (2S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol. The structural formula is:\n\n " }

SUBLOCADE Injection contains buprenorphine. Buprenorphine is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.

Mu-Opioid Receptor Occupancy and Association With Opioid Blockade

In a Positron Emission Tomography (PET) study with SUBLOCADE in 2 subjects (one subject receiving 200 mg subcutaneous injections and one subject receiving 300 mg subcutaneous injections) with opioid use disorder, 75 to 92% occupancy of the mu-opioid receptors in the brain was maintained for 28 days following the last dose under steady-state conditions.

The opioid blockade study evaluated the blockade of subjective opioid effects, pharmacokinetics (PK) and safety of subcutaneous injections of SUBLOCADE. Stabilization doses of SL buprenorphine prior to injection of SUBLOCADE failed to provide full blockade of subjective effects of hydromorphone 18 mg IM. After SUBLOCADE injections at Weeks 0 and 4, on average, subjective effects of both 6 mg and 18 mg doses of hydromorphone were blocked; however, wide variability was seen across subjects. Complete blockade continued throughout the 8 weeks of observation that followed the 2 ndSUBLOCADE injection [see Clinical Studies ( 14.1)] .

Figure 10illustrates the relationship between buprenorphine plasma level and drug liking after 18 mg hydromorphone IM.

Figure 10 Drug Liking VAS vs. Plasma Buprenorphine Concentration Following 18 mg Hydromorphone Challenges

Exposure-response relationships were assessed for illicit opioid use, based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, and withdrawal symptoms using data obtained from 489 opioid dependent patients in the double-blind Phase 3 Study (13-0001).

The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 ng/mL for illicit opioid use and 4 ng/mL for opioid withdrawal symptoms.

Population PK/PD modeling indicated that patients using opioids by the injectable route at baseline may require higher buprenorphine exposure compared to patients not using opioids by the injectable route at baseline.

Cardiac Electrophysiology

Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of SUBLOCADE on the QT interval in five clinical studies including the Phase 3 study. In a Phase 3 study, seven patients had an increase from baseline QTc greater than 60 msec at any time [2/203 patients (1.0%) in the 300 mg/100 mg group and 5/201 patients (2.0%) in the 300 mg/300 mg group] and one patient in the 300 mg/300 mg group was found to have a QTc greater than 500 msec. These QTc findings were all sporadic and transient and none led to aberrant ventricular rhythm. Review of ECG and adverse event data provided no evidence for syncope, seizure, or ventricular tachycardia or fibrillation.

Physiological Effects

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses have been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O 2saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed. The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O 2saturation to the same degree.

In clinical studies conducted with SUBLOCADE at doses ranging from 50 to 300 mg, no incidences of temperature elevations, or clinically significant lowering of oxygen saturation were observed.

Androgen Deficiency 

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

Pharmacodynamic Interaction with Fentanyl

An open-label, cross-over study was conducted in 8 opioid-tolerant subjects to assess the ability of intravenous buprenorphine to prevent respiratory depression associated with high doses of fentanyl administered in a clinical setting. Opioid-tolerant subjects were medically stable and taking oral morphine equivalents of ≥ 90 mg daily with no other CNS depressant use. Buprenorphine infusions at three dose levels and placebo infusions were administered, followed by up to four doses of fentanyl. The three intravenous buprenorphine dose levels were designated as low (0.25 mg/70kg bolus + 0.1 mg/70kg/hr), mid (0.5 mg/70kg bolus + 0.2 mg/70kg/hr), and high (1.25 mg/70kg bolus + 0.5 mg/70kg/hr). The low, mid, and high buprenorphine dose levels produced average plasma concentrations (from 2 hours to 6 hours after infusion onset) of 1.06 ng/mL, 2.26 ng/mL, and 6.04 ng/mL, respectively.

Escalating intravenous fentanyl boluses of 0.25, 0.35, 0.50 and 0.70 mg/70 kg (up to a maximum cumulative dose of 1.8 mg/70 kg) were administered over 90 seconds at + 2hr, + 3hr, + 4hr and + 5hr after the start of intravenous infusion of buprenorphine or placebo. Apnea events after each fentanyl bolus are shown in Figure 11. Four of the 8 subjects in the placebo infusion groups discontinued prior to the fourth fentanyl bolus because of apnea (2 after the second bolus and 2 after the third bolus); 3 of the remaining 4 subjects experienced apnea after the fourth fentanyl dose. All 8 subjects in the buprenorphine infusion groups completed the fentanyl boluses and 2 of the 8 experienced apnea.

Figure 11 Occurrence of Apnea Events After Fentanyl Doses in a Pharmacodynamic Interaction Study

There were 2 opioid-tolerant subjects in the low intravenous buprenorphine (BUP) group (Arm A), 3 in the mid BUP group (Arm B), and 3 in the high BUP group (Arm C). The numbers in parentheses represent the geometric mean of buprenorphine plasma concentrations in each group from 2 hours to 6 hours after infusion onset. The escalating fentanyl doses 1 to 4 were 0.25, 0.35, 0.50 and 0.70 mg/70 kg body weight. The same subject in the low BUP group had apnea after the third and fourth fentanyl boluses.

Absorption

The pharmacokinetics (PK) of buprenorphine following subcutaneous injection of SUBLOCADE was evaluated in subjects with opioid use disorder after single doses (50 mg to 200 mg) and repeated doses (50 to 300 mg) separated by 28 days for up to 12 injections.

After SUBLOCADE injection, an initial buprenorphine peak was observed and the median T maxoccurred at 24 hours after injection. After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly to a plateau. Steady-state was achieved at 4-6 months.

Mean buprenorphine plasma concentrations levels for C avg, C maxand C troughat steady-state are presented in Table 7for SUBLOCADE in comparison to daily transmucosal buprenorphine.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 7 Comparison of Steady-state Buprenorphine Plasma Exposure Between Daily Transmucosal Buprenorphine and Once Monthly SUBLOCADE at Trough (C <span class="Sub">trough</span>), Average (C <span class="Sub">avg</span>) and Peak (C <span class="Sub">max</span>) Levels (Geometric Mean (CV%)) </span> </caption> <col align="left" width="19.286%"/> <col align="left" width="14.371%"/> <col align="left" width="13.200%"/> <col align="left" width="13.214%"/> <col align="left" width="13.214%"/> <col align="left" width="13.357%"/> <col align="left" width="13.357%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"><span class="Bold">Pharmacokinetic parameters</span></td><td align="center" class="Botrule Rrule Toprule" colspan="4" valign="middle"><span class="Bold">Transmucosal Buprenorphine</span></td><td align="center" class="Botrule Rrule Toprule" colspan="2" valign="middle"><span class="Bold">SUBLOCADE</span></td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">8 mg</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">12 mg</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">16 mg</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">24 mg</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">100 mg</span></td><td align="center" class="Botrule Rrule" valign="middle"><span class="Bold">300 mg</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">C <span class="Sub">avg,ss</span>(ng/mL) </td><td align="center" class="Botrule Rrule" valign="middle">1.37 <br/> (40) </td><td align="center" class="Botrule Rrule" valign="middle">1.79 <br/> (40) </td><td align="center" class="Botrule Rrule" valign="middle">2.16 <br/> (40) </td><td align="center" class="Botrule Rrule" valign="middle">2.84 <br/> (40) </td><td align="center" class="Botrule Rrule" valign="middle">2.87 <br/> (32) </td><td align="center" class="Botrule Rrule" valign="middle">6.32 <br/> (32) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle">C <span class="Sub">max,ss</span>(ng/mL) </td><td align="center" class="Botrule Rrule" valign="middle">4.27 <br/> (45) </td><td align="center" class="Botrule Rrule" valign="middle">5.60 <br/> (45) </td><td align="center" class="Botrule Rrule" valign="middle">6.77 <br/> (45) </td><td align="center" class="Botrule Rrule" valign="middle">8.86 <br/> (45) </td><td align="center" class="Botrule Rrule" valign="middle">5.10 <br/> (33) </td><td align="center" class="Botrule Rrule" valign="middle">11.81 <br/> (35) </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule" valign="middle">C <span class="Sub">trough,ss</span>(ng/mL) </td><td align="center" class="Botrule Rrule" valign="middle">0.66 <br/> (63) </td><td align="center" class="Botrule Rrule" valign="middle">0.87 <br/> (63) </td><td align="center" class="Botrule Rrule" valign="middle">1.04 <br/> (61) </td><td align="center" class="Botrule Rrule" valign="middle">1.37 <br/> (62) </td><td align="center" class="Botrule Rrule" valign="middle">2.46 <br/> (40) </td><td align="center" class="Botrule Rrule" valign="middle">5.47 <br/> (39) </td> </tr> </tbody> </table></div>

At steady state, buprenorphine plasma concentrations achieved with 100 mg monthly dosing are contained within the range obtained with transmucosal treatment; peak concentrations with SUBLOCADE may be lower, while average and trough concentrations may be higher. Potential differences in steady state levels need to be taken into consideration when transitioning a patient established on long term treatment with transmucosal buprenorphine to SUBLOCADE.

Distribution

Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.

Elimination

Buprenorphine is metabolized and eliminated in urine and feces. The apparent terminal plasma half-life of buprenorphine following subcutaneous injection of SUBLOCADE ranged between 43 to 60 days as a result of the slow release of buprenorphine from the subcutaneous depot.

A study assessing buprenorphine exposure 22 to 38 months following the last SUBLOCADE injection indicated that buprenorphine could potentially be detected in plasma and urine over that time period. Concentrations in urine were more variable than in plasma and generally higher depending on the test used. Hence, it is expected that buprenorphine will be detected in patients for a longer time in urine than in plasma.

Metabolism

Buprenorphine is metabolized to its major metabolite, norbuprenorphine, primarily by CYP3A4. Norbuprenorphine can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been studied clinically for opioid-like activity. Norbuprenorphine steady-state plasma concentrations in humans after subcutaneous injection of SUBLOCADE are low compared to buprenorphine (AUC norbuprenorphine/buprenorphine ratio of 0.20 to 0.40).

Excretion

A mass balance study of buprenorphine administered by IV infusion in humans showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine were conjugated (buprenorphine: 1% free and 9.4% conjugated; norbuprenorphine: 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine: 33% free and 5% conjugated; norbuprenorphine: 21% free and 2% conjugated).

Drug Interaction Studies

CYP3A4 Inhibitors and Inducers

The effects of co-administered CYP3A4 inhibitors and inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied; however, such interactions have been established in studies using transmucosal buprenorphine. The effects of buprenorphine may be dependent on the route of administration.

Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, potential interactions may occur when SUBLOCADE is given concurrently with agents that affect CYP3A4 activity. The effects of co-administered CYP3A4 inducers or inhibitors have been established in studies using transmucosal buprenorphine. Patients who transfer to SUBLOCADE treatment from a regimen of transmucosal buprenorphine used concomitantly with CYP3A4 inhibitors (e.g., ketoconazole), macrolide antibiotics (e.g., erythromycin), or HIV protease inhibitors, or CYP3A4 inducer (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) should be monitored to ensure that the plasma buprenorphine level provided by SUBLOCADE is adequate and not excessive [see Drug Interactions ( 7)].

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, the plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic SUBLOCADE doses are not expected to significantly affect metabolism of other co-medications.

Specific Populations

Based on population pharmacokinetic analyses, age, sex, and race do not have a clinically meaningful effect on PK of SUBLOCADE.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of SUBLOCADE has not been studied. However, the effect of hepatic impairment on the PK of buprenorphine has been evaluated in a study using 2 mg/0.5 mg buprenorphine/naloxone sublingual tablet in subjects with various degrees of hepatic impairment as indicated by Child-Pugh criteria. While no clinically relevant changes were observed in subjects with mild hepatic impairment, buprenorphine plasma exposure was increased by 64% and 181% in subjects with moderate and severe hepatic impairment, respectively, compared to healthy subjects [see Use in Specific Populations ( 8.6)] .

Renal Impairment

The effect of renal impairment on the pharmacokinetics of SUBLOCADE has not been studied. Clinical studies of SUBLOCADE did not include subjects with severe renal impairment.

Less than 1% is excreted as unchanged buprenorphine in urine following IV buprenorphine administration. No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 6 normal patients following IV administration of 0.3 mg buprenorphine [see Use in Specific Populations ( 8.7)] .

Population PK analyses indicated no notable relationship between creatinine clearance and steady-state buprenorphine plasma concentrations.

HCV infection

In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean C max, AUC 0-last, and half-life values of buprenorphine were not clinically significant in comparison to healthy subjects without HCV infection. No dose adjustment is needed in patients with HCV infection.

Carcinogenicity

Long-term studies in animals performed to evaluate carcinogenic potential of SUBLOCADE have not been conducted. However, the carcinogenic potential of the active drug substance in SUBLOCADE, buprenorphine, has been evaluated in Sprague-Dawley rats and CD-1 mice.

In the carcinogenicity study conducted in Sprague-Dawley rats, buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day (approximately 0.5, 5, and 50 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine) for 27 months. A statistically significant dose-related increase in Leydig cell tumors occurred. In an 86 week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (approximately 45 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine).

N-methyl-2-pyrrolidone [NMP], an excipient in SUBLOCADE, produced an increase in hepatocellular adenomas and carcinomas in male and female mice at 6 and 8 times the maximum daily dose (MDD) of NMP via SUBLOCADE. The clinical significance of these findings is unclear. No tumors were noted at 1 and 1.3 times the MDD. In 2-year inhalation and dietary studies in rats, NMP did not result in evidence of carcinogenicity.

Mutagenicity

No evidence of mutagenic potential for subcutaneous SUBLOCADE was found in in vivosubcutaneous micronucleus test using rats' marrow.

Mutagenic potential for buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast ( S. cerevisiae) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets ( E. coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivoand in vitroincorporation of [3H]thymidine, and positive in unscheduled DNA synthesis test using testicular cells from mice.

Impairment of Fertility

In a fertility study in rats, SUBLOCADE or ATRIGEL ®was administered every 28 days for 3 months (males) or once before mating and once on GD 7; female mating, fertility, and fecundity indices were unaffected by the subcutaneous administration of SUBLOCADE up to 900 mg/kg buprenorphine (approximately 38 times the maximum recommended human dose [MRHD] of 300 mg on an AUC basis). However, higher mean post-implantation loss was observed with SUBLOCADE at 900 mg/kg buprenorphine and at an equivalent level of ATRIGEL ®alone, which correlated with higher mean number of resorptions and reduced mean number of viable fetuses/litter size. Mean gravid uterine weight and mean final body weight were lower with SUBLOCADE at 900 mg/kg buprenorphine and an equivalent level of the ATRIGEL ®alone, and correlated with higher mean number of resorptions and lower fetal body weights. The NOAEL for female fertility was 900 mg/kg and the NOAEL for female-mediated developmental parameters was 600 mg/kg (approximately 25 times the MRHD on an AUC basis).

Male fertility and reproduction indices were lower as evidenced by abnormal sperm parameters (low motility, low mean number of sperm, and higher percentage of abnormal sperm) with SUBLOCADE at 600 mg/kg and with an equivalent level of ATRIGEL ®. The NOAEL for male fertility parameters, including sperm analysis, and male-mediated developmental parameters was 300 mg/kg (approximately 32 times the MRHD on an AUC basis).

The opioid blockade study evaluated the blockade of subjective opioid effects, PK and safety of subcutaneous injections of SUBLOCADE in 39 subjects with OUD (not treatment-seeking).

The peak (E max) effect of “Drug Liking” Visual Analog Scale (VAS) measurement after challenge with IM injections of 6 mg and 18 mg hydromorphone (HM) was not inferior (i.e., shown to be not substantially more likeable) compared to the E maxof “Drug Liking” VAS measured after challenge with placebo (at weeks 1 through 4 following the first injection of 300 mg SUBLOCADE). The noninferiority (NI) margin, the largest difference allowed for the 6 or 18 mg HM VAS to exceed the placebo VAS (the maximum VAS recorded following IM injection of 0 mg HM) before being considered significant, was set at 20. Based on comparison to the historical response to opioid agonists in unblocked subjects, a difference of less than 20 points (on a unipolar scale) between the mean maximum response to hydromorphone and the mean maximum placebo response for the same challenge was considered to indicate near-complete blockade.

All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg following SUBLOCADE injections. However, wide variation can be seen in isolated measurements from individual subjects, shown in the figure below. For comparison, stabilization doses of SL buprenorphine in Week 0 failed to provide full blockade to 18 mg of HM. Complete blockade continued throughout the 8 weeks of observation that followed the 2 ndSUBLOCADE injection.

