Hyperqbank

dexmedetomidine

PRECEDEX

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

PRECEDEX

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION, USP

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

200

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

400

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION, USP

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

100

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

MCG

INTRAVENOUS

SOLUTION

Marketed

[ "dexmedetomidine (dexmedetomidine hydrochloride)" ]

Product Monograph

[ "Alpha-2 Adrenergic Agonists" ]

[ "Sedatives", "Anxiolytics" ]

[ "Anorexigenic Agents" ]

8ccb45a7-8290-469c-9644-a4dca967d88f

DEXMEDETOMIDINE HYDROCHLORIDE injection

1 Indications And Usage

1.1 Intensive Care Unit Sedation

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered by continuous infusion not to exceed 24 hours.

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been continuously infused in mechanically ventilated adult patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue dexmedetomidine hydrochloride in 0.9% sodium chloride injection prior to extubation.

1.2 Procedural Sedation

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures.

Pediatric use information is approved for Hospira Inc.’s PRECEDEXTM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

2 Dosage And Administration

2.1 Administration Instructions

2.2 Recommended Dosage

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 1: Recommended Dosage in Adult Patients </caption> <col width="22%"/> <col width="78%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> INDICATION </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> DOSAGE AND ADMINISTRATION </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Initiation of Intensive Care Unit Sedation </dd> </dl> </td><td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> For adult patients: a loading infusion of one mcg/kg over 10 minutes.</dd> <dt> </dt> <dd> For adult patients being converted from alternate sedative therapy: a loading dose may not be required.</dd> <dt> </dt> <dd> For patients over 65 years of age: Consider a dose reduction [see <a href="#ID_827901b0-b5c4-46ae-8640-883faad5498f">Use in Specific Populations (8.5)</a>].</dd> <dt> </dt> <dd> For adult patients with impaired hepatic function: Consider a dose reduction [see <a href="#ID_9ad2df38-f46b-49ca-9ab1-2aedea82a187">Use in Specific Populations (8.6)</a>, <a href="#ID_990504c6-1b48-45c5-ad5e-a185c665a80a">Clinical Pharmacology (12.3)</a>].</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Maintenance of Intensive Care Unit Sedation </dd> </dl> </td><td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation.</dd> <dt> </dt> <dd> For patients over 65 years of age: Consider a dose reduction [see <a href="#ID_827901b0-b5c4-46ae-8640-883faad5498f">Use in Specific Populations (8.5)</a>].</dd> <dt> </dt> <dd> For adult patients with impaired hepatic function: Consider a dose reduction [see <a href="#ID_9ad2df38-f46b-49ca-9ab1-2aedea82a187">Use in Specific Populations (8.6)</a>, <a href="#ID_990504c6-1b48-45c5-ad5e-a185c665a80a">Clinical Pharmacology (12.3)</a>].</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Initiation of Procedural Sedation </dd> </dl> </td><td class="Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.</dd> <dt> </dt> <dd> For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes.</dd> <dt> </dt> <dd> For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [see <a href="#ID_827901b0-b5c4-46ae-8640-883faad5498f">Use in Specific Populations (8.5)</a>].</dd> <dt> </dt> <dd> For adult patients with impaired hepatic function: Consider a dose reduction [see <a href="#ID_9ad2df38-f46b-49ca-9ab1-2aedea82a187">Use in Specific Populations (8.6)</a>, <a href="#ID_990504c6-1b48-45c5-ad5e-a185c665a80a">Clinical Pharmacology (12.3)</a>].</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Maintenance of Procedural Sedation </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. Adjust the rate of the maintenance infusion to achieve the targeted level of sedation.</dd> <dt> </dt> <dd> For patients over 65 years of age: Consider a dose reduction [see <a href="#ID_827901b0-b5c4-46ae-8640-883faad5498f">Use in Specific Populations (8.5)</a>].</dd> <dt> </dt> <dd> For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.</dd> <dt> </dt> <dd> For adult patients with impaired hepatic function: Consider a dose reduction [see <a href="#ID_9ad2df38-f46b-49ca-9ab1-2aedea82a187">Use in Specific Populations (8.6)</a>, <a href="#ID_990504c6-1b48-45c5-ad5e-a185c665a80a">Clinical Pharmacology (12.3)</a>].</dd> </dl> </td> </tr> </tbody> </table></div>

2.3 Dosage Adjustment

Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug Interactions (7.1)].

Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients [see Warnings and Precautions (5.8), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Preparation Of Solution

Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if product is discolored or if precipitate matter is present.

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is supplied in Galaxy containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations is necessary.

2.5 Administration With Other Fluids

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection infusion should not be co‑administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be compatible when administered with the following intravenous fluids:

2.6 Compatibility With Natural Rubber

Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride in 0.9% sodium chloride injection to some types of natural rubber. Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

3 Dosage Forms And Strengths

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a clear and colorless solution, ready to use. It is available as:

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Dexmedetomidine hydrochloride in 0.9% sodium chloride injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) in 50 mL Galaxy container.

{ "type": "p", "children": [], "text": "Dexmedetomidine hydrochloride in 0.9% sodium chloride injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) in 50 mL Galaxy container." }

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) in 100 mL Galaxy container.

{ "type": "p", "children": [], "text": "Dexmedetomidine hydrochloride in 0.9% sodium chloride injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) in 100 mL Galaxy container. " }

4 Contraindications

None.

{ "type": "p", "children": [], "text": "None." }

5 Warnings And Precautions

5.1 Drug Administration

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection, patients should be continuously monitored while receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

5.2 Hypotension, Bradycardia, And Sinus Arrest

Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine hydrochloride in 0.9% sodium chloride injection administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.

Reports of hypotension and bradycardia have been associated with dexmedetomidine hydrochloride in 0.9% sodium chloride injection infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine hydrochloride in 0.9% sodium chloride injection has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine hydrochloride-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

Caution should be exercised when administering dexmedetomidine hydrochloride in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine hydrochloride in 0.9% sodium chloride injection decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.

In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

5.3 Transient Hypertension

Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

5.4 Arousability

Some patients receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.

5.5 Withdrawal

Intensive Care Unit Sedation With administration up to 7 days, regardless of dose, 12 (5%) dexmedetomidine hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation [see Adverse Reactions (6.1)].

In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%.

Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of dexmedetomidine hydrochloride in 0.9% sodium chloride injection (<6 hours).

In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short-term infusions of dexmedetomidine hydrochloride in 0.9% sodium chloride injection (<2 hours).

5.6 Tolerance And Tachyphylaxis

Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see Adverse Reactions (6.1)].