Figure 12 Median (95% Confidence Interval) of Placebo-Corrected Drug-Liking Scores by Hydromorphone Dose and by Week

The efficacy of SUBLOCADE for the treatment of opioid use disorder was evaluated in a Phase 3, 24- week, randomized, double-blind, placebo-controlled, multicenter trial in treatment-seeking patients who met the DSM-5 criteria for moderate or severe opioid use disorder. Patients were randomized to one of following dosing regimens: 6 once-monthly 300 mg doses, 2 once-monthly 300 mg doses followed by 4 once-monthly 100 mg doses, or 6 once-monthly subcutaneous injections of placebo. All doses were administered by a physician or suitably qualified designee and were separated by 28 ± 2 days. In addition to study medication, all subjects received manual-guided psychosocial support at least once a week (Individual Drug Counseling = IDC).

Prior to the first dose, treatment was initiated with SUBOXONE ®(buprenorphine/naloxone) sublingual film (SUBOXONE SL Film); doses were adjusted from 8/2 mg to 24/6 mg per day over a period of 7-14 days. Patients were randomized to SUBLOCADE injection or placebo after cravings and withdrawal symptoms were clinically controlled. After randomization, supplemental dosing with SUBOXONE SL Film was not permitted during the study.

Efficacy was evaluated over Weeks 5 through 24 based on weekly urine drug screens combined with self-reported use of illicit opioid use. A “grace period” was applied for Weeks 1 through 4 to allow patients to stabilize in treatment. During this period, opioid use, if it occurred, was not considered in the analysis. Missing urine drug screen samples and/or self-reports during Weeks 5-24 were counted as positive for illicit opioids.

A total of 504 patients were randomized 4:4:1:1 [203 subjects in the 300 mg/100 mg group, 201 patients in the 300 mg/300 mg group and 100 patients in the placebo group (2 groups of volume-matched placebo)]. Patient demographics and baseline characteristics are provided in Table 8.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 8 Patient Demographics and Baseline Characteristics</span> </caption> <col align="left" width="47.100%"/> <col align="left" width="18.300%"/> <col align="left" width="18.300%"/> <col align="left" width="16.300%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">SUBLOCADE 300/100 mg % <br/> (N = 194) </span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">SUBLOCADE 300/300 mg % <br/> (N = 196) </span></td><td align="center" class="Botrule Rrule Toprule" valign="top"><span class="Bold">Placebo % <br/> <br/> (N = 99) </span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Mean Age (years)</span></td><td align="center" class="Botrule Rrule" valign="top">40.4</td><td align="center" class="Botrule Rrule" valign="top">39.3</td><td align="center" class="Botrule Rrule" valign="top">39.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Sex</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Male</td><td align="center" class="Botrule Rrule" valign="top">66.0</td><td align="center" class="Botrule Rrule" valign="top">67.3</td><td align="center" class="Botrule Rrule" valign="top">64.6</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Female</td><td align="center" class="Botrule Rrule" valign="top">34.0</td><td align="center" class="Botrule Rrule" valign="top">32.7</td><td align="center" class="Botrule Rrule" valign="top">35.4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Race or Ethnicity</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     White</td><td align="center" class="Botrule Rrule" valign="top">68.0</td><td align="center" class="Botrule Rrule" valign="top">71.4</td><td align="center" class="Botrule Rrule" valign="top">77.8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Black or African American</td><td align="center" class="Botrule Rrule" valign="top">28.9</td><td align="center" class="Botrule Rrule" valign="top">27.6</td><td align="center" class="Botrule Rrule" valign="top">20.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Hispanic or Latino</td><td align="center" class="Botrule Rrule" valign="top">6.2</td><td align="center" class="Botrule Rrule" valign="top">9.2</td><td align="center" class="Botrule Rrule" valign="top">10.1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Substance Use At Screening</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Opioid Use - Injectable Route</td><td align="center" class="Botrule Rrule" valign="top">43.3</td><td align="center" class="Botrule Rrule" valign="top">40.8</td><td align="center" class="Botrule Rrule" valign="top">50.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Tobacco</td><td align="center" class="Botrule Rrule" valign="top">91.8</td><td align="center" class="Botrule Rrule" valign="top">92.3</td><td align="center" class="Botrule Rrule" valign="top">92.9</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Alcohol</td><td align="center" class="Botrule Rrule" valign="top">78.4</td><td align="center" class="Botrule Rrule" valign="top">79.1</td><td align="center" class="Botrule Rrule" valign="top">80.8</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Drug Use History</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Cannabinoids</td><td align="center" class="Botrule Rrule" valign="top">54.6</td><td align="center" class="Botrule Rrule" valign="top">47.4</td><td align="center" class="Botrule Rrule" valign="top">52.5</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Cocaine</td><td align="center" class="Botrule Rrule" valign="top">47.4</td><td align="center" class="Botrule Rrule" valign="top">39.8</td><td align="center" class="Botrule Rrule" valign="top">42.4</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Amphetamine/Methamphetamine</td><td align="center" class="Botrule Rrule" valign="top">25.3</td><td align="center" class="Botrule Rrule" valign="top">14.8</td><td align="center" class="Botrule Rrule" valign="top">19.2</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Medical History</span></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td><td align="center" class="Botrule Rrule" valign="top"></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Depression</td><td align="center" class="Botrule Rrule" valign="top">14.4</td><td align="center" class="Botrule Rrule" valign="top">11.2</td><td align="center" class="Botrule Rrule" valign="top">13.1</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">     Anxiety</td><td align="center" class="Botrule Rrule" valign="top">9.3</td><td align="center" class="Botrule Rrule" valign="top">9.7</td><td align="center" class="Botrule Rrule" valign="top">10.1</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">     Back Pain</td><td align="center" class="Botrule Rrule" valign="top">14.9</td><td align="center" class="Botrule Rrule" valign="top">16.3</td><td align="center" class="Botrule Rrule" valign="top">13.1</td> </tr> </tbody> </table></div>

Based on the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use collected from Week 5 through Week 24 ( Table 9), regardless of dose, SUBLOCADE was superior to the placebo group with statistical significance. The proportion of patients achieving treatment success (defined as patients with ≥ 80% opioid-free weeks) was statistically significantly higher in both groups receiving SUBLOCADE compared to the placebo group (28.4% [300 mg/100 mg], 29.1% [300 mg/300mg], 2% [placebo]).

For various percentages of opioid-free weeks, Table 9shows the fraction of patients achieving that criterion. The table is cumulative, so that a patient whose percent of opioid-free weeks is, for example, 50%, is also included at every level of opioid-free week percentage below 50%. Missing values and values after premature discontinuation were considered positive.

Figure 13 Subjects Achieving Varying Percentages of Opioid-Free Weeks

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 9 Cumulative Distribution Function of Percentage of Opioid-Free Weeks</span> </caption> <col align="left" width="31.708%"/> <col align="left" width="25.031%"/> <col align="left" width="25.031%"/> <col align="left" width="18.230%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule Toprule" rowspan="3" valign="top"></td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="top"><span class="Bold">Number (%) of Subjects</span></td> </tr> <tr> <td align="center" class="Rrule" valign="top"><span class="Bold">SUBLOCADE</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">SUBLOCADE</span></td><td align="center" class="Rrule" valign="top"></td> </tr> <tr> <td align="center" class="Rrule" valign="top"><span class="Bold">300 mg/100 mg + IDC</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">300 mg/300 mg + IDC</span></td><td align="center" class="Rrule" valign="top"><span class="Bold">Placebo + IDC</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">Percentage Opioid-Free Weeks</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N = 194)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N = 196)</span></td><td align="center" class="Botrule Rrule" valign="top"><span class="Bold">(N = 99)</span></td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 0%</td><td align="center" class="Botrule Rrule" valign="top">194 (100.0)</td><td align="center" class="Botrule Rrule" valign="top">196 (100.0)</td><td align="center" class="Botrule Rrule" valign="top">99 (100.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 10%</td><td align="center" class="Botrule Rrule" valign="top">139 (71.6)</td><td align="center" class="Botrule Rrule" valign="top">126 (64.3)</td><td align="center" class="Botrule Rrule" valign="top">11 (11.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 20%</td><td align="center" class="Botrule Rrule" valign="top">115 (59.3)</td><td align="center" class="Botrule Rrule" valign="top">111 (56.6)</td><td align="center" class="Botrule Rrule" valign="top">7 (7.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 30%</td><td align="center" class="Botrule Rrule" valign="top">101 (52.1)</td><td align="center" class="Botrule Rrule" valign="top">101 (51.5)</td><td align="center" class="Botrule Rrule" valign="top">6 (6.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 40%</td><td align="center" class="Botrule Rrule" valign="top">90 (46.4)</td><td align="center" class="Botrule Rrule" valign="top">90 (45.9)</td><td align="center" class="Botrule Rrule" valign="top">6 (6.1)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 50%</td><td align="center" class="Botrule Rrule" valign="top">86 (44.3)</td><td align="center" class="Botrule Rrule" valign="top">82 (41.8)</td><td align="center" class="Botrule Rrule" valign="top">4 (4.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 60%</td><td align="center" class="Botrule Rrule" valign="top">78 (40.2)</td><td align="center" class="Botrule Rrule" valign="top">70 (35.7)</td><td align="center" class="Botrule Rrule" valign="top">4 (4.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 70%</td><td align="center" class="Botrule Rrule" valign="top">66 (34.0)</td><td align="center" class="Botrule Rrule" valign="top">67 (34.2)</td><td align="center" class="Botrule Rrule" valign="top">2 (2.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 80%</td><td align="center" class="Botrule Rrule" valign="top">55 (28.4)</td><td align="center" class="Botrule Rrule" valign="top">57 (29.1)</td><td align="center" class="Botrule Rrule" valign="top">2 (2.0)</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top">≥ 90%</td><td align="center" class="Botrule Rrule" valign="top">41 (21.1)</td><td align="center" class="Botrule Rrule" valign="top">48 (24.5)</td><td align="center" class="Botrule Rrule" valign="top">2 (2.0)</td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top">= 100%</td><td align="center" class="Botrule Rrule" valign="top">25 (13)</td><td align="center" class="Botrule Rrule" valign="top">23 (12)</td><td align="center" class="Botrule Rrule" valign="top">1 (1.0)</td> </tr> </tbody> </table></div>

Induction on SUBLOCADE following a single dose of 4 mg transmucosal buprenorphine was compared to standard induction (minimum of 7 days of transmucosal buprenorphine) based on data from 723 treatment-seeking patients with moderate to severe OUD and high-risk opioid use. High-risk opioid use was defined as using five or more days per week either via IV injection, high doses (at least 500 mg IV heroin equivalent), or potent synthetic opioids (e.g., fentanyl). At induction, 77.5% of patients were fentanyl positive by urine drug screen (UDS).

In this open-label study, patients were randomized at a 2:1 ratio to SUBLOCADE rapid induction or standard induction and stratified according to the same-day UDS result for fentanyl due to the potential for fentanyl use to impact the response to induction. For rapid induction, patients were observed at a minimum of 1 hour after receiving a single dose of 4 mg transmucosal buprenorphine to confirm tolerability before administering the first injection of 300 mg SUBLOCADE. On induction day, up to an additional 8 mg of transmucosal buprenorphine could be administered to manage withdrawal symptoms. In both treatment groups, the second 300 mg injection was administered at 1 week after the first SUBLOCADE injection and subsequent injections were scheduled every 4 weeks.

Rapid induction was effective, shown by the primary endpoint of participant retention at the second injection. The proportion of participants who received the second injection was 66.4% in the rapid induction arm and 54.5% in the standard induction arm; the estimated retention rate difference (rapid induction minus standard induction) in the overall population was 11.8% with a lower bound of multiplicity adjusted two-sided 95% confidence interval greater than the pre-specified non-inferiority margin of -10%. This demonstrated non-inferiority of rapid induction to standard induction.

Storage and Handling

Store refrigerated at 2°C to 8°C (35.6°F to 46.4°F).

Once outside the refrigerator this product may be stored in its original packaging at room temperature, 15°C to 30°C (59°F to 86°F), for up to 12 weeks prior to administration. Discard SUBLOCADE if left at room temperature for longer than 12 weeks.

SUBLOCADE is a Schedule III drug product. Handle with adequate security and accountability. After administration, syringes should be properly disposed, per facility procedure for a Schedule III drug product, and per applicable federal, state, and local regulations.

Rx Only.

SUBLOCADE Risk Evaluation and Mitigation Strategy (REMS)

Advise patients that because of the risk of serious harm or death due to intravenous self-administration, SUBLOCADE is available only through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies are certified and only dispense SUBLOCADE directly to a healthcare provider for administration by healthcare providers [see Warnings and Precautions ( 5.2)] .

Life Threatening Respiratory Depression

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions 5.4)] .

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Because patients being treated for opioid use disorder are at risk for relapse, discuss the importance of having access to naloxone with the patient and caregiver. Also discuss the importance of having access to naloxone if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

Inform patients and caregivers of the options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose.

Explain to patients and caregivers that naloxone's effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered. Repeat administration may be necessary, particularly for overdose involving buprenorphine, because naloxone is often not effective at the doses available for patient access [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.4), Overdosage ( 10)] .

If naloxone is prescribed, also advise patients and caregivers:

Interaction With Benzodiazepines and Other CNS Depressants

Inform patients and caregivers that potentially fatal additive effects may occur if SUBLOCADE is used with benzodiazepines or other CNS depressants, including alcohol. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4, 5.5), Drug Interactions ( 7)].

Serotonin Syndrome

Inform patients that SUBLOCADE could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions ( 7)].

Adrenal Insufficiency

Inform patients that SUBLOCADE could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.8)].

Anaphylaxis

Inform patients that anaphylaxis has been reported with buprenorphine. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions ( 5.11)].

Driving or Operating Heavy Machinery

Caution patients that SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving or operating hazardous machinery. Instruct patients not to drive or operate hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities [see Warnings and Precautions ( 5.17)] .

Dependence and Withdrawal

Inform patients that SUBLOCADE can cause drug dependence and that withdrawal signs and symptoms may occur when the medication is discontinued [see Warnings and Precautions ( 5.9, 5.12)].

Orthostatic Hypotension

Inform patients that, like other opioids, SUBLOCADE may produce orthostatic hypotension in ambulatory individuals [see Warnings and Precautions ( 5.18)].

Long Duration of Action

Inform patients that they may have detectable levels of buprenorphine for a prolonged period of time after treatment with SUBLOCADE. Considerations of drug-drug interactions, buprenorphine effects, and analgesia may continue to be relevant for several months after the last injection [see Clinical Pharmacology ( 12.3)] .

Drug Interactions

Instruct patients to inform their healthcare providers of any other prescription medications, over the-counter medications, or herbal preparations that are prescribed or currently being used [see Drug Interactions ( 7)].

Pregnancy

Neonatal Opioid Withdrawal Syndrome

Advise women that if they are pregnant while being treated with SUBLOCADE, the baby may have signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions ( 5.6), Use in Specific Populations ( 8.1)].

Embryofetal Toxicity

Advise women of childbearing potential who become pregnant or are planning to become pregnant to consult their healthcare provider regarding the possible effects of using SUBLOCADE during pregnancy [see Use in Specific Populations ( 8.1)].

Lactation

Warn patients that buprenorphine passes into breast milk. Advise the nursing mother taking buprenorphine to monitor the infant for increased drowsiness and breathing difficulties [see Use in Specific Populations ( 8.2)].

Infertility

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3), Clinical Pharmacology ( 12.2)].

Emergency Analgesia

Patients should be advised to instruct their family members to, in the event of emergency, inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with SUBLOCADE [see Warnings and Precautions ( 5.13)] .

Clinical Monitoring

Tell your patients to seek emergency attention if they have signs or symptoms of respiratory or CNS depression or overdose [see Warnings and Precautions ( 5.4, 5.5)] .

Tell your patients not to tamper with or try to remove their depot [see Dosage and Administration ( 2.7)].

© 2025, Indivior UK Limited. All Rights Reserved.

SUBLOCADE® is a registered trademark of Indivior UK Limited.

All third-party trademarks used herein are registered trademarks of their respective owners.