5.7 Hyperthermia Or Pyrexia

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine hydrochloride in 0.9% sodium chloride injection if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.

5.8 Hepatic Impairment

Since dexmedetomidine hydrochloride in 0.9% sodium chloride injection clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2, 2.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

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

Most common treatment-emergent adverse reactions, occurring in greater than 2% of adult patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.

Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 3. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)].

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 3: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation Population <24 hours<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </caption> <col width="29%"/> <col width="23%"/> <col width="29%"/> <col width="10%"/> <col width="10%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>26 subjects in the all dexmedetomidine hydrochloride in 0.9% sodium chloride injection group and 10 subjects in the randomized dexmedetomidine hydrochloride in 0.9% sodium chloride injection group had exposure for greater than 24 hours.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <dl> <dt> </dt> <dd> Adverse Event </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> All Dexmedetomidine (N = 1007) (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Randomized Dexmedetomidine (N = 798) (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Placebo (N = 400) (%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Propofol (N = 188) (%) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypotension</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 25% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 24% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypertension</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 12%<a class="Sup" href="#footnote-1">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Nausea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Bradycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Atrial Fibrillation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pyrexia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dry Mouth</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vomiting</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypovolemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Atelectasis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pleural Effusion</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Agitation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Tachycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Anemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperthermia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Chills</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperglycemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypoxia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Post-procedural Hemorrhage</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Pulmonary Edema</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Hypocalcemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Acidosis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Urine Output Decreased</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Sinus Tachycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Ventricular Tachycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Wheezing</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Edema Peripheral</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> </tbody> </table></div>

Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 4).

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 4: Treatment-Emergent Adverse Events Occurring in >1% of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies </caption> <col width="28%"/> <col width="55%"/> <col width="17%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <dl> <dt> </dt> <dd> Adverse Event </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="bottom"> <dl> <dt> </dt> <dd> Randomized Dexmedetomidine </dd> <dt> </dt> <dd> (N = 387) </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Placebo (N = 379) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypotension</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 28% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypertension</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 16% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 18% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Nausea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 11% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 9% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Bradycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Fever</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Vomiting</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Atrial Fibrillation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypoxia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Tachycardia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hemorrhage</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Anemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Dry Mouth</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Rigors</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Agitation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperpyrexia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pain</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Hyperglycemia</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Acidosis</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Pleural Effusion</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Oliguria</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <1% </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Thirst</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <1% </td> </tr> </tbody> </table></div>

In a controlled clinical trial, dexmedetomidine hydrochloride in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated adult patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 5. The number (%) of adult subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group is provided in Table 6.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 5: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study </caption> <col width="55%"/> <col width="27%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value.</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">‡</a> </dt> <dd>Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">§</a> </dt> <dd>Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">¶</a> </dt> <dd>Includes any type of hypertension.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Adverse Event </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Dexmedetomidine </dd> <dt> </dt> <dd> (N = 244) </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Midazolam (N = 122) </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypotension<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>56%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 56% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypotension Requiring Intervention</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>28%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 27% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Bradycardia<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>42%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Bradycardia Requiring Intervention</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>5%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Systolic Hypertension<a class="Sup" href="#footnote-4" name="footnote-reference-4">‡</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>28%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 42% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Tachycardia<a class="Sup" href="#footnote-5" name="footnote-reference-5">§</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>25%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 44% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Tachycardia Requiring Intervention</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>10%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 10% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Diastolic Hypertension<a class="Sup" href="#footnote-4">‡</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>12%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypertension<a class="Sup" href="#footnote-4">‡</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>11%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 15% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypertension Requiring Intervention<a class="Sup" href="#footnote-6" name="footnote-reference-6">¶</a> </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>19%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 30% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypokalemia</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>9%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 13% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Pyrexia</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>7%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Agitation</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>7%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hyperglycemia</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>7%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Constipation</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>6%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hypoglycemia</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>5%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Respiratory Failure</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>5%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Renal Failure Acute</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>2%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Acute Respiratory Distress Syndrome</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>2%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Generalized Edema</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>2%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 6% </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Hypomagnesemia</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>1%</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 7% </td> </tr> </tbody> </table></div>

The following adverse events occurred between 2 and 5% for dexmedetomidine hydrochloride in 0.9% sodium chloride injection and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 6. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Group </caption> <col width="43%"/> <col width="20%"/> <col width="20%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Average maintenance dose over the entire study drug administration.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> <dl> <dt> </dt> <dd> Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride (mcg/kg/hr) </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd> Adverse Event </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> ≤0.7<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a> (N = 95) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> >0.7 to ≤1.1<a class="Sup" href="#footnote-7">*</a> (N = 78) </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd> >1.1<a class="Sup" href="#footnote-7">*</a> (N = 71) </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Constipation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 6% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>14%</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Agitation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 8% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>14%</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Anxiety</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>9%</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Edema Peripheral</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>7%</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Atrial Fibrillation</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 4% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>9%</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Respiratory Failure</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 6% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>10%</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>Acute Respiratory Distress Syndrome</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 3% </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>9%</dd> </dl> </td> </tr> </tbody> </table></div>

Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [see Clinical Studies (14.2)] in which 318 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian.

Treatment-emergent adverse reactions occurring in adults at an incidence of >2% are provided in Table 7. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups in both studies.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 7: Adverse Reactions with an Incidence > 2%-Adult Procedural Sedation Population </caption> <col width="29%"/> <col width="53%"/> <col width="18%"/> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">†</a> </dt> <dd>Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">‡</a> </dt> <dd>Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value. Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see <a href="#ID_f97685cd-58a8-467b-b1ff-dbb47ba8f3f6">Clinical Studies (14.2)</a>].</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">§</a> </dt> <dd>Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg.</dd> <dt> <a href="#footnote-reference-12" name="footnote-12">¶</a> </dt> <dd>Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">#</a> </dt> <dd>Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd> Adverse Event </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd> Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection N = 318 (%) </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd> Placebo N = 113 (%) </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Hypotension<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 54% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 30% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Respiratory Depression<a class="Sup" href="#footnote-9" name="footnote-reference-9">†</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 37% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 32% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Bradycardia<a class="Sup" href="#footnote-10" name="footnote-reference-10">‡</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 14% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 4% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Hypertension<a class="Sup" href="#footnote-11" name="footnote-reference-11">§</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 13% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 24% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Tachycardia<a class="Sup" href="#footnote-12" name="footnote-reference-12">¶</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 5% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 17% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Nausea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Dry mouth</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 3% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1% </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <dl> <dt> </dt> <dd>Hypoxia<a class="Sup" href="#footnote-13" name="footnote-reference-13">#</a> </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 3% </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd>Bradypnea</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 4% </td> </tr> </tbody> </table></div>

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. 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.

Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine hydrochloride in 0.9% sodium chloride injection during post-approval use of the drug.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection </caption> <col width="39%"/> <col width="61%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> System Organ Class </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Preferred Term </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Blood and Lymphatic System Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Anemia</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Cardiac Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Eye Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Photopsia, visual impairment</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Gastrointestinal Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Abdominal pain, diarrhea, nausea, vomiting</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>General Disorders and Administration Site Conditions</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Chills, hyperpyrexia, pain, pyrexia, thirst</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Hepatobiliary Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Hepatic function abnormal, hyperbilirubinemia</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Investigations</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Metabolism and Nutrition Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Nervous System Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Psychiatric Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Agitation, confusional state, delirium, hallucination, illusion</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Renal and Urinary Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Oliguria, polyuria</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Respiratory, Thoracic and Mediastinal Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Skin and Subcutaneous Tissue Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Hyperhidrosis, pruritus, rash, urticaria</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>Surgical and Medical Procedures</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Light anesthesia</dd> </dl> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Vascular Disorders</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Blood pressure fluctuation, hemorrhage, hypertension, hypotension</dd> </dl> </td> </tr> </tbody> </table></div>

7 Drug Interactions

7.1 Anesthetics, Sedatives, Hypnotics, Opioids

Co-administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine hydrochloride in 0.9% sodium chloride injection and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or the concomitant anesthetic, sedative, hypnotic or opioid may be required.

7.2 Neuromuscular Blockers

In one study of 10 healthy adult volunteers, administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta.

In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day.

Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data).

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 2-4% and 15-20%, respectively.

Data

Animal Data

Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported.

No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18).

Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21).

In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.

8.2 Lactation

Risk Summary

Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data). There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dexmedetomidine hydrochloride in 0.9% sodium chloride injection and any potential adverse effects on the breastfed infant from dexmedetomidine hydrochloride in 0.9% sodium chloride injection or from the underlying condition.

Data

In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2–0.7 mcg/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%.

8.4 Pediatric Use

Sedation for Non-Invasive Procedures

The safety and effectiveness of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients less than 1 month of age.

ICU Sedation

The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients for ICU sedation. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for these patient populations.

8.5 Geriatric Use

Intensive Care Unit Sedation

A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection [see Warnings and Precautions (5.2)]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

Procedural Sedation

A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine hydrochloride in 0.9% sodium chloride injection-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.

8.6 Hepatic Impairment

Since dexmedetomidine hydrochloride in 0.9% sodium chloride injection clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

9 Drug Abuse And Dependence

9.1 Controlled Substance

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (dexmedetomidine hydrochloride) is not a controlled substance.

9.3 Dependence

The dependence potential of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine hydrochloride in 0.9% sodium chloride injection exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine hydrochloride in 0.9% sodium chloride injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions (5.5)].

10 Overdosage

The tolerability of dexmedetomidine hydrochloride was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute.

{ "type": "p", "children": [], "text": "The tolerability of dexmedetomidine hydrochloride was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute." }

Five adult patients received an overdose of dexmedetomidine hydrochloride in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted dexmedetomidine hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

{ "type": "p", "children": [], "text": "Five adult patients received an overdose of dexmedetomidine hydrochloride in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted dexmedetomidine hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated." }

11 Description

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is a central alpha2-adrenergic agonist. Dexmedetomidine hydrochloride is the S‑enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3dimethylphenyl)ethyl]-, monohydrochloride, (S). Dexmedetomidine hydrochloride has a molecular weight of 236.7 and the empirical formula is C13H16N2•HCl and the structural formula is:

{ "type": "p", "children": [], "text": "Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is a central alpha2-adrenergic agonist. Dexmedetomidine hydrochloride is the S‑enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3dimethylphenyl)ethyl]-, monohydrochloride, (S). Dexmedetomidine hydrochloride has a molecular weight of 236.7 and the empirical formula is C13H16N2•HCl and the structural formula is:" }

Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89.

{ "type": "p", "children": [], "text": "Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89." }

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 5.5. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers.

{ "type": "p", "children": [], "text": "Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 5.5. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Dexmedetomidine hydrochloride is a relatively selective centrally acting alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration.

12.2 Pharmacodynamics

In a study in healthy adult volunteers (N=10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was administered by intravenous infusion at doses within the recommended dose range (0.2-0.7 mcg/kg/hr).

12.3 Pharmacokinetics

Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.

Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 10: Mean ± SD Pharmacokinetic Parameters in Adults </caption> <col width="21%"/> <col width="20%"/> <col width="19%"/> <col width="19%"/> <col width="20%"/> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>Presented as harmonic mean and pseudo standard deviation.</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Mean Css = Average steady-state concentration of dexmedetomidine. The mean Css was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. </dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="4" valign="bottom"> <dl> <dt> </dt> <dd> Parameter </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> Loading Infusion (min)/Total Infusion Duration (hrs) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 10 min/12 hrs </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 10 min/24 hrs </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 10 min/24 hrs </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 35 min/24 hrs </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="4" valign="middle"> Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.3/0.17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.3/0.17 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.6/0.33 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1.25/0.70 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> t1/2<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a>, hour </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1.78 ± 0.30 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2.22 ± 0.59 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2.23 ± 0.21 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 2.50 ± 0.61 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> CL, liter/hour </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 46.3 ± 8.3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 43.1 ± 6.5 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 35.3 ± 6.8 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 36.5 ± 7.5 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Vss, liter </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 88.7 ± 22.9 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 102.4 ± 20.3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 93.6 ± 17.0 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 99.6 ± 17.8 </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Avg Css<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a>, ng/mL </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.27 ± 0.05 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.27 ± 0.05 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 0.67 ± 0.10 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 1.37 ± 0.20 </td> </tr> <tr class="Last"> <td class="Toprule" colspan="5" valign="top"> Abbreviations: t1/2 = half-life, CL = clearance, Vss = steady-state volume of distribution. </td> </tr> </tbody> </table></div>

The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.

Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.

Distribution

The steady-state volume of distribution (Vss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine hydrochloride in 0.9% sodium chloride injection that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.

The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine hydrochloride in 0.9% sodium chloride injection was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

Elimination Metabolism

Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy‑dexmedetomidine, and 3-carboxy-dexmedetomidine; and N‑methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3‑carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N‑methyl O-glucuronide.

Excretion

The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3‑hydroxy-dexmedetomidine, and 3‑carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3‑carboxy N‑methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.

Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine hydrochloride in 0.9% sodium chloride injection pharmacokinetics due to sex.