Manufactured for Indivior Inc., North Chesterfield VA, 23235

<div class="scrollingtable"><table width="100%"> <col align="left" width="33.325%"/> <col align="left" width="16.675%"/> <col align="left" width="16.675%"/> <col align="left" width="33.325%"/> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top"> <p class="First Footnote">This Medication Guide has been approved by the U.S. Food and Drug Administration.   Revised: 02/2025</p> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" colspan="4" valign="top"><span class="Bold">MEDICATION GUIDE</span> <br/> SUBLOCADE (SUB-lo-kade) (buprenorphine extended-release) injection, for subcutaneous use, (CIII) </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">What is the most important information I should know about SUBLOCADE?</span> <br/> <ul class="Disc"> <li>Because of the serious risk of potential harm or death from self-injecting SUBLOCADE into a vein (intravenously), it is only available through a restricted program called the SUBLOCADE REMS Program. <ul class="Circle"> <li>SUBLOCADE is not available in retail pharmacies.</li> <li>Your SUBLOCADE injection will only be given to you by a certified healthcare provider.</li> </ul> </li> <li>SUBLOCADE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.</li> <li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to people for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat overdose or accidental use of an opioid.</li> <li> <span class="Bold">SUBLOCADE may cause serious and life-threatening breathing problems. Get emergency medical help right away if you</span>: <div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="50.200%"/> <col align="left" width="49.800%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ul class="Circle"> <li>feel faint</li> <li>feel dizzy</li> <li>are confused</li> <li>feel sleepy or uncoordinated</li> </ul> </td><td align="left" valign="top"> <ul class="Circle"> <li>have blurred vision</li> <li>have slurred speech</li> <li>are breathing slower than normal</li> <li>cannot think well or clearly</li> </ul> </td> </tr> </tbody> </table></div> </li> <li> <span class="Bold">Do not take SUBLOCADE with certain medicines. Taking SUBLOCADE with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span> </li> <li>In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBLOCADE.</li> <li>You may have detectable levels of SUBLOCADE in your body for several months after stopping treatment with SUBLOCADE.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">What is SUBLOCADE?</span> <br/> SUBLOCADE is a prescription medicine used to treat adults with moderate to severe addiction (dependence) to opioid drugs (prescription or illegal) who: <br/> <ul class="Disc"> <li>have started treatment with a single dose of a buprenorphine medicine in the form of a sublingual tablet or buccal film (transmucosal) or</li> <li>are already being treated with buprenorphine.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top">SUBLOCADE is part of a complete treatment plan that should include counseling and psychosocial support.</td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Who should not receive SUBLOCADE?</span> <br/> <span class="Bold">Do not receive SUBLOCADE</span>if you are allergic to buprenorphine or any ingredients in the prefilled syringe (ATRIGEL® delivery system). See the end of this Medication Guide for a list of ingredients in SUBLOCADE. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Before receiving SUBLOCADE, tell your healthcare provider about all your medical conditions, including if you have:</span></td> </tr> <tr> <td align="left" class="Lrule" valign="top"> <ul class="Disc"> <li>trouble breathing or lung problems</li> <li>a curve in your spine that affects your breathing</li> <li>Addison's disease</li> </ul> </td><td align="left" colspan="2" valign="top"> <ul class="Disc"> <li>an enlarged prostate (men)</li> <li>problems urinating</li> <li>liver, kidney, or gallbladder problems</li> <li>alcoholism</li> </ul> </td><td align="left" class="Rrule" valign="top"> <ul class="Disc"> <li>a head injury or brain problem</li> <li>mental health problems</li> <li>adrenal gland or thyroid gland problems</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">Tell your healthcare provider if you are:</span> <br/> <ul class="Disc"> <li> <span class="Bold">pregnant or plan to become pregnant.</span>If you receive SUBLOCADE while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant. </li> <li> <span class="Bold">breastfeeding or plan to breastfeed.</span>SUBLOCADE can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with SUBLOCADE. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with SUBLOCADE. <br/> </li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">Tell your healthcare provider about all the medicines you take, including</span>prescription and over-the-counter medicines, vitamins and herbal supplements. Talk with your healthcare provider before starting any new medicines during or after stopping treatment with SUBLOCADE. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">How will I receive SUBLOCADE?</span> <br/> <ul class="Disc"> <li>You will receive SUBLOCADE by your healthcare provider as an injection just under the skin (subcutaneous) of your stomach (abdomen), thigh, buttock, or back of the upper arm. After the first two injections, you will receive SUBLOCADE monthly (with at least 26 days between doses).</li> <li>If you are not currently receiving buprenorphine treatment, your healthcare provider will give you a test dose of buprenorphine first to see if you are able to tolerate it, before switching to SUBLOCADE.</li> <li>SUBLOCADE is injected as a liquid. After the injection, SUBLOCADE changes to a solid form called a depot. The depot may be seen or felt as a small bump under your skin at the injection site for several weeks. The depot will get smaller over time.</li> <li>Do not try to remove the depot.</li> <li>Do not rub or massage the injection site.</li> <li>Try not to let any restrictive clothing such as belts, waistbands, or sleeves rub against the injection site.</li> <li>If you miss a dose of SUBLOCADE, see your healthcare provider to get your SUBLOCADE injection as soon as possible.</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">What should I avoid while being treated with SUBLOCADE?</span> <br/> <ul class="Disc"> <li> <span class="Bold">Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how SUBLOCADE affects you.</span>SUBLOCADE can cause drowsiness and slow reaction times. SUBLOCADE can make you sleepy, dizzy, or lightheaded. This may happen more often in the first few days after your injection and when your dose is changed. </li> <li> <span class="Bold">You should not drink alcohol</span>or take prescription or over-the-counter medicines that contain alcohol during treatment with SUBLOCADE, because this can lead to loss of consciousness or even death. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">What are the possible side effects of SUBLOCADE?</span> <br/> <span class="Bold">SUBLOCADE can cause serious side effects, including:</span> <br/> <ul class="Disc"> <li> <span class="Bold">Trouble breathing.</span>Taking SUBLOCADE with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death. </li> <li> <span class="Bold">Sleepiness, dizziness, and problems with coordination.</span> </li> <li> <span class="Bold">Physical dependence or abuse.</span> </li> <li> <span class="Bold">Liver problems</span>. Call your healthcare provider right away if you notice any of these symptoms: <div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="50.100%"/> <col align="left" width="49.900%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ul class="Circle"> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light colored stools (bowel movements)</li> </ul> </td><td align="left" valign="top"> <ul class="Circle"> <li>loss of appetite</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> <li>nausea</li> </ul> </td> </tr> </tbody> </table></div> <br/> Your healthcare provider should do blood tests to check your liver before you start and during treatment with SUBLOCADE. </li> <li> <span class="Bold">Allergic reaction.</span>You may have a rash, hives, swelling of your face, wheezing, light-headedness, feeling faint or loss of consciousness. Call your healthcare provider or get emergency help right away. </li> <li> <span class="Bold">Opioid withdrawal.</span>Call your healthcare provider right away if you get any of these symptoms: <div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="50.050%"/> <col align="left" width="49.950%"/> <tbody class="Headless"> <tr> <td align="left" valign="top"> <ul class="Circle"> <li>shaking</li> <li>sweating more than normal</li> <li>feeling hot or cold more than normal</li> <li>runny nose</li> <li>watery eyes</li> </ul> </td><td align="left" valign="top"> <ul class="Circle"> <li>goose bumps</li> <li>diarrhea</li> <li>vomiting</li> <li>muscle aches</li> </ul> </td> </tr> </tbody> </table></div> </li> <li> <span class="Bold">Decrease in blood pressure.</span>You may feel dizzy when you get up from sitting or lying down. <br/> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">The most common side effects of SUBLOCADE include:</span></td> </tr> <tr> <td align="left" class="Lrule" colspan="2" valign="top"> <ul class="Disc"> <li>constipation</li> <li>headache</li> <li>nausea</li> <li>injection site itching</li> </ul> </td><td align="left" class="Rrule" colspan="2" valign="top"> <ul class="Disc"> <li>vomiting</li> <li>increase in liver enzymes</li> <li>tiredness</li> <li>injection site pain</li> </ul> </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top">SUBLOCADE may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you. <br/> These are not all the possible side effects of SUBLOCADE. <br/> Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top"><span class="Bold">General information about SUBLOCADE</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your doctor or pharmacist for information that is written for healthcare professionals. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="4" valign="top"><span class="Bold">What are the ingredients in SUBLOCADE?</span> <br/> Active ingredient: buprenorphine <br/> ATRIGEL <span class="Sup">®</span>Delivery system: biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent, <span class="Italics">N</span>-methyl-2-pyrrolidone (NMP). </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" colspan="4" valign="top">© 2025, Indivior UK Limited. All Rights Reserved. <br/> SUBLOCADE® is a registered trademark of Indivior UK Limited. <br/> Manufactured for Indivior Inc., North Chesterfield VA, 23235 <br/> For more information, go to www.SUBLOCADE.com or call 1-877-782-6966. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" width=\"33.325%\"/>\n<col align=\"left\" width=\"16.675%\"/>\n<col align=\"left\" width=\"16.675%\"/>\n<col align=\"left\" width=\"33.325%\"/>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"4\" valign=\"top\">\n<p class=\"First Footnote\">This Medication Guide has been approved by the U.S. Food and Drug Administration.   Revised: 02/2025</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/> SUBLOCADE (SUB-lo-kade) (buprenorphine extended-release) injection, for subcutaneous use, (CIII)\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">What is the most important information I should know about SUBLOCADE?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Because of the serious risk of potential harm or death from self-injecting SUBLOCADE into a vein (intravenously), it is only available through a restricted program called the SUBLOCADE REMS Program.\n \n <ul class=\"Circle\">\n<li>SUBLOCADE is not available in retail pharmacies.</li>\n<li>Your SUBLOCADE injection will only be given to you by a certified healthcare provider.</li>\n</ul>\n</li>\n<li>SUBLOCADE contains a medicine called buprenorphine. Buprenorphine is an opioid that can cause serious and life-threatening breathing problems, especially if you take or use certain other medicines or drugs.</li>\n<li>Talk to your healthcare provider about naloxone. Naloxone is a medicine that is available to people for the emergency treatment of an opioid overdose. If naloxone is given, you must call 911 or get emergency medical help right away to treat overdose or accidental use of an opioid.</li>\n<li>\n<span class=\"Bold\">SUBLOCADE may cause serious and life-threatening breathing problems. Get emergency medical help right away if you</span>:\n \n <div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"50.200%\"/>\n<col align=\"left\" width=\"49.800%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>feel faint</li>\n<li>feel dizzy</li>\n<li>are confused</li>\n<li>feel sleepy or uncoordinated</li>\n</ul>\n</td><td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>have blurred vision</li>\n<li>have slurred speech</li>\n<li>are breathing slower than normal</li>\n<li>cannot think well or clearly</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>\n</li>\n<li>\n<span class=\"Bold\">Do not take SUBLOCADE with certain medicines. Taking SUBLOCADE with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</span>\n</li>\n<li>In an emergency, have family members tell emergency department staff that you are physically dependent on an opioid and are being treated with SUBLOCADE.</li>\n<li>You may have detectable levels of SUBLOCADE in your body for several months after stopping treatment with SUBLOCADE.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">What is SUBLOCADE?</span>\n<br/> SUBLOCADE is a prescription medicine used to treat adults with moderate to severe addiction (dependence) to opioid drugs (prescription or illegal) who: \n <br/>\n<ul class=\"Disc\">\n<li>have started treatment with a single dose of a buprenorphine medicine in the form of a sublingual tablet or buccal film (transmucosal) or</li>\n<li>are already being treated with buprenorphine.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">SUBLOCADE is part of a complete treatment plan that should include counseling and psychosocial support.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">Who should not receive SUBLOCADE?</span>\n<br/>\n<span class=\"Bold\">Do not receive SUBLOCADE</span>if you are allergic to buprenorphine or any ingredients in the prefilled syringe (ATRIGEL® delivery system). See the end of this Medication Guide for a list of ingredients in SUBLOCADE.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">Before receiving SUBLOCADE, tell your healthcare provider about all your medical conditions, including if you have:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>trouble breathing or lung problems</li>\n<li>a curve in your spine that affects your breathing</li>\n<li>Addison's disease</li>\n</ul>\n</td><td align=\"left\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>an enlarged prostate (men)</li>\n<li>problems urinating</li>\n<li>liver, kidney, or gallbladder problems</li>\n<li>alcoholism</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" valign=\"top\">\n<ul class=\"Disc\">\n<li>a head injury or brain problem</li>\n<li>mental health problems</li>\n<li>adrenal gland or thyroid gland problems</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">Tell your healthcare provider if you are:</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">pregnant or plan to become pregnant.</span>If you receive SUBLOCADE while pregnant, your baby may have symptoms of opioid withdrawal at birth that could be life-threatening if not recognized and treated. Talk to your healthcare provider if you are pregnant or plan to become pregnant.\n \n </li>\n<li>\n<span class=\"Bold\">breastfeeding or plan to breastfeed.</span>SUBLOCADE can pass into your breast milk and harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with SUBLOCADE. Monitor your baby for increased drowsiness and breathing problems if you breastfeed during treatment with SUBLOCADE. \n <br/>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">Tell your healthcare provider about all the medicines you take, including</span>prescription and over-the-counter medicines, vitamins and herbal supplements. Talk with your healthcare provider before starting any new medicines during or after stopping treatment with SUBLOCADE.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">How will I receive SUBLOCADE?</span>\n<br/>\n<ul class=\"Disc\">\n<li>You will receive SUBLOCADE by your healthcare provider as an injection just under the skin (subcutaneous) of your stomach (abdomen), thigh, buttock, or back of the upper arm. After the first two injections, you will receive SUBLOCADE monthly (with at least 26 days between doses).</li>\n<li>If you are not currently receiving buprenorphine treatment, your healthcare provider will give you a test dose of buprenorphine first to see if you are able to tolerate it, before switching to SUBLOCADE.</li>\n<li>SUBLOCADE is injected as a liquid. After the injection, SUBLOCADE changes to a solid form called a depot. The depot may be seen or felt as a small bump under your skin at the injection site for several weeks. The depot will get smaller over time.</li>\n<li>Do not try to remove the depot.</li>\n<li>Do not rub or massage the injection site.</li>\n<li>Try not to let any restrictive clothing such as belts, waistbands, or sleeves rub against the injection site.</li>\n<li>If you miss a dose of SUBLOCADE, see your healthcare provider to get your SUBLOCADE injection as soon as possible.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">What should I avoid while being treated with SUBLOCADE?</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not drive, operate heavy machinery, or perform any other dangerous activities until you know how SUBLOCADE affects you.</span>SUBLOCADE can cause drowsiness and slow reaction times. SUBLOCADE can make you sleepy, dizzy, or lightheaded. This may happen more often in the first few days after your injection and when your dose is changed.\n \n </li>\n<li>\n<span class=\"Bold\">You should not drink alcohol</span>or take prescription or over-the-counter medicines that contain alcohol during treatment with SUBLOCADE, because this can lead to loss of consciousness or even death.\n \n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">What are the possible side effects of SUBLOCADE?</span>\n<br/>\n<span class=\"Bold\">SUBLOCADE can cause serious side effects, including:</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Trouble breathing.</span>Taking SUBLOCADE with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants can cause breathing problems that can lead to coma and death.\n \n </li>\n<li>\n<span class=\"Bold\">Sleepiness, dizziness, and problems with coordination.</span>\n</li>\n<li>\n<span class=\"Bold\">Physical dependence or abuse.</span>\n</li>\n<li>\n<span class=\"Bold\">Liver problems</span>. Call your healthcare provider right away if you notice any of these symptoms:\n \n <div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"50.100%\"/>\n<col align=\"left\" width=\"49.900%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>your skin or the white part of your eyes turns yellow (jaundice)</li>\n<li>dark or “tea-colored” urine</li>\n<li>light colored stools (bowel movements)</li>\n</ul>\n</td><td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>loss of appetite</li>\n<li>pain, aching, or tenderness on the right side of your stomach area</li>\n<li>nausea</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>\n<br/> Your healthcare provider should do blood tests to check your liver before you start and during treatment with SUBLOCADE.\n \n </li>\n<li>\n<span class=\"Bold\">Allergic reaction.</span>You may have a rash, hives, swelling of your face, wheezing, light-headedness, feeling faint or loss of consciousness. Call your healthcare provider or get emergency help right away.\n \n </li>\n<li>\n<span class=\"Bold\">Opioid withdrawal.</span>Call your healthcare provider right away if you get any of these symptoms:\n \n <div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"50.050%\"/>\n<col align=\"left\" width=\"49.950%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>shaking</li>\n<li>sweating more than normal</li>\n<li>feeling hot or cold more than normal</li>\n<li>runny nose</li>\n<li>watery eyes</li>\n</ul>\n</td><td align=\"left\" valign=\"top\">\n<ul class=\"Circle\">\n<li>goose bumps</li>\n<li>diarrhea</li>\n<li>vomiting</li>\n<li>muscle aches</li>\n</ul>\n</td>\n</tr>\n</tbody>\n</table></div>\n</li>\n<li>\n<span class=\"Bold\">Decrease in blood pressure.</span>You may feel dizzy when you get up from sitting or lying down. \n <br/>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">The most common side effects of SUBLOCADE include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>constipation</li>\n<li>headache</li>\n<li>nausea</li>\n<li>injection site itching</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\" valign=\"top\">\n<ul class=\"Disc\">\n<li>vomiting</li>\n<li>increase in liver enzymes</li>\n<li>tiredness</li>\n<li>injection site pain</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">SUBLOCADE may affect fertility in males and females. Talk to your healthcare provider if this is a concern for you. \n <br/> These are not all the possible side effects of SUBLOCADE. \n <br/> Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">General information about SUBLOCADE</span>\n<br/> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your doctor or pharmacist for information that is written for healthcare professionals.\n \n </td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"4\" valign=\"top\"><span class=\"Bold\">What are the ingredients in SUBLOCADE?</span>\n<br/> Active ingredient: buprenorphine \n <br/> ATRIGEL\n \n <span class=\"Sup\">®</span>Delivery system: biodegradable 50:50 poly(DL-lactide-co-glycolide) polymer and a biocompatible solvent,\n \n <span class=\"Italics\">N</span>-methyl-2-pyrrolidone (NMP).\n \n </td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Botrule Lrule Rrule\" colspan=\"4\" valign=\"top\">© 2025, Indivior UK Limited. All Rights Reserved. \n <br/> SUBLOCADE® is a registered trademark of Indivior UK Limited. \n <br/> Manufactured for Indivior Inc., North Chesterfield VA, 23235 \n <br/> For more information, go to www.SUBLOCADE.com or call 1-877-782-6966.\n </td>\n</tr>\n</tbody>\n</table></div>" }

Principal Display Panel - Sublocade 100 mg Carton Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - Sublocade 100 mg Carton Label\n" }

NDC 12496-0100-1

{ "type": "p", "children": [], "text": "\nNDC 12496-0100-1\n" }

Sublocade ®

{ "type": "p", "children": [], "text": "\nSublocade\n \n ®\n" }

(buprenorphine extended-release)

{ "type": "p", "children": [], "text": "(buprenorphine extended-release)" }

injection for subcutaneous use

{ "type": "p", "children": [], "text": "injection for subcutaneous use" }

CIII

{ "type": "p", "children": [], "text": "CIII" }

100 mg

{ "type": "p", "children": [], "text": "\n100 mg\n" }

Principal Display Panel - Sublocade 300 mg Carton Label

{ "type": "p", "children": [], "text": "\nPrincipal Display Panel - Sublocade 300 mg Carton Label\n" }

NDC 12496-0300-1

{ "type": "p", "children": [], "text": "\nNDC 12496-0300-1\n" }

Sublocade ®

{ "type": "p", "children": [], "text": "\nSublocade\n \n ®\n" }

(buprenorphine extended-release)

{ "type": "p", "children": [], "text": "(buprenorphine extended-release)" }

injection for subcutaneous use

{ "type": "p", "children": [], "text": "injection for subcutaneous use" }

CIII

{ "type": "p", "children": [], "text": "CIII" }

300 mg

{ "type": "p", "children": [], "text": "\n300 mg\n" }

Buprenorphine transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.

{ "type": "p", "children": [], "text": "\nBuprenorphine transdermal system is indicated for the management of severe and persistent pain that requires an extended treatment period with a daily opioid analgesic and for which alternative treatment options are inadequate.\n" }

Limitations of Use

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{ "type": "ul", "children": [ "\nBecause of the risks of addiction, abuse and misuse with opioids, which can occur at any dosage or duration, and because of the greater risk of overdose and death with extended-release/long acting opioid formulations\n \n [see Warnings and Precautions (5.1)], reserve buprenorphine transdermal system for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate‑release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.\n \n \n", "\nBuprenorphine transdermal system is not indicated as an as-needed (prn) analgesic\n" ], "text": "" }

Buprenorphine transdermal system is for transdermal use (on intact skin) only. Each buprenorphine transdermal system patch is intended to be worn for 7 days.

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with buprenorphine transdermal system [see Warnings and Precautions (5.2)].

Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.1, 5.2,5.3), Overdosage ( 10)].

Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental exposure or overdose.

Use of Buprenorphine Transdermal System as the First Opioid Analgesic(opioid-naive patients)

Initiate treatment with buprenorphine transdermal system with a 5 mcg/hour patch.

Conversion from Other Opioids to Buprenorphine Transdermal System

When buprenorphine transdermal system therapy is initiated, discontinue all other opioid analgesics other than those used on an as needed basis for breakthrough pain when appropriate.

There is a potential for buprenorphine to precipitate withdrawal in patients who are already on opioids.

Prior Total Daily Dose of Opioid Less than 30 mg of Oral Morphine Equivalents per Day: Initiate treatment with buprenorphine transdermal system 5 mcg/hour at the next dosing interval (see Table 1 below, middle column).

Prior Total Daily Dose of Opioid Between 30 mg to 80 mg of Oral Morphine Equivalents per Day:

Taper the patient’s current around-the-clock opioids for up to 7 days to no more than 30 mg of morphine or equivalent per day before beginning treatment with buprenorphine transdermal system. Then initiate treatment with buprenorphine transdermal system 10 mcg/hour at the next dosing interval (see Table 1 below, right column). Patients may use short-acting analgesics as needed until analgesic efficacy with buprenorphine transdermal system is attained.

Prior Total Daily Dose of Opioid Greater than 80 mg of Oral Morphine Equivalents per Day: Buprenorphine transdermal system 20 mcg/hour may not provide adequate analgesia for patients requiring greater than 80 mg/day oral morphine equivalents. Consider the use of an alternate analgesic.

Table 1: Initial Buprenorphine Transdermal System Dose

Conversion from Methadone to Buprenorphine Transdermal System

Regular evaluation is of particular importance when converting from methadone to other opioid agonists. The ratio between methadone and other opioid agonists may vary widely as a function of previous dose exposure. Methadone has a long half-life and can accumulate in the plasma.

Individually titrate buprenorphine transdermal system to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving buprenorphine transdermal system to assess the maintenance of pain control, signs and symptoms of opioid withdrawal and other adverse reactions, as well as reassessing for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1,5.19)]. Frequent communication is important among the prescriber, other members of healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. During use of opioid therapy for an extended period of time, periodically reassess the continued need for opioid analgesics.

The minimum buprenorphine transdermal system titration interval is 72 hours, based on the pharmacokinetic profile and time to reach steady state levels [see Clinical Pharmacology (12.3)].

The maximum buprenorphine transdermal system dose is 20 mcg/hour. Do not exceed a dose of one 20 mcg/hour buprenorphine transdermal system due to the risk of QTc interval prolongation. In a clinical trial, buprenorphine transdermal system 40 mcg/hour (given as two buprenorphine transdermal system 20 mcg/hour systems) resulted in prolongation of the QTc interval [see Warnings and Precautions (5.17), Clinical Pharmacology ( 12.2)] .

Patients who experience breakthrough pain may require dosage adjustment increase of buprenorphine transdermal system, or may need rescue medication with an appropriate dose of an immediate-release analgesic. 

If the level of pain increases after dose stabilization, attempt to identify the source of increased pain before increasing the buprenorphine transdermal system dose. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase) consider reducing the dosage [see Warnings and Precautions ( 5)] . Adjust the dosage to obtain an appropriate balance between the management of pain and opioid-related adverse reactions.

Because steady-state plasma concentrations are achieved within 72 hours, buprenorphine transdermal system dosage may be adjusted every 3 days. Dose adjustments may be made in 5 mcg/hour, 7.5 mcg/hour, or 10 mcg/hour increments by using no more than two patches of the 5 mcg/hour, or 7.5 mcg/hour, or 10 mcg/hour system(s). The total dose from both patches should not exceed 20 mcg/hour. For the use of two patches, instruct patients to remove their current patch, and apply the two new patches at the same time, adjacent to one another at a different application site [see Dosage and Administration ( 2.7)].

Do not abruptly discontinue buprenorphine transdermal system in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.  

When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking buprenorphine transdermal system, there are a variety of factors that should be considered, including the total daily dose of opioid (including buprenorphine transdermal system) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist.  

There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on buprenorphine transdermal system who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper.  

It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances.  

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.19), Drug Abuse and Dependence ( 9.3)] .

Buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment. As buprenorphine transdermal system is only intended for 7-day application, consider use of an alternate analgesic that may permit more flexibility with the dosing in patients with severe hepatic impairment [see Warnings and Precautions ( 5.14), Use in Specific Populations ( 8.6) ,  Clinical Pharmacology ( 12.3)].

Patients should refer to the Instructions for Use for proper disposal of buprenorphine transdermal system. Dispose of used and unused patches by following the instructions on the Patch-Disposal Unit that is packaged with the buprenorphine transdermal system patches.

Alternatively, patients can dispose of used patches by folding the adhesive side of the patch to itself, then flushing the patch down the toilet immediately upon removal. Unused patches should be removed from their pouches, the protective liners removed, the patches folded so that the adhesive side of the patch adheres to itself, and immediately flushed down the toilet.

Patients should dispose of any patches remaining from a prescription as soon as they are no longer needed.

Buprenorphine transdermal system is a rectangular or square, tan-colored system consisting of a protective liner and functional layers. Buprenorphine transdermal system is available in five strengths:

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Buprenorphine transdermal system is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Buprenorphine transdermal system is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Significant respiratory depression\n \n [see Warnings and Precautions (5.2)]\n", "Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment \n \n [see Warnings and Precautions (5.10)] \n", "Known or suspected gastrointestinal obstruction, including paralytic ileus \n \n [see Warnings and Precautions (5.15)] \n", "Hypersensitivity (e.g., anaphylaxis) to buprenorphine \n \n [see Warnings and Precautions (5.18), Adverse Reactions (\n \n 6)]\n \n \n" ], "text": "" }

Buprenorphine transdermal system contains buprenorphine, a Schedule III controlled substance. As an opioid, buprenorphine transdermal system exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9)] . Because extended-release products such as buprenorphine transdermal system deliver the opioid over an extended period of time, there is a greater risk for overdose and death, due to the larger amount of buprenorphine present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed buprenorphine transdermal system. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing buprenorphine transdermal system, and reassess all patients receiving buprenorphine transdermal system for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as buprenorphine transdermal system but use in such patients necessitates intensive counseling about the risks and proper use of buprenorphine transdermal system, along with frequent reevaluation for signs of addiction, abuse, or misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

Abuse or misuse of buprenorphine transdermal system by placing it in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking, overdose and death [see Overdosage ( 10)] .

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing buprenorphine transdermal system. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO 2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of buprenorphine transdermal system, the risk is greatest during the initiation of therapy or following a dosage increase.

To reduce the risk of respiratory depression, proper dosing and titration of buprenorphine transdermal system are essential [see Dosage and Administration (2)]. Overestimating the buprenorphine transdermal system dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental exposure to buprenorphine transdermal system, especially in children, can result in respiratory depression and death due to an overdose of buprenorphine.

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose .

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5)].

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with buprenorphine transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered .

Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration (2.2), Warnings and Precautions (5.1,5.3), Overdosage (10)].

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of buprenorphine transdermal system with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.2), Overdosage (10)].

Advise both patients and caregivers about the risks of respiratory depression and sedation when buprenorphine transdermal system is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7), Patient Counseling Information (17)].

Use of buprenorphine transdermal system for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1)] .

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following:

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1‑800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint.

Advise patients and their caregivers to avoid exposing the buprenorphine transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds while wearing the system because an increase in absorption of buprenorphine may occur  [see Clinical Pharmacology ( 12.3)] . Advise patients against exposure of the buprenorphine transdermal system application site and surrounding area to hot water or prolonged exposure to direct sunlight. There is a potential for temperature-dependent increases in buprenorphine released from the system resulting in possible overdose and death.

Regularly evaluate patients wearing buprenorphine transdermal system systems who develop fever or increased core body temperature due to strenuous exertion for opioid side effects and adjust the buprenorphine transdermal system dose if signs of respiratory or central nervous system depression occur.

In rare cases, severe application site skin reactions with signs of marked inflammation including “burn,” “discharge,” and “vesicles” have occurred. Time of onset varies, ranging from days to months following the initiation of buprenorphine transdermal system treatment. Instruct patients to promptly report the development of severe application site reactions and discontinue therapy.

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. 

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5), Warnings and Precautions (5.19)].

The use of buprenorphine transdermal system in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease:Buprenorphine transdermal system-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of buprenorphine transdermal system [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients:Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2)].

Regularly evaluate patients particularly when initiating and titrating buprenorphine transdermal system and when buprenorphine transdermal system is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2,5.3) ,Drug Interactions (7)]. Alternatively, consider the use of non-opioid analgesics in these patients.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Buprenorphine transdermal system may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7)] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of buprenorphine transdermal system. In patients with circulatory shock, buprenorphine transdermal system may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of buprenorphine transdermal system in patients with circulatory shock.

In patients who may be susceptible to the intracranial effects of CO 2retention (e.g., those with evidence of increased intracranial pressure or brain tumors), buprenorphine transdermal system may reduce respiratory drive, and the resultant CO 2retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with buprenorphine transdermal system.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of buprenorphine transdermal system in patients with impaired consciousness or coma.

Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving sublingual buprenorphine for the treatment of opioid dependence, both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injection drug abuse may have played a causative or contributory role. For patients at increased risk of hepatotoxicity (e.g., patients with a history of excessive alcohol intake, intravenous drug abuse or liver disease), obtain baseline liver enzyme levels and monitor periodically and during treatment with buprenorphine transdermal system.

Buprenorphine transdermal system is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The buprenorphine in buprenorphine transdermal system may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

The buprenorphine in buprenorphine transdermal system may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during buprenorphine transdermal system therapy.

Thorough QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec. This QTc prolongation effect does not appear to be mediated by hERG channels. Based on these two findings, buprenorphine is unlikely to be pro-arrhythmic when used alone in patients without risk factors. The risk of combining buprenorphine with other QT-prolonging agents is not known.

Consider these observations in clinical decisions when prescribing buprenorphine transdermal system to patients with risk factors such as hypokalemia, bradycardia, recent conversion from atrial fibrillation, congestive heart failure, digitalis therapy, baseline QT prolongation, subclinical long-QT syndrome, or severe hypomagnesemia.

Cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in the post-marketing experience. The most common signs and symptoms include rashes, hives, and pruritus. Cases of bronchospasm, angioneurotic edema, and anaphylactic shock have been reported. A history of hypersensitivity to buprenorphine is a contraindication to the use of buprenorphine transdermal system.

Do not abruptly discontinue buprenorphine in a patient physically dependent on opioids. When discontinuing buprenorphine transdermal system in a physically dependent patient, gradually taper the dosage. Rapid tapering of buprenorphine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5), Drug Abuse and Dependence (9.3)].

Additionally, the use of buprenorphine transdermal system, a partial agonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms. Avoid concomitant use of buprenorphine transdermal system with a full opioid agonist analgesic.

Buprenorphine transdermal system may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of buprenorphine transdermal system and know how they will react to the medication.

Buprenorphine transdermal system has not been studied and is not approved for use in the management of addictive disorders.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 5,415 patients were treated with buprenorphine transdermal system in controlled and open-label chronic pain clinical trials. Nine hundred twenty-four subjects were treated for approximately six months and 183 subjects were treated for approximately one year. The clinical trial population consisted of patients with persistent moderate to severe pain.

The most common serious adverse drug reactions (all <0.1%) occurring during clinical trials with buprenorphine transdermal system were: chest pain, abdominal pain, vomiting, dehydration, and hypertension/blood pressure increased.

The most common adverse events (≥ 2%) leading to discontinuation were: nausea, dizziness, vomiting, headache, and somnolence.