Geriatric Patients The pharmacokinetic profile of dexmedetomidine hydrochloride in 0.9% sodium chloride injection was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine hydrochloride in 0.9% sodium chloride injection in young (18-40 years), middle age (41-65 years), and elderly (>65 years) subjects.

Pediatric Patients

Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine hydrochloride in 0.9% sodium chloride injection were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively.

Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.8)].

Patients with Renal Impairment Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.

Drug Interaction Studies In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis Animal carcinogenicity studies have not been performed with dexmedetomidine.

Mutagenesis Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.

Impairment of Fertility Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

13.2 Animal Toxicology And/Or Pharmacology

There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.

14 Clinical Studies

14.1 Intensive Care Unit Sedation

Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 12.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 12: Ramsay Level of Sedation Scale </caption> <col width="25%"/> <col width="75%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Clinical Score </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Level of Sedation Achieved </dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 6 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Asleep, no response</dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 5 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Asleep, sluggish response to light glabellar tap or loud auditory stimulus</dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 4 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Asleep, but with brisk response to light glabellar tap or loud auditory stimulus</dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 3 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Patient responds to commands</dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 2 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Patient cooperative, oriented, and tranquil</dd> </dl> </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>Patient anxious, agitated, or restless</dd> </dl> </td> </tr> </tbody> </table></div>

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to dexmedetomidine hydrochloride in 0.9% sodium chloride injection (see Table 13).

A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13).

<div class="scrollingtable"><table cellpadding="0pt" width="100.14%"> <caption> Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One </caption> <col width="45%"/> <col width="14%"/> <col width="30%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>ANOVA model with treatment center.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>Chi-square.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Placebo (N = 175) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (N = 178) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> p-value </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> Mean Total Dose (mg) of Midazolam Standard deviation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 19 mg 53 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5 mg 19 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.0011<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="middle"> Categorized Midazolam Use </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 43 (25%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 108 (61%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <0.001<a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> 0–4 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 34 (19%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 36 (20%) </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> >4 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 98 (56%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 34 (19%) </td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr class="Last"> <td class="Toprule" colspan="4" valign="bottom"> ITT (intent-to-treat) population includes all randomized patients. </td> </tr> </tbody> </table></div>

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of dexmedetomidine hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.

In a second study, 198 adult patients were randomized to receive placebo and 203 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated.

Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine hydrochloride in 0.9% sodium chloride injection (see Table 14).

A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 14).

<div class="scrollingtable"><table width="100%"> <caption> Table 14: Propofol Use as Rescue Medication During Intubation (ITT) Study Two </caption> <col width="40%"/> <col width="14%"/> <col width="24%"/> <col width="22%"/> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-18" name="footnote-18">*</a> </dt> <dd>ANOVA model with treatment center.</dd> <dt> <a href="#footnote-reference-19" name="footnote-19">†</a> </dt> <dd>Chi-square.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" valign="middle"> <dl> <dt> </dt> <dd> Placebo </dd> <dt> </dt> <dd> (N = 198) </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (N = 203) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> p-value </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Mean Total Dose (mg) of Propofol Standard deviation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 513 mg 782 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 72 mg 249 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <0.0001<a class="Sup" href="#footnote-18" name="footnote-reference-18">*</a> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="4" valign="top"> <dl> <dt> </dt> <dd> Categorized Propofol Use </dd> </dl> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> 0 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 47 (24%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 122 (60%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <0.001<a class="Sup" href="#footnote-19" name="footnote-reference-19">†</a> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="middle"> 0–50 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 30 (15%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 43 (21%) </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> >50 mg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 121 (61%) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> 38 (19%) </td><td class="Botrule Lrule Rrule Toprule" valign="middle"></td> </tr> </tbody> </table></div>

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of dexmedetomidine hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.

In a controlled clinical trial, dexmedetomidine hydrochloride in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration. dexmedetomidine hydrochloride in 0.9% sodium chloride injection was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions (6.1)].

14.2 Procedural Sedation

Adult Patients The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation of non-intubated adult patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine hydrochloride in 0.9% sodium chloride injection in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.

In Study 1, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 15).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> Table 15: Observer’s Assessment of Alertness/Sedation </caption> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="24%"/> <col width="16%"/> <tbody class="Headless"> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> Assessment Categories </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Responsiveness </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Speech </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Facial Expression </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Eyes </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Composite Score </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Responds readily to name spoken in normal tone </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Normal </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Normal </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Clear, no ptosis </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 5 (alert) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Lethargic response to name spoken in normal tone </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Mild slowing or thickening </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Mild relaxation </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Glazed or mild ptosis (less than half the eye) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Responds only after name is called loudly and/or repeatedly </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Slurring or prominent slowing </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Marked relaxation (slack jaw) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Glazed and marked ptosis (half the eye or more) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="top"> Responds only after mild prodding or shaking </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Few recognizable words </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> - </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> - </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2 </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Does not respond to mild prodding or shaking </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> - </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> - </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> - </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1 (deep sleep) </td> </tr> </tbody> </table></div>

Adult patients were randomized to receive a loading infusion of either dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg, dexmedetomidine hydrochloride in 0.9% sodium chloride injection 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer’s Assessment of Alertness/Sedation Scale ≤4). Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer’s Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. Efficacy results showed that dexmedetomidine hydrochloride in 0.9% sodium chloride injection was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 15).

In Study 2, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 12). Adult patients were randomized to receive a loading infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. For efficacy results see Table 16.

<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <caption> Table 16: Key Efficacy Results of Adult Procedural Sedation Studies </caption> <col width="10%"/> <col width="19%"/> <col width="12%"/> <col width="13%"/> <col width="16%"/> <col width="13%"/> <col width="17%"/> <tfoot> <tr> <td align="left" colspan="7"> <dl class="Footnote"> <dt> <a href="#footnote-reference-20" name="footnote-20">*</a> </dt> <dd>Based on ITT population defined as all randomized and treated patients.</dd> <dt> <a href="#footnote-reference-21" name="footnote-21">†</a> </dt> <dd>Normal approximation to the binomial with continuity correction.</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> Study </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Loading Infusion Treatment Arm </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Number of Patients Enrolled<a class="Sup" href="#footnote-20" name="footnote-reference-20">*</a> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> % Not Requiring Midazolam Rescue </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Confidence<a class="Sup" href="#footnote-21" name="footnote-reference-21">†</a> Interval on the Difference vs. Placebo </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Mean (SD) Total Dose (mg) of Rescue Midazolam Required </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Confidence<a class="Sup" href="#footnote-21">†</a> Intervals of the Mean Rescue Dose </td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule" rowspan="3" valign="top"> Study 1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Dexmedetomidine 0.5 mcg/kg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 134 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 40 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 37 (27, 48) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.4 (1.7) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> -2.7 (-3.4, -2.0) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Dexmedetomidine 1 mcg/kg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 129 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 54 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 51 (40, 62) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 0.9 (1.5) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> -3.1 (-3.8, -2.5) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Placebo </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 63 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 3 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> – </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 4.1 (3.0) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> – </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule Toprule" rowspan="2" valign="top"> Study 2 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Dexmedetomidine 1 mcg/kg </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 55 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 53 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 39 (20, 57) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 1.1 (1.5) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> -1.8 (-2.7, -0.9) </td> </tr> <tr class="Last"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Placebo </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 50 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 14 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> – </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 2.9 (3.0) </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> – </td> </tr> </tbody> </table></div>