The most common adverse reactions (≥ 5%) reported by patients in clinical trials comparing buprenorphine transdermal system 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing buprenorphine transdermal system 20 mcg/hour to buprenorphine transdermal system 5 mcg/hour are shown in Table 3 below:

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 2: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold">Open-Label <br/> Titration Period </span> </p> <p> <span class="Bold">Buprenorphine</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Double-Blind Treatment Period</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Buprenorphine</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Placebo</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">MedDRA Preferred Term</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 1024)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 256)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 283)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule">23%</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Dizziness</td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site pruritus</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Somnolence</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Vomiting</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 3: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients</span> </caption> <col/> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2"></td><td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2"> <p class="First"> <span class="Bold">Open-Label <br/> Titration Period </span> </p> <p> <span class="Bold">Buprenorphine</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Double-Blind Treatment Period</span></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Buprenorphine 20</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">Buprenorphine 5</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">MedDRA Preferred Term</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 1160)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 219)</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">(N = 221)</span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td><td align="center" class="Botrule Lrule Rrule Toprule">11%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site pruritus</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Somnolence</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Dizziness</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site erythema</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td><td align="center" class="Botrule Lrule Rrule Toprule">10%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site rash</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td><td align="center" class="Botrule Lrule Rrule Toprule">8%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Application site irritation</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> </tbody> </table></div>

The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-controlled titration-to-effect trials.

<div class="scrollingtable"><table border="1" width="80%"> <caption> <span>Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active-Controlled Clinical Trials with Incidence ≥ 2%</span> </caption> <col width="33*"/> <col width="33*"/> <col width="33*"/> <tbody class="Headless"> <tr class="First"> <td class="Lrule Rrule"><span class="Bold">MedDRA Preferred Term</span></td><td align="center" class="Lrule Rrule"><span class="Bold">Buprenorphine <br/> (N = 392) </span></td><td align="center" class="Lrule Rrule"><span class="Bold">Placebo <br/> (N = 261) </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Nausea</td><td align="center" class="Botrule Lrule Rrule Toprule">21%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site pruritus</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td><td align="center" class="Botrule Lrule Rrule Toprule">12%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Dizziness</td><td align="center" class="Botrule Lrule Rrule Toprule">15%</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Headache</td><td align="center" class="Botrule Lrule Rrule Toprule">14%</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Somnolence</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">4%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Constipation</td><td align="center" class="Botrule Lrule Rrule Toprule">13%</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Vomiting</td><td align="center" class="Botrule Lrule Rrule Toprule">9%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site erythema</td><td align="center" class="Botrule Lrule Rrule Toprule">7%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Application site rash</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Dry mouth</td><td align="center" class="Botrule Lrule Rrule Toprule">6%</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Fatigue</td><td align="center" class="Botrule Lrule Rrule Toprule">5%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td>Hyperhidrosis</td><td align="center">4%</td><td align="center">1%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Peripheral edema</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td><td align="center" class="Botrule Lrule Rrule Toprule">1%</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Pruritus</td><td align="center" class="Botrule Lrule Rrule Toprule">3%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Stomach discomfort</td><td align="center" class="Botrule Lrule Rrule Toprule">2%</td><td align="center" class="Botrule Lrule Rrule Toprule">0%</td> </tr> </tbody> </table></div>

The adverse reactions seen in controlled and open-label studies are presented below in the following manner: most common (≥ 5%), common (≥ 1% to < 5%), and less common (< 1%).

The most common adverse reactions (≥ 5%) reported by patients treated with buprenorphine transdermal system in the clinical trials were nausea, headache, application site pruritus, dizziness, constipation, somnolence, vomiting, application site erythema, dry mouth, and application site rash.

The common (≥ 1% to < 5%) adverse reactions reported by patients treated with buprenorphine transdermal system in the clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were:

Gastrointestinal disorders: diarrhea, dyspepsia, and upper abdominal pain

General disorders and administration site conditions: fatigue, peripheral edema, application site irritation, pain, pyrexia, chest pain, and asthenia

Infections and infestations: urinary tract infection, upper respiratory tract infection, nasopharyngitis, influenza, sinusitis, and bronchitis

Injury, poisoning and procedural complications: fall

Metabolism and nutrition disorders: anorexia

Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity, muscle spasms, musculoskeletal pain, joint swelling, neck pain, and myalgia

Nervous system disorders: hypoesthesia, tremor, migraine, and paresthesia

Psychiatric disorders: insomnia, anxiety, and depression

Respiratory, thoracic and mediastinal disorders: dyspnea, pharyngolaryngeal pain, and cough

Skin and subcutaneous tissue disorders: pruritus, hyperhidrosis, rash, and generalized pruritus

Vascular disorders: hypertension

Other less common adverse reactions, including those known to occur with opioid treatment, that were seen in < 1% of the patients in the buprenorphine transdermal system trials include the following in alphabetical order:

Abdominal distention, abdominal pain, accidental injury, affect lability, agitation, alanine aminotransferase increased, angina pectoris, angioedema, apathy, application site dermatitis, asthma aggravated, bradycardia, chills, confusional state, contact dermatitis, coordination abnormal, dehydration, depersonalization, depressed level of consciousness, depressed mood, disorientation, disturbance in attention, diverticulitis, drug hypersensitivity, drug withdrawal syndrome, dry eye, dry skin, dysarthria, dysgeusia, dysphagia, euphoric mood, face edema, flatulence, flushing, gait disturbance, hallucination, hiccups, hot flush, hyperventilation, hypotension, hypoventilation, ileus, insomnia, libido decreased, loss of consciousness, malaise, memory impairment, mental impairment, mental status changes, miosis, muscle weakness, nervousness, nightmare, orthostatic hypotension, palpitations, psychotic disorder, respiration abnormal, respiratory depression, respiratory distress, respiratory failure, restlessness, rhinitis, sedation, sexual dysfunction, syncope, tachycardia, tinnitus, urinary hesitation, urinary incontinence, urinary retention, urticaria, vasodilatation, vertigo, vision blurred, visual disturbance, weight decreased, and wheezing.

The following adverse reactions have been identified during post approval use of buprenorphine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in buprenorphine transdermal system.

Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2)].

Hyperalgesia and Allodynia:Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.9)].

Hypoglycemia:Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

Table 5 Includes clinically significant drug interactions with buprenorphine transdermal system.

{ "type": "p", "children": [], "text": "Table 5 Includes clinically significant drug interactions with buprenorphine transdermal system." }

<div class="scrollingtable"><table border="1" width="100%"> <caption> <span>Table 5: Significant Drug Interactions with Buprenorphine Transdermal System</span> </caption> <col width="18*"/> <col width="81*"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Benzodiazepines</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Regularly evaluate patients with concurrent use of buprenorphine transdermal system and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine transdermal system and warn patients to use benzodiazepines concurrently with buprenorphine transdermal system only as directed by their physician.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#Section_5.2">5.3</a></span><span class="Italics">)].</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose  <span class="Italics">[see Dosage and Administration ( <a href="#_44426b62-a8c4-ead9-4b57-f783ff8c5075">2.2</a>), Warnings and Precautions <a href="#Section_5.1">(5.1</a>, </span><span class="Italics"><a href="#_b4aea535-3389-d718-3e21-3296906bf9b8">5.2</a></span><span class="Italics">,</span><span class="Italics"><a href="#Section_5.2">5.3</a></span><span class="Italics">)]</span>. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Inhibitors of CYP3A4</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine transdermal system is achieved. <br/> <br/> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease <span class="Italics">[see Clinical Pharmacology ( <a href="#Section_12.3">12.3</a>)] </span>, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">If concomitant use is necessary, consider dosage reduction of buprenorphine transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. <br/> <br/> If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">CYP3A4 Inducers</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine <span class="Italics">[see Clinical Pharmacology ( <a href="#Section_12.3">12.3</a>)] </span>, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. <br/> <br/> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase <span class="Italics">[see Clinical Pharmacology ( <a href="#Section_12.3">12.3</a>)] </span>, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">If concomitant use is necessary, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. <br/> <br/> If a CYP3A4 inducer is discontinued, consider buprenorphine transdermal system dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. </td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Rifampin, carbamazepine, phenytoin</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Serotonergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine transdermal system if serotonin syndrome is suspected.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Monoamine Oxidase Inhibitors (MAOIs)</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <span class="Italics">[see Warnings and Precautions (</span><span class="Italics"><a href="#_b4aea535-3389-d718-3e21-3296906bf9b8">5.2</a></span><span class="Italics">)]</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">The use of buprenorphine transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">phenelzine, tranylcypromine, linezolid</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Mixed Agonist/Antagonist Opioid Analgesics</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">May reduce the analgesic effect of buprenorphine transdermal system and/or precipitate withdrawal symptoms.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Avoid concomitant use.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Examples:</span></td><td class="Botrule Lrule Rrule Toprule">butorphanol, nalbuphine, pentazocine</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Muscle Relaxants</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Because respiratory depression  may be greater than otherwise expected, decrease the dosage of buprenorphine transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <span class="Italics">[see Dosage and Administration ( <a href="#Section_10">2.2</a>), Warnings and Precautions ( <a href="#_b4aea535-3389-d718-3e21-3296906bf9b8">5.2</a>,  <a href="#Section_5.4">5.3</a>)]. </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Diuretics</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"><span class="Bold">Anticholinergic Drugs</span></td> </tr> <tr> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Clinical Impact:</span></td><td class="Botrule Lrule Rrule Toprule">The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td> </tr> <tr class="Last"> <td align="right" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Italics">Intervention:</span></td><td class="Botrule Lrule Rrule Toprule">Evaluate patients for signs of urinary retention or reduced gastric motility when buprenorphine transdermal system is used concomitantly with anticholinergic drugs.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"1\" width=\"100%\">\n<caption>\n<span>Table 5: Significant Drug Interactions with Buprenorphine Transdermal System</span>\n</caption>\n<col width=\"18*\"/>\n<col width=\"81*\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Regularly evaluate patients with concurrent use of buprenorphine transdermal system and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine transdermal system and warn patients to use benzodiazepines concurrently with buprenorphine transdermal system only as directed by their physician.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Benzodiazepines and Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death\n \n <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#Section_5.2\">5.3</a></span><span class=\"Italics\">)].</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose \n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#_44426b62-a8c4-ead9-4b57-f783ff8c5075\">2.2</a>), Warnings and Precautions\n \n <a href=\"#Section_5.1\">(5.1</a>,\n \n </span><span class=\"Italics\"><a href=\"#_b4aea535-3389-d718-3e21-3296906bf9b8\">5.2</a></span><span class=\"Italics\">,</span><span class=\"Italics\"><a href=\"#Section_5.2\">5.3</a></span><span class=\"Italics\">)]</span>.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Inhibitors of CYP3A4</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine transdermal system is achieved. \n <br/>\n<br/> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#Section_12.3\">12.3</a>)]\n \n </span>, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">If concomitant use is necessary, consider dosage reduction of buprenorphine transdermal system until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. \n <br/>\n<br/> If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal.\n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">CYP3A4 Inducers</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#Section_12.3\">12.3</a>)]\n \n </span>, potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. \n <br/>\n<br/> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase\n \n <span class=\"Italics\">[see Clinical Pharmacology (\n \n <a href=\"#Section_12.3\">12.3</a>)]\n \n </span>, which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.\n \n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">If concomitant use is necessary, consider increasing the buprenorphine transdermal system dosage until stable drug effects are achieved. Assess for signs of opioid withdrawal. \n <br/>\n<br/> If a CYP3A4 inducer is discontinued, consider buprenorphine transdermal system dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.\n </td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Rifampin, carbamazepine, phenytoin</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Serotonergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine transdermal system if serotonin syndrome is suspected.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Monoamine Oxidase Inhibitors (MAOIs)</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)\n \n <span class=\"Italics\">[see Warnings and Precautions (</span><span class=\"Italics\"><a href=\"#_b4aea535-3389-d718-3e21-3296906bf9b8\">5.2</a></span><span class=\"Italics\">)]</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The use of buprenorphine transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">phenelzine, tranylcypromine, linezolid</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Mixed Agonist/Antagonist Opioid Analgesics</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">May reduce the analgesic effect of buprenorphine transdermal system and/or precipitate withdrawal symptoms.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Avoid concomitant use.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Examples:</span></td><td class=\"Botrule Lrule Rrule Toprule\">butorphanol, nalbuphine, pentazocine</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Muscle Relaxants</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Because respiratory depression  may be greater than otherwise expected, decrease the dosage of buprenorphine transdermal system and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose\n \n <span class=\"Italics\">[see Dosage and Administration (\n \n <a href=\"#Section_10\">2.2</a>), Warnings and Precautions (\n \n <a href=\"#_b4aea535-3389-d718-3e21-3296906bf9b8\">5.2</a>, \n \n <a href=\"#Section_5.4\">5.3</a>)].\n \n </span></td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Diuretics</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Anticholinergic Drugs</span></td>\n</tr>\n<tr>\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Clinical Impact:</span></td><td class=\"Botrule Lrule Rrule Toprule\">The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"><span class=\"Italics\">Intervention:</span></td><td class=\"Botrule Lrule Rrule Toprule\">Evaluate patients for signs of urinary retention or reduced gastric motility when buprenorphine transdermal system is used concomitantly with anticholinergic drugs.</td>\n</tr>\n</tbody>\n</table></div>" }

Risk Summary

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4)] . Available data with buprenorphine transdermal system in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, buprenorphine caused an increase in the number of stillborn offspring, reduced litter size, and reduced offspring growth in rats at maternal exposure levels that were approximately 10 times that of human subjects who received one buprenorphine transdermal system 20 mcg/hour, the maximum recommended human dose (MRHD) [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4)].

Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. An opioid antagonist such as naloxone must be available for reversal of opioid-induced respiratory depression in the neonate. Buprenorphine transdermal system is not recommended for use in women immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics, including buprenorphine transdermal system, can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.

Data

Animal Data

Studies in rats and rabbits demonstrated no evidence of teratogenicity following buprenorphine transdermal system or subcutaneous (SC) administration of buprenorphine during the period of organogenesis. Rats were administered up to one buprenorphine transdermal system 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, & 15) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6 to 17). Rabbits were administered four buprenorphine transdermal system 20 mcg/hour every 3 days (Gestation Days 6, 9, 12, 15, 18, and 19) or received daily SC buprenorphine up to 5 mg/kg (Gestation Days 6-19). No teratogenicity was observed at any dose. AUC values for buprenorphine with buprenorphine transdermal system application and SC injection were approximately 110 and 140 times, respectively, that of human subjects who received the MRHD of one buprenorphine transdermal system 20 mcg/hour.

In a pre- and post-natal study conducted in pregnant and lactating rats, administration of buprenorphine either as buprenorphine transdermal system or SC buprenorphine was associated with toxicity to offspring. Buprenorphine was present in maternal milk. Pregnant rats were administered 1/4 of one buprenorphine transdermal system 5 mcg/hour every 3 days or received daily SC buprenorphine at doses of 0.05, 0.5, or 5 mg/kg from Gestation Day 6 to Lactation Day 21 (weaning). Administration of buprenorphine transdermal system or SC buprenorphine at 0.5 or 5 mg/kg caused maternal toxicity and an increase in the number of stillborns, reduced litter size, and reduced offspring growth at maternal exposure levels that were approximately 10 times that of human subjects who received the MRHD of one buprenorphine transdermal system 20 mcg/hour. Maternal toxicity was also observed at the no observed adverse effect level (NOAEL) for offspring.

Risk Summary

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with buprenorphine transdermal system.

Clinical Considerations

Monitor infants exposed to buprenorphine transdermal system through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of buprenorphine is stopped or when breast-feeding is stopped.

Infertility

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6.2), Preclinical Pharmacology ( 12.2), Nonclinical Toxicology ( 13.1)] .

The safety and efficacy of buprenorphine transdermal system in patients under 18 years of age has not been established. Buprenorphine transdermal system has been evaluated in an open-label clinical trial in pediatric patients. However, definitive conclusions are not possible because of the small sample size.

Of the total number of subjects in the clinical trials (5,415), buprenorphine transdermal system was administered to 1,377 patients aged 65 years and older. Of those, 457 patients were 75 years of age and older. In the clinical program, the incidences of selected buprenorphine transdermal system-related AEs were higher in older subjects. The incidences of application site AEs were slightly higher among subjects < 65 years of age than those ≥ 65 years of age for both buprenorphine transdermal system and placebo treatment groups.

In a single-dose study of healthy elderly and healthy young subjects treated with buprenorphine transdermal system 10 mcg/hour, the pharmacokinetics were similar. In a separate dose-escalation safety study, the pharmacokinetics in the healthy elderly and hypertensive elderly subjects taking thiazide diuretics were similar to those in the healthy young adults. In the elderly groups evaluated, adverse event rates were similar to or lower than rates in healthy young adult subjects, except for constipation and urinary retention, which were more common in the elderly. Although specific dose adjustments on the basis of advanced age are not required for pharmacokinetic reasons, use caution in the elderly population to ensure safe use [see Clinical Pharmacology ( 12.3)] .

Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of buprenorphine transdermal system slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.10)] .

In a study utilizing intravenous buprenorphine, peak plasma levels (C max) and exposure (AUC) of buprenorphine in patients with mild and moderate hepatic impairment did not increase as compared to those observed in subjects with normal hepatic function. Buprenorphine transdermal system has not been evaluated in patients with severe hepatic impairment. As buprenorphine transdermal system is intended for 7-day dosing, consider the use of alternate analgesic therapy in patients with severe hepatic impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Buprenorphine transdermal system contains buprenorphine, a Schedule III controlled substance.

Buprenorphine transdermal system contains buprenorphine, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed.

Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of buprenorphine transdermal system increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of buprenorphine transdermal system with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction.

All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of buprenorphine transdermal system abuse include those with a history of prolonged use of any opioid, including products containing buprenorphine, those with a history of drug or alcohol abuse, or those who use buprenorphine transdermal system in combination with other abused drugs.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control.

Buprenorphine transdermal system, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of Buprenorphine Transdermal System

Abuse of buprenorphine transdermal system poses a risk of overdose and death. This risk is increased with the concurrent use of buprenorphine transdermal system with alcohol and/or other substances including other opioids and benzodiazepines [see Warnings and Precautions (5.1,5.3), Drug Interactions (7)].

Buprenorphine transdermal system is approved for transdermal use only.

Intentional compromise of the transdermal delivery system will result in the uncontrolled delivery of buprenorphine and pose a significant risk to the abuser that could result in overdose and death [see Warnings and Precautions (5.1)].Abuse may occur by applying the transdermal system in the absence of legitimate purpose, or by chewing, swallowing, snorting, or injecting buprenorphine extracted from the transdermal system.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Both tolerance and physical dependence can develop during use of opioid therapy.

Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use.

Do not abruptly discontinue buprenorphine transdermal system in a patient physically dependent on opioids. Rapid tapering of buprenorphine transdermal system in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse.

When discontinuing buprenorphine transdermal system, gradually taper the dosage using a patient-specific plan that considers the following: the dose of buprenorphine transdermal system the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.1), Warnings and Precautions (5.19)].

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1)].

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Acute overdosage with buprenorphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology ( 12.2)] .

{ "type": "p", "children": [], "text": "Acute overdosage with buprenorphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations\n \n [see Clinical Pharmacology (\n \n 12.2)]\n \n .\n\n " }

Treatment of Overdose

{ "type": "p", "children": [], "text": "\nTreatment of Overdose\n" }

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures.

{ "type": "p", "children": [], "text": "In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support measures." }

Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. However, naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10 to 35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used.

{ "type": "p", "children": [], "text": "Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. However, naloxone may not be effective in reversing any respiratory depression produced by buprenorphine. High doses of naloxone, 10 to 35 mg/70 kg, may be of limited value in the management of buprenorphine overdose. The onset of naloxone effect may be delayed by 30 minutes or more. Doxapram hydrochloride (a respiratory stimulant) has also been used." }

Remove buprenorphine transdermal system immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from buprenorphine transdermal system, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of buprenorphine transdermal system, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10 to 24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours.

{ "type": "p", "children": [], "text": "Remove buprenorphine transdermal system immediately. Because the duration of reversal would be expected to be less than the duration of action of buprenorphine from buprenorphine transdermal system, carefully monitor the patient until spontaneous respiration is reliably re-established. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects as buprenorphine continues to be absorbed from the skin. After removal of buprenorphine transdermal system, the mean buprenorphine concentrations decrease approximately 50% in 12 hours (range 10 to 24 hours) with an apparent terminal half-life of approximately 26 hours. Due to this long apparent terminal half-life, patients may require monitoring and treatment for at least 24 hours." }

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

{ "type": "p", "children": [], "text": "In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist." }

Buprenorphine transdermal system is a transdermal system providing systemic delivery of buprenorphine, a mu opioid partial agonist analgesic, continuously for 7 days. The chemical name of buprenorphine is (5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol. The structural formula is:

{ "type": "p", "children": [], "text": "Buprenorphine transdermal system is a transdermal system providing systemic delivery of buprenorphine, a mu opioid partial agonist analgesic, continuously for 7 days. The chemical name of buprenorphine is (5R,6R,7R,9R,13S,14S)-17-Cyclopropylmethyl-7-[(S)-3,3-dimethyl-2-hydroxybutan-2-yl]-6-methoxy-4,5-epoxy-6,14-ethanomorphinan-3-ol. The structural formula is:" }

The molecular weight of buprenorphine is 467.64; the empirical formula is C 29H 41NO 4.

{ "type": "p", "children": [], "text": "The molecular weight of buprenorphine is 467.64; the empirical formula is C\n \n 29H\n \n 41NO\n \n 4.\n\n " }

Buprenorphine occurs as a white or almost white crystalline powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol, and slightly soluble in cyclohexane. It dissolves in dilute solutions of acids.

{ "type": "p", "children": [], "text": "Buprenorphine occurs as a white or almost white crystalline powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol, and slightly soluble in cyclohexane. It dissolves in dilute solutions of acids." }

The pKa is 8.35 and the melting point is about 217°C.

{ "type": "p", "children": [], "text": "The pKa is 8.35 and the melting point is about 217°C." }

System Components and Structure

{ "type": "p", "children": [], "text": "\nSystem Components and Structure\n" }

Five different strengths of buprenorphine transdermal system are available: 5, 7.5, 10, 15, and 20 mcg/hour (Table 6). The proportion of buprenorphine mixed in the adhesive matrix is the same in each of the five strengths. The amount of buprenorphine released from each system per hour is proportional to the active surface area of the system. The skin is the limiting barrier to diffusion from the system into the bloodstream.

{ "type": "p", "children": [], "text": "Five different strengths of buprenorphine transdermal system are available: 5, 7.5, 10, 15, and 20 mcg/hour (Table 6). The proportion of buprenorphine mixed in the adhesive matrix is the same in each of the five strengths. The amount of buprenorphine released from each system per hour is proportional to the active surface area of the system. The skin is the limiting barrier to diffusion from the system into the bloodstream." }

Table 6: Buprenorphine Transdermal System Product Specifications

{ "type": "p", "children": [], "text": "\nTable 6: Buprenorphine Transdermal System Product Specifications\n" }

<div class="scrollingtable"><table width="60%"> <tbody align="center" class="Headless"> <tr class="First"> <td align="left"><span class="Bold">Buprenorphine Delivery <br/> Rate (mcg/hour) </span></td><td><span class="Bold">Active Surface <br/> Area (cm <span class="Sup">2</span>) </span></td><td><span class="Bold">Total Buprenorphine <br/> Content (mg) </span></td> </tr> <tr> <td align="left">Buprenorphine transdermal system 5</td><td>6.25</td><td>4.75</td> </tr> <tr> <td align="left">Buprenorphine transdermal system 7.5</td><td>9.375</td><td>7.125</td> </tr> <tr> <td align="left">Buprenorphine transdermal system 10</td><td>12.5</td><td>9.5</td> </tr> <tr> <td align="left">Buprenorphine transdermal system 15</td><td>18.75</td><td>14.25</td> </tr> <tr class="Last"> <td align="left">Buprenorphine transdermal system 20</td><td>25</td><td>19.00</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"60%\">\n<tbody align=\"center\" class=\"Headless\">\n<tr class=\"First\">\n<td align=\"left\"><span class=\"Bold\">Buprenorphine Delivery \n <br/> Rate (mcg/hour)\n </span></td><td><span class=\"Bold\">Active Surface \n <br/> Area (cm\n \n <span class=\"Sup\">2</span>)\n \n </span></td><td><span class=\"Bold\">Total Buprenorphine \n <br/> Content (mg)\n </span></td>\n</tr>\n<tr>\n<td align=\"left\">Buprenorphine transdermal system 5</td><td>6.25</td><td>4.75</td>\n</tr>\n<tr>\n<td align=\"left\">Buprenorphine transdermal system 7.5</td><td>9.375</td><td>7.125</td>\n</tr>\n<tr>\n<td align=\"left\">Buprenorphine transdermal system 10</td><td>12.5</td><td>9.5</td>\n</tr>\n<tr>\n<td align=\"left\">Buprenorphine transdermal system 15</td><td>18.75</td><td>14.25</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\">Buprenorphine transdermal system 20</td><td>25</td><td>19.00</td>\n</tr>\n</tbody>\n</table></div>" }

Buprenorphine transdermal system is a rectangular or square, tan-colored system consisting of a protective liner and functional layers. Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a beige-colored web backing layer; (2) an adhesive rim without buprenorphine; (3) a separating layer over the buprenorphine-containing adhesive matrix; (4) the buprenorphine-containing adhesive matrix; and (5) a peel-off release liner. Before use, the release liner covering the adhesive layer is removed and discarded.

{ "type": "p", "children": [], "text": "Buprenorphine transdermal system is a rectangular or square, tan-colored system consisting of a protective liner and functional layers. Proceeding from the outer surface toward the surface adhering to the skin, the layers are (1) a beige-colored web backing layer; (2) an adhesive rim without buprenorphine; (3) a separating layer over the buprenorphine-containing adhesive matrix; (4) the buprenorphine-containing adhesive matrix; and (5) a peel-off release liner. Before use, the release liner covering the adhesive layer is removed and discarded." }

Figure 1: Cross-Section Diagram of Buprenorphine Transdermal System (not to scale).

{ "type": "p", "children": [], "text": "\nFigure 1: Cross-Section Diagram of Buprenorphine Transdermal System (not to scale).\n" }

The active ingredient in buprenorphine transdermal system is buprenorphine. The inactive ingredients in each system are: levulinic acid, oleyl oleate, povidone, and polyacrylate cross-linked with aluminum.

{ "type": "p", "children": [], "text": "The active ingredient in buprenorphine transdermal system is buprenorphine. The inactive ingredients in each system are: levulinic acid, oleyl oleate, povidone, and polyacrylate cross-linked with aluminum." }

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptors, an agonist at delta-opioid receptors, and a partial agonist at ORL-1 (nociceptin) receptors. The contributions of these actions to its analgesic profile are unclear.

Effects on the Central Nervous System

Buprenorphine produces respiratory depression by direct action on brainstem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brainstem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Buprenorphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen with worsening hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Buprenorphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

Effects on the Cardiovascular System

Buprenorphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on Cardiac Electrophysiology

The effect of buprenorphine transdermal system 10 mcg/hour and 2 x buprenorphine transdermal system 20 mcg/hour on QTc interval was evaluated in a double-blind (buprenorphine transdermal system vs. placebo), randomized, placebo and active-controlled (moxifloxacin 400 mg, open label), parallel-group, dose-escalating, single-dose study in 132 healthy male and female subjects aged 18 to 55 years. The dose escalation sequence for buprenorphine transdermal system during the titration period was: Buprenorphine transdermal system 5 mcg/hour for 3 days, then buprenorphine transdermal system 10 mcg/hour for 3 days, then buprenorphine transdermal system 20 mcg/hour for 3 days, then 2 x buprenorphine transdermal system 20 mcg/hour for 4 days. The QTc evaluation was performed during the third day of buprenorphine transdermal system 10 mcg/hour and the fourth day of 2 x buprenorphine transdermal system 20 mcg/hour when the plasma levels of buprenorphine were at steady state for the corresponding doses [see Warnings and Precautions (5.17)].

There was no clinically meaningful effect on mean QTc with a buprenorphine transdermal system dose of 10 mcg/hour. A buprenorphine transdermal system dose of 40 mcg/hour (given as two 20 mcg/hour buprenorphine transdermal system) prolonged mean QTc by a maximum of 9.2 (90% CI: 5.2-13.3) msec across the 13 assessment time points.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2)] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2)] .

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.  Overall, the effects of opioids appear to be modestly immunosuppressive.

Concentration–Efficacy Relationships

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of buprenorphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1, 2.4)] .

Concentration–Adverse Reaction Relationships

There is a relationship between increasing buprenorphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1, 2.3, 2.4)] .

Absorption

Each buprenorphine transdermal system provides delivery of buprenorphine for 7 days. Steady state was achieved during the first application by Day 3 (see Figure 2).

Figure 2

Mean (SD) Buprenorphine Plasma Concentrations Following Three Consecutive Applications of Buprenorphine Transdermal System 10 mcg/hour (N = 36 Healthy Subjects)

Buprenorphine transdermal system 5, 10, and 20 mcg/hour provide dose-proportional total buprenorphine exposures (AUC) following 7-day applications. Buprenorphine transdermal system single 7-day application and steady-state pharmacokinetic parameters are summarized in Table 7. Plasma buprenorphine concentrations after titration showed no further change over the 60-day period studied.

Table 7: Pharmacokinetic Parameters of Buprenorphine Transdermal System in Healthy Subjects, Mean (%CV)

<div class="scrollingtable"><table width="80%"> <col/> <col/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Single 7-day Application</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC <span class="Sub">inf</span> <br/> (pg.h/mL) </span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">C <span class="Sub">max</span> <br/> (pg/mL) </span></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Buprenorphine transdermal system 5 mcg/hour</td><td align="center" class="Botrule Lrule Rrule Toprule">12087 (37)</td><td align="center" class="Botrule Lrule Rrule Toprule">176 (67)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Buprenorphine transdermal system 10 mcg/hour</td><td align="center" class="Botrule Lrule Rrule Toprule">27035 (29)</td><td align="center" class="Botrule Lrule Rrule Toprule">191 (34)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule">Buprenorphine transdermal system 20 mcg/hour</td><td align="center" class="Botrule Lrule Rrule Toprule">54294 (36)</td><td align="center" class="Botrule Lrule Rrule Toprule">471 (49)</td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"><span class="Bold">Multiple 7-day Applications</span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">AUC <span class="Sub">tau,ss</span> <br/> (pg.h/mL) </span></td><td align="center" class="Botrule Lrule Rrule Toprule"><span class="Bold">C <span class="Sub">max,ss</span> <br/> (pg/mL) </span></td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule">Buprenorphine transdermal system 10 mcg/hour, steady-state</td><td align="center" class="Botrule Lrule Rrule Toprule">27543 (33)</td><td align="center" class="Botrule Lrule Rrule Toprule">224 (35)</td> </tr> </tbody> </table></div>

Transdermal delivery studies showed that intact human skin is permeable to buprenorphine. In clinical pharmacology studies, the median time for buprenorphine transdermal system 10 mcg/hour to deliver quantifiable buprenorphine concentrations (≥ 25 pg/mL) was approximately 17 hours.

The absolute bioavailability of buprenorphine transdermal system relative to IV administration, following a 7-day application, is approximately 15% for all doses (buprenorphine transdermal system 5, 10, and 20 mcg/hour).

Effects of Application Site

A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by buprenorphine transdermal system 10 mcg/hour is similar when applied to the upper outer arm, upper chest, upper back, or the side of the chest [see Dosage and Administration ( 2.7)].

The reapplication of buprenorphine transdermal system 10 mcg/hour after various rest periods to the same application site in healthy subjects showed that the minimum rest period needed to avoid variability in drug absorption is 3 weeks (21 days) [see Dosage and Administration ( 2.7)] .

Effects of Heat

In a study of healthy subjects, application of a heating pad directly on the buprenorphine transdermal system 10 mcg/hour system caused a 26% to 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, instruct patients not to apply heating pads directly to the buprenorphine transdermal system during system wear [see Warnings and Precautions ( 5.6)].

Fever may increase the permeability of the skin, leading to increased buprenorphine concentrations during buprenorphine transdermal system treatment. As a result, febrile patients are at increased risk for the possibility of buprenorphine transdermal system-related reactions during treatment with buprenorphine transdermal system. Monitor patients with febrile illness for adverse effects and consider dose adjustment [see Warnings and Precautions ( 5.7)] . In a crossover study of healthy subjects receiving endotoxin or placebo challenge during buprenorphine transdermal system 10 mcg/hour wear, the AUC and C maxwere similar despite a physiologic response of mild fever to endotoxin.

Distribution

Buprenorphine is approximately 96% bound to plasma proteins, mainly to alpha- and beta-globulin.

Studies of IV buprenorphine have shown a large volume of distribution (approximately 430 L), implying extensive distribution of buprenorphine.

CSF buprenorphine concentrations appear to be approximately 15 to 25% of concurrent plasma concentrations.

Elimination

Metabolism

Buprenorphine metabolism in the skin following buprenorphine transdermal system application is negligible.

Buprenorphine primarily undergoes N-dealkylation by CYP3A4 to norbuprenorphine and glucuronidation by UGT-isoenzymes (mainly UGT1A1 and 2B7) to buprenorphine 3β- O-glucuronide. Norbuprenorphine, the major metabolite, is also glucuronidated (mainly UGT1A3) prior to excretion.