16 How Supplied/Storage And Handling

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection

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

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Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is clear and colorless, and available as 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL) in 50 mL and 100 mL Galaxy containers, respectively. Galaxy containers are intended for single dose. Discard unused portion.

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<div class="scrollingtable"><table cellpadding="0pt" width="100%"> <col width="14%"/> <col width="18%"/> <col width="25%"/> <col width="11%"/> <col width="32%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> Code </dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd> NDC No. </dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Container </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Size </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Number of Containers/Carton </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <dl> <dt> </dt> <dd>2G3496</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>0338-9555-24</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Galaxy single-dose </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 50 mL </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Twenty-four (24) (2 x 12) - 200 mcg/50 mL Containers </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>2G3497</dd> </dl> </td><td class="Botrule Lrule Rrule Toprule" valign="top"> <dl> <dt> </dt> <dd>0338-9557-12</dd> </dl> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Galaxy single-dose </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> 100 mL </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> Twelve (12) (2 x 6) - 400 mcg/100 mL Containers </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0pt\" width=\"100%\">\n<col width=\"14%\"/>\n<col width=\"18%\"/>\n<col width=\"25%\"/>\n<col width=\"11%\"/>\n<col width=\"32%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\nCode\n</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\nNDC No.\n</dd>\n</dl>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nContainer\n\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nSize\n\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nNumber of Containers/Carton\n\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2G3496</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0338-9555-24</dd>\n</dl>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nGalaxy single-dose\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n50 mL\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\nTwenty-four (24) (2 x 12) - 200 mcg/50 mL Containers\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>2G3497</dd>\n</dl>\n</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>0338-9557-12</dd>\n</dl>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n\nGalaxy single-dose\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n100 mL\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\nTwelve (12) (2 x 6) - 400 mcg/100 mL Containers\n</td>\n</tr>\n</tbody>\n</table></div>" }

17 Patient Counseling Information

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection and as clinically appropriate after discontinuation.

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Baxter and Galaxy are trademarks of Baxter International Inc. or its subsidiaries.

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Any other trademarks, product names or brand images appearing herein are the property of their respective owners.

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Baxter Logo Baxter Healthcare Corporation Deerfield, IL 60015 USA

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Made in USA

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071909102

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Package/Label Principal Display Panel

{ "type": "", "children": [], "text": "" }

NDC 0338-9555-24

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Dexmedetomidine Hydrochloride in0.9% Sodium Chloride Injection

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200 mcg per 50 mL(4 mcg / mL)*

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GALAXY50 mL Single Dose ContainerDiscard unused portionFor Intravenous InfusionCode 2G3496

{ "type": "p", "children": [], "text": "\nGALAXY50 mL Single Dose ContainerDiscard unused portionFor Intravenous InfusionCode 2G3496\n" }

*Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcgdexmedetomidine HCI, USP; 9 mg sodium chloride, USP; 483 mcg sodium acetatetrihydrate, USP; 87 mcg glacial acetic acid, USP; and Water forInjection, USP. pH is 4.5 to 5.5.

{ "type": "p", "children": [], "text": "*Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcgdexmedetomidine HCI, USP; 9 mg sodium chloride, USP; 483 mcg sodium acetatetrihydrate, USP; 87 mcg glacial acetic acid, USP; and Water forInjection, USP. pH is 4.5 to 5.5." }

Usual Dosage: See prescribing information.

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Rx only

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

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Do not freeze.

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Baxter Logo Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USA

{ "type": "p", "children": [], "text": "\nBaxter Logo\nBaxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation, Deerfield, IL 60015 USA" }

Made in USA

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07-34-00-2289

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BAR CODEPOSITION ONLY

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303389555247

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GALAXY Container

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Baxter Logo Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA

{ "type": "p", "children": [], "text": "\nBaxter Logo\n\nBaxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA" }

07-04-00-1266

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Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride InjectionRx OnlyNDC 0338-9555-24 200 mcg per 50 mL (4 mcg / mL)* Code 2G3496

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*FOR BAR CODE POSITION ONLY(01) 20303389555241

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For Intravenous Infusion *Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcg dexmedetomidine HCl, USP; 9 mg sodiumchloride, USP; 483 mcg sodium acetate trihydrate, USP; 87 mcg glacial acetic acid, USP; and Water for Injection,USP. pH is 4.5 to 5.5.

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Usual Dosage: See prescribing information.

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{ "type": "", "children": [], "text": "" }

NDC 0338-9557-12

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Dexmedetomidine Hydrochloride in0.9% Sodium Chloride Injection

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400 mcg per 100 mL(4 mcg / mL)*

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GALAXYCode 2G3497100 mL Single Dose ContainerDiscard unused portionFor Intravenous Infusion

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*Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcgdexmedetomidine HCl, USP; 9 mg sodium chloride, USP; 483 mcgsodium acetate trihydrate, USP; 87 mcg glacial acetic acid, USP; andWater for Injection, USP. pH is 4.5 to 5.5.

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Usual Dosage: See prescribing information.

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Rx only

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

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Do not freeze.

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Baxter Logo Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA

{ "type": "p", "children": [], "text": "\nBaxter Logo\nBaxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA" }

07-34-00-2290

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BAR CODEPOSITION ONLY

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303389557128

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{ "type": "", "children": [], "text": "" }

GALAXY Container

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Baxter Logo Baxter and Galaxy are registered trademarks of Baxter International Inc. Baxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA

{ "type": "p", "children": [], "text": "\nBaxter Logo\nBaxter and Galaxy are registered trademarks of Baxter International Inc.\nBaxter Healthcare Corporation, Deerfield, IL 60015 USAMade in USA" }

07-04-00-1267

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Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection Rx Only NDC 0338-9557-12 400 mcg per 100 mL (4 mcg / mL)* Code 2G3497

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Contains 6 (1 x 6) 100 mL Single Dose ContainersStore at 20° to 25°C (68° to 77°F)[See USP Controlled Room Temperature]. Do not freeze.