Norbuprenorphine is the only known active metabolite of buprenorphine. It has been shown to be a respiratory depressant in rats, but only at concentrations at least 50-fold greater than those observed following application to humans of buprenorphine transdermal system 20 mcg/hour.

Excretion

Following IV administration, buprenorphine and its metabolites are secreted into bile and excreted in urine.

Following intramuscular administration of 2 mcg/kg dose of buprenorphine, approximately 70% of the dose was excreted in feces within 7 days. Approximately 27% was excreted in urine.

Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. After removal of buprenorphine transdermal system, mean buprenorphine concentrations decrease approximately 50% within 10 to 24 hours, followed by decline with an apparent terminal half-life of approximately 26 hours.

Since metabolism and excretion of buprenorphine occur mainly via hepatic elimination, reductions in hepatic blood flow induced by some general anesthetics (e.g., halothane) and other drugs may result in a decreased rate of hepatic elimination of the drug, leading to increased plasma concentrations.

The total clearance of buprenorphine is approximately 55 L/hour in postoperative patients.

Drug Interaction Studies

Effect of CYP3A4 inhibitors

In a drug-drug interaction study, buprenorphine transdermal system 10 mcg/hour (single dose x 7 days) was coadministered with 200 mg ketoconazole, a strong CYP3A4 inhibitor or ketoconazole placebo twice daily for 11 days and the pharmacokinetics of buprenorphine and its metabolites were evaluated. Plasma buprenorphine concentrations did not accumulate during co-medication with ketoconazole 200 mg twice daily. Based on the results from this study, metabolism during therapy with buprenorphine transdermal system is not expected to be affected by co-administration of CYP3A4 inhibitors [see Drug Interactions ( 7)].

Antiretroviral agents have been evaluated for CYP3A4 mediated interactions with sublingual buprenorphine. Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) do not appear to have clinically significant interactions with buprenorphine. However, certain protease inhibitors (PIs) with CYP3A4 inhibitory activity such as atazanavir and atazanavir/ritonavir resulted in elevated levels of buprenorphine and norbuprenorphine when buprenorphine and naloxone were administered sublingually. C max and AUC for buprenorphine increased by up to 1.6 and 1.9 fold, and C maxand AUC for norbuprenorphine increased by up to 1.6 and 2.0 fold respectively, when sublingual buprenorphine was administered with these PIs. Patients in this study reported increased sedation, and symptoms of opiate excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. It should be noted that atazanavir is both a CYP3A4 and UGT1A1 inhibitor. As such, the drug-drug interaction potential for buprenorphine with CYP3A4 inhibitors is likely to be dependent on the route of administration as well as the specificity of enzyme inhibition [see Drug Interactions ( 7)].

Effect of CYP3A4 Inducers

The interaction between buprenorphine and CYP3A4 inducers has not been studied.

Specific Populations

Age: Geriatric Patients

Following a single application of buprenorphine transdermal system 10 mcg/hour to 12 healthy young adults (mean age 32 years) and 12 healthy elderly subjects (mean age 72 years), the pharmacokinetic profile of buprenorphine transdermal system was similar in healthy elderly and healthy young adult subjects, though the elderly subjects showed a trend toward higher plasma concentrations immediately after buprenorphine transdermal system removal. Both groups eliminated buprenorphine at similar rates after system removal [see Use in Specific Populations ( 8.5)] .

In a study of healthy young subjects, healthy elderly subjects, and elderly subjects treated with thiazide diuretics, buprenorphine transdermal system at a fixed dose-escalation schedule (buprenorphine transdermal system 5 mcg/hour for 3 days, followed by buprenorphine transdermal system 10 mcg/hour for 3 days and buprenorphine transdermal system 20 mcg/hour for 7 days) produced similar mean plasma concentration vs. time profiles for each of the three subject groups. There were no significant differences between groups in buprenorphine C maxor AUC [see Use in Specific Populations ( 8.5)].

Sex

In a pooled data analysis utilizing data from several studies that administered buprenorphine transdermal system 10 mcg/hour to healthy subjects, no differences in buprenorphine C maxand AUC or body-weight normalized C maxand AUC were observed between males and females treated with buprenorphine transdermal system.

Hepatic Impairment

The pharmacokinetics of buprenorphine following an IV infusion of 0.3 mg of buprenorphine were compared in 8 patients with mild impairment (Child-Pugh A), 4 patients with moderate impairment (Child-Pugh B) and 12 subjects with normal hepatic function. Buprenorphine and norbuprenorphine exposure did not increase in the mild and moderate hepatic impairment patients.

Buprenorphine transdermal system has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment. [see Warnings and Precautions ( 5.14), Use in Specific Populations ( 8.6)].

Renal Impairment

No studies in patients with renal impairment have been performed with buprenorphine transdermal system.

In an independent study, the effect of impaired renal function on buprenorphine pharmacokinetics after IV bolus and after continuous IV infusion administrations was evaluated. It was found that plasma buprenorphine concentrations were similar in patients with normal renal function and in patients with impaired renal function or renal failure. In a separate investigation of the effect of intermittent hemodialysis on buprenorphine plasma concentrations in chronic pain patients with end-stage renal disease who were treated with a transdermal buprenorphine product (marketed outside the US) up to 70 mcg/hour, no significant differences in buprenorphine plasma concentrations before or after hemodialysis were observed.

No notable relationship was observed between estimated creatinine clearance rates and steady-state buprenorphine concentrations among patients during buprenorphine transdermal system therapy.

Carcinogenesis

Buprenorphine administered daily by skin painting to Sprague Dawley rats for 100 weeks at dosages (20, 60, or 200 mg/kg) produced systemic exposures (based on AUC) that ranged from approximately 130 to 350 times that of human subjects administered the maximum recommended human dose (MRHD) of buprenorphine transdermal system 20 mcg/hour. An increased incidence of benign testicular interstitial cell tumors, considered buprenorphine treatment-related, was observed in male rats compared with concurrent controls. The tumor incidence was also above the highest incidence in the historical control database of the testing facility. These tumors were noted at 60 mg/kg/day and higher at approximately 220 times the proposed MRHD based on AUC. The no observed effect level (NOEL) was 20 mg/kg/day (approximately 140 times the proposed MRHD based on AUC). The mechanism leading to the tumor findings and the relevance to humans is unknown.

Buprenorphine was administered by skin painting to hemizygous Tg.AC mice over a 6-month study period. At the dosages administered daily (18.75, 37.5, 150, or 600 mg/kg/day), buprenorphine was not carcinogenic or tumorigenic at systemic exposure to buprenorphine, based on AUC, of up to approximately 1000 times that of human subjects administered buprenorphine transdermal system 20 mcg/hour, the MRHD.

Mutagenesis

Buprenorphine was not genotoxic in three in vitro genetic toxicology studies (bacterial mutagenicity test, mouse lymphoma assay, chromosomal aberration assay in human peripheral blood lymphocytes), and in one in vivo mouse micronucleus test.

Impairment of Fertility

Buprenorphine transdermal system (1/4 of a buprenorphine transdermal system 5 mcg/hour, one buprenorphine transdermal system 5 mcg/hour, or one buprenorphine transdermal system 20 mcg/hour every 3 days in males for 4 weeks prior to mating for a total of 10 weeks and in females for 2 weeks prior to mating through Gestation Day 7) had no effect on fertility or general reproductive performance of rats at AUC-based exposure levels as high as approximately 65 times (females) and 100 times (males) that for human subjects who received buprenorphine transdermal system 20 mcg/hour, the MRHD.

The efficacy of buprenorphine transdermal system has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain and one study in osteoarthritis did not show a statistically significant pain reduction for either buprenorphine transdermal system or the respective active comparators.

{ "type": "p", "children": [], "text": "The efficacy of buprenorphine transdermal system has been evaluated in four 12-week double-blind, controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate to severe chronic low back pain or osteoarthritis using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain and one study in osteoarthritis did not show a statistically significant pain reduction for either buprenorphine transdermal system or the respective active comparators." }

12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain

{ "type": "p", "children": [], "text": "\n12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain\n" }

A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to four weeks. Patients initiated therapy with three days of treatment with buprenorphine transdermal system 5 mcg/hour. After three days, if adverse events were tolerated, the dose was increased to buprenorphine transdermal system 10 mcg/hour. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to buprenorphine transdermal system 20 mcg/hour for an additional 10 to 12 days. Patients who achieved adequate analgesia and tolerable adverse effects on buprenorphine transdermal system 10 or 20 mcg/hour were then randomized to remain on their titrated dose of buprenorphine transdermal system or matching placebo. Fifty-three percent of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty-three percent of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons.

{ "type": "p", "children": [], "text": "A total of 1,024 patients with chronic low back pain who were suboptimally responsive to their non-opioid therapy entered an open-label, dose-titration period for up to four weeks. Patients initiated therapy with three days of treatment with buprenorphine transdermal system 5 mcg/hour. After three days, if adverse events were tolerated, the dose was increased to buprenorphine transdermal system 10 mcg/hour. If adverse effects were tolerated but adequate analgesia was not reached, the dose was increased to buprenorphine transdermal system 20 mcg/hour for an additional 10 to 12 days. Patients who achieved adequate analgesia and tolerable adverse effects on buprenorphine transdermal system 10 or 20 mcg/hour were then randomized to remain on their titrated dose of buprenorphine transdermal system or matching placebo. Fifty-three percent of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Twenty-three percent of patients discontinued due to an adverse event from the open-label titration period and 14% discontinued due to lack of a therapeutic effect. The remaining 10% of patients were dropped due to various administrative reasons." }

During the first seven days of double-blind treatment patients were allowed up to two tablets per day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of four tablets per day. Sixty-six percent of the patients treated with buprenorphine transdermal system completed the 12-week treatment compared to 70% of the patients treated with placebo. Of the 256 patients randomized to buprenorphine transdermal system, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events.

{ "type": "p", "children": [], "text": "During the first seven days of double-blind treatment patients were allowed up to two tablets per day of immediate-release oxycodone 5 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to either acetaminophen 500 mg or ibuprofen 200 mg at a maximum of four tablets per day. Sixty-six percent of the patients treated with buprenorphine transdermal system completed the 12-week treatment compared to 70% of the patients treated with placebo. Of the 256 patients randomized to buprenorphine transdermal system, 9% discontinued due to lack of efficacy and 16% due to adverse events. Of the 283 patients randomized to placebo, 13% discontinued due to lack of efficacy and 7% due to adverse events." }

Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the buprenorphine transdermal system and placebo groups, respectively.

{ "type": "p", "children": [], "text": "Of the patients who were randomized, the mean pain (SE) NRS scores were 7.2 (0.08) and 7.2 (0.07) at screening and 2.6 (0.08) and 2.6 (0.07) at pre-randomization (beginning of double-blind phase) for the buprenorphine transdermal system and placebo groups, respectively." }

The score for average pain over the last 24 hours at the end of the study (Week 12/Early Termination) was statistically significantly lower for patients treated with buprenorphine transdermal system compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 3 below.

{ "type": "p", "children": [], "text": "The score for average pain over the last 24 hours at the end of the study (Week 12/Early Termination) was statistically significantly lower for patients treated with buprenorphine transdermal system compared with patients treated with placebo. The proportion of patients with various degrees of improvement, from screening to study endpoint, is shown in Figure 3 below." }

Figure 3: Percent Reduction in Pain Intensity

{ "type": "p", "children": [], "text": "\nFigure 3: Percent Reduction in Pain Intensity\n" }

12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain

{ "type": "p", "children": [], "text": "\n12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain\n" }

One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30 to 80 mg morphine equivalent) entered an open-label, dose-titration period with buprenorphine transdermal system for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with buprenorphine transdermal system 10 mcg/hour for three days. After three days, if the patient tolerated the adverse effects, the dose was increased to buprenorphine transdermal system 20 mcg/hour for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on buprenorphine transdermal system 20 mcg/hour were randomized to remain on buprenorphine transdermal system 20 mcg/hour or were switched to a low-dose control (buprenorphine transdermal system 5 mcg/hour) or an active control. Fifty-seven percent of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of buprenorphine transdermal system 20 mcg/hour and were randomized into a 12-week double-blind treatment phase. Twelve percent of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period.

{ "type": "p", "children": [], "text": "One thousand one hundred and sixty (1,160) patients on chronic opioid therapy (total daily dose 30 to 80 mg morphine equivalent) entered an open-label, dose-titration period with buprenorphine transdermal system for up to 3 weeks, following taper of prior opioids. Patients initiated therapy with buprenorphine transdermal system 10 mcg/hour for three days. After three days, if the patient tolerated the adverse effects, the dose was increased to buprenorphine transdermal system 20 mcg/hour for up to 18 days. Patients with adequate analgesia and tolerable adverse effects on buprenorphine transdermal system 20 mcg/hour were randomized to remain on buprenorphine transdermal system 20 mcg/hour or were switched to a low-dose control (buprenorphine transdermal system 5 mcg/hour) or an active control. Fifty-seven percent of the patients who entered the open-label titration period were able to titrate to and tolerate the adverse effects of buprenorphine transdermal system 20 mcg/hour and were randomized into a 12-week double-blind treatment phase. Twelve percent of patients discontinued due to an adverse event and 21% discontinued due to lack of a therapeutic effect during the open-label titration period." }

During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hours as needed for supplemental analgesia (up to 3200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty-seven percent of patients treated with buprenorphine transdermal system 20 mcg/hour and 58% of patients treated with buprenorphine transdermal system 5 mcg/hour completed the 12-week treatment. Of the 219 patients randomized to buprenorphine transdermal system 20 mcg/hour, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to buprenorphine transdermal system 5 mcg/hour, 24% discontinued due to lack of efficacy and 6% due to adverse events.

{ "type": "p", "children": [], "text": "During the double-blind period, patients were permitted to take ibuprofen (200 mg tablets) or acetaminophen (500 mg tablets) every 4 hours as needed for supplemental analgesia (up to 3200 mg of ibuprofen and 4 grams of acetaminophen daily). Sixty-seven percent of patients treated with buprenorphine transdermal system 20 mcg/hour and 58% of patients treated with buprenorphine transdermal system 5 mcg/hour completed the 12-week treatment. Of the 219 patients randomized to buprenorphine transdermal system 20 mcg/hour, 11% discontinued due to lack of efficacy and 13% due to adverse events. Of the 221 patients randomized to buprenorphine transdermal system 5 mcg/hour, 24% discontinued due to lack of efficacy and 6% due to adverse events." }

Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at pre-randomization (beginning of Double-Blind Period) for the buprenorphine transdermal system 5 mcg/hour and buprenorphine transdermal system 20 mcg/hour, respectively.

{ "type": "p", "children": [], "text": "Of the patients who were able to be randomized in the double-blind period, the mean pain (SE) NRS scores were 6.4 (0.08) and 6.5 (0.08) at screening and were 2.8 (0.08) and 2.9 (0.08) at pre-randomization (beginning of Double-Blind Period) for the buprenorphine transdermal system 5 mcg/hour and buprenorphine transdermal system 20 mcg/hour, respectively." }

The score for average pain over the last 24 hours at Week 12 was statistically significantly lower for subjects treated with buprenorphine transdermal system 20 mcg/hour compared to subjects treated with buprenorphine transdermal system 5 mcg/hour. A higher proportion of buprenorphine transdermal system 20 mcg/hour patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to buprenorphine transdermal system 5 mcg/hour patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 4 below.

{ "type": "p", "children": [], "text": "The score for average pain over the last 24 hours at Week 12 was statistically significantly lower for subjects treated with buprenorphine transdermal system 20 mcg/hour compared to subjects treated with buprenorphine transdermal system 5 mcg/hour. A higher proportion of buprenorphine transdermal system 20 mcg/hour patients (49%) had at least a 30% reduction in pain score from screening to study endpoint when compared to buprenorphine transdermal system 5 mcg/hour patients (33%). The proportion of patients with various degrees of improvement from screening to study endpoint is shown in Figure 4 below." }

Figure 4: Percent Reduction in Pain Intensity

{ "type": "p", "children": [], "text": "\nFigure 4: Percent Reduction in Pain Intensity\n" }

Buprenorphine Transdermal System is supplied in cartons containing 4 individually packaged systems and a pouch containing 4 Patch-Disposal Units.