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*FOR BAR CODE POSITION ONLY(01) 20303389557122

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For Intravenous Infusion

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*Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcg dexmedetomidine HCl, USP; 9 mg sodiumchloride, USP; 483 mcg sodium acetate trihydrate, USP; 87 mcg glacial acetic acid, USP; and Water for Injection,USP. pH is 4.5 to 5.5.

{ "type": "p", "children": [], "text": "*Each mL contains: 4 mcg dexmedetomidine provided as 4.72 mcg dexmedetomidine HCl, USP; 9 mg sodiumchloride, USP; 483 mcg sodium acetate trihydrate, USP; 87 mcg glacial acetic acid, USP; and Water for Injection,USP. pH is 4.5 to 5.5." }

Usual Dosage: See prescribing information.

{ "type": "p", "children": [], "text": "Usual Dosage: See prescribing information." }

9eb336de-5fa5-4b46-b40b-a7ca5a0864bd

PRECEDEX- dexmedetomidine hydrochloride injection, solution, concentrate

1 Indications And Usage

1.1 Intensive Care Unit Sedation

{ "type": "p", "children": [], "text": "1.1 Intensive Care Unit Sedation" }

Precedex™ is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Precedex should be administered by continuous infusion not to exceed 24 hours.

{ "type": "p", "children": [], "text": "Precedex™ is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Precedex should be administered by continuous infusion not to exceed 24 hours." }

Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation.

{ "type": "p", "children": [], "text": "Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation." }

1.2 Procedural Sedation

{ "type": "p", "children": [], "text": "1.2 Procedural Sedation" }

Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.

{ "type": "p", "children": [], "text": "Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures." }

2 Dosage And Administration

2.1 Dosing Guidelines

{ "type": "p", "children": [], "text": "\n2.1 Dosing Guidelines\n" }

{ "type": "ul", "children": [ "Precedex dosing should be individualized and titrated to desired clinical response.", "Precedex is not indicated for infusions lasting longer than 24 hours.", "Precedex should be administered using a controlled infusion device." ], "text": "" }

2.2 Dosage Information

{ "type": "p", "children": [], "text": "\n2.2 Dosage Information\n" }

<div class="scrollingtable"><table width="100%"> <caption> Table 1: Dosage Information </caption> <colgroup> <col width="29%"/> <col width="71%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> INDICATION </td><td class="Botrule Lrule Toprule" valign="top"> DOSAGE AND ADMINISTRATION </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Initiation of Intensive Care Unit Sedation </td><td class="Botrule Lrule" valign="top"> For adult patients: a loading infusion of one mcg/kg over 10 minutes. For adult patients being converted from alternate sedative therapy:a loading dose may not be required [see DOSAGE AND ADMINISTRATION (2.2)]. For patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic-function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Maintenance of Intensive Care Unit Sedation </td><td class="Botrule Lrule" valign="top"> For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)] </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Initiation of Procedural Sedation </td><td class="Botrule Lrule" valign="top"> For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes. For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Maintenance of Procedural Sedation </td><td class="Botrule Lrule" valign="top"> For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\nTable 1: Dosage Information\n</caption>\n<colgroup>\n<col width=\"29%\"/>\n<col width=\"71%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"top\">\nINDICATION\n</td><td class=\"Botrule Lrule Toprule\" valign=\"top\">\nDOSAGE AND ADMINISTRATION \n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nInitiation of Intensive Care Unit Sedation\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nFor adult patients: a loading infusion of one mcg/kg over 10 minutes.\nFor adult patients being converted from alternate sedative therapy:a loading dose may not be required [see DOSAGE AND ADMINISTRATION (2.2)].\nFor patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].\nFor adult patients with impaired hepatic-function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nMaintenance of Intensive Care Unit Sedation\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nFor adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation.\nFor patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].\nFor adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nInitiation of Procedural Sedation\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nFor adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.\nFor awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes.\nFor patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [see USE IN SPECIFIC POPULATIONS (8.5)].\nFor adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nMaintenance of Procedural Sedation\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nFor adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.\nFor awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.\nFor patients over 65 years of age: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].\nFor adult patients with impaired hepatic function: a dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].\n</td>\n</tr>\n</tbody>\n</table></div>" }

2.3 Dosage Adjustment

{ "type": "p", "children": [], "text": "\n2.3 Dosage Adjustment\n" }

Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see DRUG INTERACTIONS (7.1)].

{ "type": "p", "children": [], "text": "Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see DRUG INTERACTIONS (7.1)]." }

Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients [see WARNINGS AND PRECAUTIONS (5.7), USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].

{ "type": "p", "children": [], "text": "Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients [see WARNINGS AND PRECAUTIONS (5.7), USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]." }

2.4 Preparation of Solution

{ "type": "p", "children": [], "text": "\n2.4 Preparation of Solution\n" }

Strict aseptic technique must always be maintained during handling of Precedex.

{ "type": "p", "children": [], "text": "Strict aseptic technique must always be maintained during handling of Precedex." }

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

{ "type": "p", "children": [], "text": "Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit." }

Precedex Injection, 200 mcg/2 mL (100 mcg/mL)

{ "type": "p", "children": [], "text": "Precedex Injection, 200 mcg/2 mL (100 mcg/mL)" }

Precedex must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion.

{ "type": "p", "children": [], "text": "Precedex must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion." }

To prepare the infusion, withdraw 2 mL of Precedex Injection, and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well.

{ "type": "p", "children": [], "text": "To prepare the infusion, withdraw 2 mL of Precedex Injection, and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well." }

Precedex in 0.9% Sodium Chloride Injection, 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)

{ "type": "p", "children": [], "text": "Precedex in 0.9% Sodium Chloride Injection, 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)" }

Precedex in 0.9% Sodium Chloride Injection is supplied in glass containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations are necessary.

{ "type": "p", "children": [], "text": "Precedex in 0.9% Sodium Chloride Injection is supplied in glass containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations are necessary." }

2.5 Administration with Other Fluids

{ "type": "p", "children": [], "text": "\n2.5 Administration with Other Fluids\n" }

Precedex infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

{ "type": "p", "children": [], "text": "Precedex infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established." }

Precedex has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.

{ "type": "p", "children": [], "text": "Precedex has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam." }

Precedex has been shown to be compatible when administered with the following intravenous fluids:

{ "type": "p", "children": [], "text": "Precedex has been shown to be compatible when administered with the following intravenous fluids:" }

•0.9% sodium chloride in water•5% dextrose in water•20% mannitol•Lactated Ringer's solution•100 mg/mL magnesium sulfate solution•0.3% potassium chloride solution

{ "type": "p", "children": [], "text": "•0.9% sodium chloride in water•5% dextrose in water•20% mannitol•Lactated Ringer's solution•100 mg/mL magnesium sulfate solution•0.3% potassium chloride solution" }

2.6 Compatibility with Natural Rubber

{ "type": "p", "children": [], "text": "\n2.6 Compatibility with Natural Rubber\n" }

Compatibility studies have demonstrated the potential for absorption of Precedex to some types of natural rubber. Although Precedex is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

{ "type": "p", "children": [], "text": "Compatibility studies have demonstrated the potential for absorption of Precedex to some types of natural rubber. Although Precedex is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets." }

3 Dosage Forms And Strengths

Precedex Injection

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

Precedex Injection, 200 mcg/2 mL dexmedetomidine (100 mcg/mL) in a glass vial. To be used after dilution.

{ "type": "p", "children": [], "text": "Precedex Injection, 200 mcg/2 mL dexmedetomidine (100 mcg/mL) in a glass vial. To be used after dilution." }

Precedex in 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "\nPrecedex in 0.9% Sodium Chloride Injection\n" }

Precedex Injection, 80 mcg dexmedetomidine/20 mL (4 mcg/mL) dexmedetomidine in a 20 mL glass vial. Ready to use.

{ "type": "p", "children": [], "text": "Precedex Injection, 80 mcg dexmedetomidine/20 mL (4 mcg/mL) dexmedetomidine in a 20 mL glass vial. Ready to use." }

Precedex Injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) dexmedetomidine in a 50 mL glass bottle. Ready to use.

{ "type": "p", "children": [], "text": "Precedex Injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) dexmedetomidine in a 50 mL glass bottle. Ready to use." }

Precedex Injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) dexmedetomidine in a 100 mL glass bottle. Ready to use.

{ "type": "p", "children": [], "text": "Precedex Injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) dexmedetomidine in a 100 mL glass bottle. Ready to use." }

4 Contraindications

None

{ "type": "p", "children": [], "text": "None" }

5 Warnings And Precautions

5.1 Drug Administration

{ "type": "p", "children": [], "text": "\n5.1 Drug Administration\n" }

Precedex should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously monitored while receiving Precedex.

{ "type": "p", "children": [], "text": "Precedex should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously monitored while receiving Precedex." }

5.2 Hypotension, Bradycardia, and Sinus Arrest

{ "type": "p", "children": [], "text": "\n5.2 Hypotension, Bradycardia, and Sinus Arrest\n" }

Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.

{ "type": "p", "children": [], "text": "Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration." }

Reports of hypotension and bradycardia have been associated with Precedex infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because Precedex has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of Precedex-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

{ "type": "p", "children": [], "text": "Reports of hypotension and bradycardia have been associated with Precedex infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because Precedex has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of Precedex-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required." }

Caution should be exercised when administering Precedex to patients with advanced heart block and/or severe ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.

{ "type": "p", "children": [], "text": "Caution should be exercised when administering Precedex to patients with advanced heart block and/or severe ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients." }

In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with Precedex.

{ "type": "p", "children": [], "text": "In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with Precedex." }

5.3 Transient Hypertension

{ "type": "p", "children": [], "text": "\n5.3 Transient Hypertension\n" }

Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Precedex. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

{ "type": "p", "children": [], "text": "Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Precedex. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable." }

5.4 Arousability

{ "type": "p", "children": [], "text": "\n5.4 Arousability\n" }

Some patients receiving Precedex have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.

{ "type": "p", "children": [], "text": "Some patients receiving Precedex have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms." }

5.5 Withdrawal

{ "type": "p", "children": [], "text": "\n5.5 Withdrawal\n" }

Intensive Care Unit Sedation

{ "type": "p", "children": [], "text": "\nIntensive Care Unit Sedation\n" }

With administration up to 7 days, regardless of dose, 12 (5%) Precedex adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation.

{ "type": "p", "children": [], "text": "With administration up to 7 days, regardless of dose, 12 (5%) Precedex adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation." }

In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated.

{ "type": "p", "children": [], "text": "In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated." }

Procedural Sedation

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

In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours).

{ "type": "p", "children": [], "text": "In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours)." }

5.6 Tolerance and Tachyphylaxis

{ "type": "p", "children": [], "text": "\n5.6 Tolerance and Tachyphylaxis\n" }

Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see ADVERSE REACTIONS (6.1)].

{ "type": "p", "children": [], "text": "Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see ADVERSE REACTIONS (6.1)]." }

5.7 Hyperthermia or Pyrexia PRECEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue PRECEDEX if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.

{ "type": "p", "children": [], "text": "\n5.7 Hyperthermia or Pyrexia\nPRECEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue PRECEDEX if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes." }

5.8 Hepatic Impairment Since PRECEDEX clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION (2.2, 2.3)].

{ "type": "p", "children": [], "text": "\n5.8 Hepatic Impairment\nSince PRECEDEX clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION (2.2, 2.3)]." }

6 Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

{ "type": "p", "children": [], "text": "\nThe following clinically significant adverse reactions are described elsewhere in the labeling:\n" }

• Hypotension, bradycardia and sinus arrest [see WARNINGS AND PRECAUTIONS (5.2)]• Transient hypertension [see WARNINGS AND PRECAUTIONS (5.3)]

{ "type": "p", "children": [], "text": "• Hypotension, bradycardia and sinus arrest [see WARNINGS AND PRECAUTIONS (5.2)]• Transient hypertension [see WARNINGS AND PRECAUTIONS (5.3)]" }

6.1 Clinical Studies Experience

{ "type": "p", "children": [], "text": "\n6.1 Clinical Studies Experience\n" }

{ "type": "p", "children": [], "text": "Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice." }

Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.

{ "type": "p", "children": [], "text": "Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth." }

Intensive Care Unit Sedation

{ "type": "p", "children": [], "text": "\nIntensive Care Unit Sedation\n" }

Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1007 adult patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in TABLE 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see WARNINGS AND PRECAUTIONS (5.2)].