{ "type": "p", "children": [], "text": "Buprenorphine Transdermal System is supplied in cartons containing 4 individually packaged systems and a pouch containing 4 Patch-Disposal Units." }

Buprenorphine 5 mcg/hour Transdermal Systems are square, tan-colored adhesive patches with rounded corners measuring 45 mm by 45 mm. Each system is printed in blue with Buprenorphine and 5 mcg/hr and are supplied in a 4-count carton ( NDC 50742-372-04).

{ "type": "p", "children": [], "text": "Buprenorphine 5 mcg/hour Transdermal Systems are square, tan-colored adhesive patches with rounded corners measuring 45 mm by 45 mm. Each system is printed in blue with Buprenorphine and 5 mcg/hr and are supplied in a 4-count carton (\n \n NDC 50742-372-04).\n\n " }

Buprenorphine 7.5 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 57.5 mm by 45 mm. Each system is printed in blue with Buprenorphine and 7.5 mcg/hr and are supplied in a 4-count carton ( NDC 50742-373-04).

{ "type": "p", "children": [], "text": "Buprenorphine 7.5 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 57.5 mm by 45 mm. Each system is printed in blue with Buprenorphine and 7.5 mcg/hr and are supplied in a 4-count carton (\n \n NDC 50742-373-04).\n\n " }

Buprenorphine 10 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 68 mm by 45 mm. Each system is printed in blue with Buprenorphine and 10 mcg/hr and are supplied in a 4-count carton ( NDC50742-374-04).

{ "type": "p", "children": [], "text": "Buprenorphine 10 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 68 mm by 45 mm. Each system is printed in blue with Buprenorphine and 10 mcg/hr and are supplied in a 4-count carton (\n \n NDC50742-374-04).\n\n " }

Buprenorphine 15 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 72 mm by 59 mm. Each system is printed in blue with Buprenorphine and 15 mcg/hr and are supplied in a 4-count carton ( NDC 50742-375-04).

{ "type": "p", "children": [], "text": "Buprenorphine 15 mcg/hour Transdermal Systems are rectangular, tan-colored adhesive patches with rounded corners measuring 72 mm by 59 mm. Each system is printed in blue with Buprenorphine and 15 mcg/hr and are supplied in a 4-count carton (\n \n NDC 50742-375-04).\n\n " }

Buprenorphine 20 mcg/hour Transdermal Systems are square, tan-colored adhesive patches with rounded corners measuring 72 mm by 72 mm. Each system is printed in blue with Buprenorphine and 20mcg/hr and are supplied in a 4-count carton ( NDC 50742-376-04).

{ "type": "p", "children": [], "text": "Buprenorphine 20 mcg/hour Transdermal Systems are square, tan-colored adhesive patches with rounded corners measuring 72 mm by 72 mm. Each system is printed in blue with Buprenorphine and 20mcg/hr and are supplied in a 4-count carton (\n \n NDC 50742-376-04).\n\n " }

Store buprenorphine transdermal system securely and dispose of properly [see Patient Counseling Information ( 17)] .

{ "type": "p", "children": [], "text": "Store buprenorphine transdermal system securely and dispose of properly\n \n [see Patient Counseling Information (\n \n 17)]\n \n .\n\n " }

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Storage and Disposal:

{ "type": "p", "children": [], "text": "\nStorage and Disposal:\n" }

Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store buprenorphine transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving buprenorphine transdermal system unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1,5.2, Drug Abuse and Dependence (9.2)].

{ "type": "p", "children": [], "text": "Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store buprenorphine transdermal system securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving buprenorphine transdermal system unsecured can pose a deadly risk to others in the home\n \n [see Warnings and Precautions (5.1,5.2, Drug Abuse and Dependence (9.2)].\n\n " }

Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Buprenorphine transdermal system patches can be disposed of by using the Patch-Disposal Unit [see Instructions for Use]. Alternatively, expired, unwanted, or unused buprenorphine transdermal system should be disposed of by folding the patch in half and flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.

{ "type": "p", "children": [], "text": "Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Buprenorphine transdermal system patches can be disposed of by using the Patch-Disposal Unit\n \n [see Instructions for Use]. Alternatively, expired, unwanted, or unused buprenorphine transdermal system should be disposed of by folding the patch in half and flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.\n\n " }

Addiction, Abuse, and Misuse

{ "type": "p", "children": [], "text": "\nAddiction, Abuse, and Misuse\n" }

Inform patients that the use of buprenorphine transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death [see Warnings and Precautions (5.1)].Instruct patients not to share buprenorphine transdermal system with others and to take steps to protect buprenorphine transdermal system from theft or misuse.

{ "type": "p", "children": [], "text": "Inform patients that the use of buprenorphine transdermal system, even when taken as recommended, can result in addiction, abuse, and misuse, which could lead to overdose and death\n \n [see Warnings and Precautions (5.1)].Instruct patients not to share buprenorphine transdermal system with others and to take steps to protect buprenorphine transdermal system from theft or misuse.\n\n " }

Life-Threatening Respiratory Depression

{ "type": "p", "children": [], "text": "\nLife-Threatening Respiratory Depression\n" }

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine transdermal system or when the dosage is increased, and that it can occur even at recommended doses.

{ "type": "p", "children": [], "text": "Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting buprenorphine transdermal system or when the dosage is increased, and that it can occur even at recommended doses." }

Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2), Overdosage (10)] .

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose\n \n [see Warnings and Precautions (5.2), Overdosage (10)]\n \n .\n\n " }

Accidental Exposure

{ "type": "p", "children": [], "text": "\nAccidental Exposure\n" }

Inform patients that accidental exposure, especially in children, may result in respiratory depression or death [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Inform patients that accidental exposure, especially in children, may result in respiratory depression or death\n \n [see Warnings and Precautions (5.2)].\n\n " }

Interaction with Benzodiazepines

{ "type": "p", "children": [], "text": "\nInteraction with Benzodiazepines\n" }

Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine transdermal system, and warn patients to use benzodiazepines concurrently with buprenorphine transdermal system only as directed by their physician [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine transdermal system, and warn patients to use benzodiazepines concurrently with buprenorphine transdermal system only as directed by their physician\n \n [see Drug Interactions (7)].\n\n " }

Interaction with Benzodiazepines and Other CNS Depressants

{ "type": "p", "children": [], "text": "\nInteraction with Benzodiazepines and Other CNS Depressants\n" }

Inform patients and caregivers that potentially fatal additive effects may occur if buprenorphine transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers that potentially fatal additive effects may occur if buprenorphine transdermal system is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider\n \n [see Warnings and Precautions (5.3)].\n\n " }

Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose

{ "type": "p", "children": [], "text": "\nPatient Access to Naloxone for the Emergency Treatment of Opioid Overdose\n" }

Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with buprenorphine transdermal system. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program)\n \n [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].\n\n " }

Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.

{ "type": "p", "children": [], "text": "Educate patients and caregivers on how to recognize the signs and symptoms of an overdose." }

Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)].

{ "type": "p", "children": [], "text": "Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered\n \n [see Overdosage (10)].\n\n " }

If naloxone is prescribed, also advise patients and caregivers:

{ "type": "p", "children": [], "text": "If naloxone is prescribed, also advise patients and caregivers:" }

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Hyperalgesia and Allodynia

{ "type": "p", "children": [], "text": "\nHyperalgesia and Allodynia\n" }

Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain\n \n [see Warnings and Precautions (5.9), Adverse Reactions (6.2)].\n\n " }

Serotonin Syndrome

{ "type": "p", "children": [], "text": "\nSerotonin Syndrome\n" }

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications [see Drug Interactions (7)] .

{ "type": "p", "children": [], "text": "Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their physicians if they are taking, or plan to take serotonergic medications\n \n [see Drug Interactions (7)]\n \n .\n" }

MAOI Interaction

{ "type": "p", "children": [], "text": "\nMAOI Interaction\n" }

Inform patients to avoid taking buprenorphine transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking buprenorphine transdermal system [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Inform patients to avoid taking buprenorphine transdermal system while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking buprenorphine transdermal system\n \n [see Drug Interactions (7)].\n\n " }

Important Administration Instructions

{ "type": "p", "children": [], "text": "\nImportant Administration Instructions\n" }

Instruct patients how to properly use buprenorphine transdermal system, including the following:

{ "type": "p", "children": [], "text": "\nInstruct patients how to properly use buprenorphine transdermal system, including the following:\n" }

{ "type": "", "children": [], "text": "" }

Important Discontinuation Instructions

{ "type": "p", "children": [], "text": "\nImportant Discontinuation Instructions\n" }

In order to avoid developing withdrawal symptoms, instruct patients not to discontinue buprenorphine transdermal system without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5)].

{ "type": "p", "children": [], "text": "In order to avoid developing withdrawal symptoms, instruct patients not to discontinue buprenorphine transdermal system without first discussing a tapering plan with the prescriber\n \n [see Dosage and Administration (2.5)].\n\n " }

Driving or Operating Heavy Machinery

{ "type": "p", "children": [], "text": "\nDriving or Operating Heavy Machinery\n" }

Inform patients that buprenorphine transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.20)].

{ "type": "p", "children": [], "text": "Inform patients that buprenorphine transdermal system may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication\n \n [see Warnings and Precautions (5.20)].\n\n " }

Constipation

{ "type": "p", "children": [], "text": "\nConstipation\n" }

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology (12.2)].

{ "type": "p", "children": [], "text": "Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention\n \n [see Adverse Reactions (6), Clinical Pharmacology (12.2)].\n\n " }

Adrenal Insufficiency

{ "type": "p", "children": [], "text": "\nAdrenal Insufficiency\n" }

Inform patients that buprenorphine transdermal system could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Inform patients that buprenorphine transdermal system could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms\n \n [see Warnings and Precautions (5.11)].\n\n " }

Hypotension

{ "type": "p", "children": [], "text": "\nHypotension\n" }

Inform patients that buprenorphine transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.12)] .

{ "type": "p", "children": [], "text": "Inform patients that buprenorphine transdermal system may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position)\n \n [see Warnings and Precautions (\n \n 5.12)]\n \n .\n\n " }

Anaphylaxis

{ "type": "p", "children": [], "text": "\nAnaphylaxis\n" }

Inform patients that anaphylaxis has been reported with ingredients contained in buprenorphine transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.18), Contraindications (4), Adverse Reactions (6)].

{ "type": "p", "children": [], "text": "Inform patients that anaphylaxis has been reported with ingredients contained in buprenorphine transdermal system. Advise patients how to recognize such a reaction and when to seek medical attention\n \n [see Warnings and Precautions (5.18), Contraindications (4), Adverse Reactions (6)].\n" }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Neonatal Opioid Withdrawal Syndrome

{ "type": "p", "children": [], "text": "\nNeonatal Opioid Withdrawal Syndrome\n" }

Inform female patients of reproductive potential the use of buprenorphine transdermal system for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4)], Use in Specific Populations (8.1).

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential the use of buprenorphine transdermal system for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated\n \n [see Warnings and Precautions (5.4)], Use in Specific Populations (8.1).\n" }

Embryofetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryofetal Toxicity\n" }

Inform female patients of reproductive potential that buprenorphine transdermal system can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Inform female patients of reproductive potential that buprenorphine transdermal system can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy\n \n [see Use in Specific Populations (8.1)].\n\n " }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Advise patients that breastfeeding is not recommended during treatment with buprenorphine transdermal system [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise patients that breastfeeding is not recommended during treatment with buprenorphine transdermal system\n \n [see Use in Specific Populations (8.2)].\n" }

Infertility

{ "type": "p", "children": [], "text": "\nInfertility\n" }

Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible\n \n [see Use in Specific Populations (8.3)].\n" }

Healthcare professionals can telephone Ingenus Pharmaceuticals, LLC at 1-877-748-1970 for information on this product.

{ "type": "p", "children": [], "text": "Healthcare professionals can telephone Ingenus Pharmaceuticals, LLC at 1-877-748-1970 for information on this product." }

Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193

{ "type": "p", "children": [], "text": "\nManufactured for:\n Ingenus Pharmaceuticals, LLC \n Orlando, FL 32811-7193\n\n " }

Revised: June 2024

{ "type": "p", "children": [], "text": "Revised: June 2024" }

Instructions for Use Buprenorphine Transdermal System, CIII (bueʺ pre nor´ feen)

Be sure that you read, understand, and follow these Instructions for Use before you use buprenorphine transdermal system. Talk to your healthcare provider or pharmacist if you have any questions.

Before Applying Buprenorphine Transdermal System:

Where to apply buprenorphine transdermal system:

When to apply a new patch:

How to apply buprenorphine transdermal system:

If the patch falls off right away after applying, throw it away and put a new one on at a different skin site ( See “Disposing of Buprenorphine Transdermal System Patch”).

If a patch falls off, do not touch the sticky side of the patch with your fingers. A new patch should be applied to a different site. Patches that fall off should not be re-applied. They must be thrown away correctly.

Short-term exposure of the buprenorphine transdermal system patch to water, such as when bathing or showering, is permitted.

If the edges of the buprenorphine transdermal system patch start to loosen:

If your patch falls off later, but before 1 week (7 days) of use, throw it away properly ( See “Disposing of a Buprenorphine Transdermal System Patch”)and apply a new patch at a different skin site. Be sure to let your healthcare provider know that this has happened. Do not replace the new patch until 1 week (7 days) after you put it on (or as directed by your healthcare provider).

Disposing of Buprenorphine Transdermal System Patch:

Buprenorphine transdermal system patches should be disposed of by using the Patch-Disposal Unit. Alternatively, the patches can be flushed down the toilet if a drug take-back option is not readily available.

To dispose of buprenorphine transdermal system patches in household trash using the Patch-Disposal Unit: Remove your patch and follow the directions printed on the Patch-Disposal Unit ( See Figure J) or see complete instructions below . Use one Patch-Disposal Unit for each patch.

1. Fold the sticky sides of a used buprenorphine patch together. ( See Figure K).

2. Open the Patch-Disposal Unit pocket and place the folded buprenorphine transdermal system patch into the pocket. ( See Figure L).

3. Peel back the Patch-Disposal Unit liner to show the sticky surface. Close the disposal unit by folding the sticky side to the printed pouch surface. ( See Figure M). Press firmly and smoothly over the entire disposal unit so that the patch is sealed within.

4. The closed disposal unit, with the patch sealed inside may be thrown away in the trash ( See Figure N).

Do not putexpired, unwanted or unused patches in household trash without first sealing them in the Patch-Disposal Unit.

Always remove the leftover patches from their protective pouch and remove the protective liner.The pouch and liner can be disposed of separately in the trash and should not be sealed in the Patch-Disposal Unit.

To flush your buprenorphine transdermal system patches down the toilet: Remove your buprenorphine transdermal system patch, fold the sticky sides of a used patch together and flush it down the toilet right away ( See Figure O).

When disposing of unused buprenorphine transdermal system patches you no longer need, remove the leftover patches from their protective pouch and remove the protective liner. Fold the patches in half with the sticky sides together, and flush the patches down the toilet.

Do not flush the pouch or the protective liner down the toilet. These items can be thrown away in the trash.

If you prefer not to flush the used patch down the toilet, and if there is not a drug take-back option readily available, you must use the Patch-Disposal Unit provided to you to discard the patch.

Never put used buprenorphine transdermal system patches in the trash without first sealing them in the Patch-Disposal Unit.

This “Instructions for Use” has been approved by the U.S. Food and Drug Administration.

Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32811-7193

Revised: June 2024

Bioclusive is a trademark of Systagenix Wound Management (US), Inc. Tegaderm is a trademark of 3M.

PRINCIPAL DISPLAY PANEL - Buprenorphine 5 mcg/hour Transdermal System Carton

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NDC 50742-372-04

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PRINCIPAL DISPLAY PANEL - Buprenorphine 7.5 mcg/hour Transdermal System Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - Buprenorphine 7.5 mcg/hour Transdermal System Carton\n" }

NDC 50742-373-04

{ "type": "p", "children": [], "text": "\nNDC 50742-373-04\n" }

PRINCIPAL DISPLAY PANEL - Buprenorphine 10 mcg/hour Transdermal System Carton

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NDC 50742-374-04

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PRINCIPAL DISPLAY PANEL - Buprenorphine 15 mcg/hour Transdermal System Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - Buprenorphine 15 mcg/hour Transdermal System Carton\n" }

NDC 50742-375-04

{ "type": "p", "children": [], "text": "\nNDC 50742-375-04\n" }

PRINCIPAL DISPLAY PANEL - Buprenorphine 20 mcg/hour Transdermal System Carton

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL - Buprenorphine 20 mcg/hour Transdermal System Carton\n" }

NDC 50742-376-04

{ "type": "p", "children": [], "text": "\nNDC 50742-376-04\n" }