{ "type": "p", "children": [], "text": "Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1007 adult patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in TABLE 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see WARNINGS AND PRECAUTIONS (5.2)]." }

<div class="scrollingtable"><table width="97.72%"> <caption> Table 2: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours* </caption> <colgroup> <col width="43%"/> <col width="16%"/> <col width="15%"/> <col width="14%"/> <col width="12%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Rrule Toprule" valign="bottom">Adverse Event</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">All Precedex (N = 1007) (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Randomized Precedex (N = 798) (%)</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Placebo (N = 400) (%)</th><th align="center" class="Botrule Lrule Toprule" valign="bottom">Propofol (N = 188) (%)</th> </tr> </thead> <tfoot> <tr class="First First Last Last"> <td align="left" class="Footnote" colspan="5">*26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24 hours.</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> Hypotension </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 25% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 24% </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 12% </td><td align="center" class="Botrule Lrule Toprule" valign="bottom"> 13% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypertension </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 12% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 13% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 19% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 9% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 9% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 9% </td><td align="center" class="Botrule Lrule" valign="bottom"> 11% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Bradycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 0 </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Atrial Fibrillation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 7% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pyrexia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Dry Mouth </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypovolemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 5% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Atelectasis </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pleural Effusion </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Agitation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Tachycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Anemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hyperthermia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 0 </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Chills </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hyperglycemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypoxia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Post-procedural Hemorrhage </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pulmonary Edema </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypocalcemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0 </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Acidosis </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Urine Output Decreased </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0 </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Sinus Tachycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Ventricular Tachycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 5% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Wheezing </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0 </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Edema Peripheral </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> <1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.72%\">\n<caption>\nTable 2: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours*\n</caption>\n<colgroup>\n<col width=\"43%\"/>\n<col width=\"16%\"/>\n<col width=\"15%\"/>\n<col width=\"14%\"/>\n<col width=\"12%\"/>\n</colgroup>\n<thead>\n<tr class=\"First First Last Last\">\n<th align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"bottom\">Adverse Event</th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">All Precedex (N = 1007) (%)</th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Randomized Precedex (N = 798) (%)</th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Placebo (N = 400) (%)</th><th align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">Propofol (N = 188) (%)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" class=\"Footnote\" colspan=\"5\">*26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24 hours.</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"top\">\nHypotension\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\n25%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\n24%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\n12%\n</td><td align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">\n13%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypertension\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n12%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n13%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n19%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nNausea\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n9%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n9%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n9%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n11%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n0\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAtrial Fibrillation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n7%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPyrexia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nDry Mouth\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nVomiting\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypovolemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n5%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAtelectasis\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPleural Effusion\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAgitation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nTachycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAnemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHyperthermia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n0\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nChills\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHyperglycemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypoxia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPost-procedural Hemorrhage\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPulmonary Edema\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypocalcemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAcidosis\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nUrine Output Decreased\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nSinus Tachycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nVentricular Tachycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n<1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n5%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nWheezing\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n<1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nEdema Peripheral\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n<1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n</tbody>\n</table></div>" }

Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex for sedation in the surgical intensive care unit setting in which 387 adult patients received Precedex for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see TABLE 3).

{ "type": "p", "children": [], "text": "Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of Precedex for sedation in the surgical intensive care unit setting in which 387 adult patients received Precedex for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see TABLE 3)." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies </caption> <colgroup> <col width="30%"/> <col width="36%"/> <col width="33%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="bottom"> Adverse Event </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Randomized Dexmedetomidine (N = 387) </td><td align="center" class="Botrule Lrule Toprule" valign="bottom"> Placebo (N = 379) </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypotension </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 28% </td><td align="center" class="Botrule Lrule" valign="bottom"> 13% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypertension </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 16% </td><td align="center" class="Botrule Lrule" valign="bottom"> 18% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 11% </td><td align="center" class="Botrule Lrule" valign="bottom"> 9% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Bradycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 7% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Fever </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Vomiting </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Atrial Fibrillation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypoxia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Tachycardia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 5% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hemorrhage </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Anemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Dry Mouth </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Rigors </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Agitation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hyperpyrexia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pain </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hyperglycemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Acidosis </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pleural Effusion </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Oliguria </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> <1% </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Thirst </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> <1% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies\n</caption>\n<colgroup>\n<col width=\"30%\"/>\n<col width=\"36%\"/>\n<col width=\"33%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"bottom\">\nAdverse Event\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\nRandomized Dexmedetomidine (N = 387)\n</td><td align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">\nPlacebo (N = 379)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypotension\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n28%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n13%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypertension\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n16%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n18%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nNausea\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n11%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n9%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n7%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nFever\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nVomiting\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAtrial Fibrillation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypoxia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nTachycardia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n5%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHemorrhage\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAnemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nDry Mouth\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRigors\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAgitation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHyperpyrexia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPain\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHyperglycemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAcidosis\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPleural Effusion\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nOliguria\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n<1%\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nThirst\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n<1%\n</td>\n</tr>\n</tbody>\n</table></div>" }

In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in TABLE 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex group is provided in TABLE 5.

{ "type": "p", "children": [], "text": "In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in TABLE 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex group is provided in TABLE 5." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study </caption> <colgroup> <col width="42%"/> <col width="25%"/> <col width="33%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" class="Botrule" colspan="11" valign="top">† Includes any type of hypertension. 1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="bottom"> Adverse Event </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> Dexmedetomidine (N = 244) </td><td align="center" class="Botrule Lrule Toprule" valign="bottom"> Midazolam (N = 122) </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypotension1 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 56% </td><td align="center" class="Botrule Lrule" valign="bottom"> 56% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypotension Requiring Intervention </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 28% </td><td align="center" class="Botrule Lrule" valign="bottom"> 27% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Bradycardia2 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 42% </td><td align="center" class="Botrule Lrule" valign="bottom"> 19% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Bradycardia Requiring Intervention </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Systolic Hypertension3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 28% </td><td align="center" class="Botrule Lrule" valign="bottom"> 42% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Tachycardia4 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 25% </td><td align="center" class="Botrule Lrule" valign="bottom"> 44% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Tachycardia Requiring Intervention </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 10% </td><td align="center" class="Botrule Lrule" valign="bottom"> 10% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Diastolic Hypertension3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 12% </td><td align="center" class="Botrule Lrule" valign="bottom"> 15% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypertension3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 11% </td><td align="center" class="Botrule Lrule" valign="bottom"> 15% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypertension Requiring Intervention† </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 19% </td><td align="center" class="Botrule Lrule" valign="bottom"> 30% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypokalemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 9% </td><td align="center" class="Botrule Lrule" valign="bottom"> 13% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Pyrexia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 7% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Agitation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 7% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hyperglycemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 7% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 6% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypoglycemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Respiratory Failure </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Renal Failure Acute </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Acute Respiratory Distress Syndrome </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Generalized Edema </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 6% </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Hypomagnesemia </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule" valign="bottom"> 7% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study\n</caption>\n<colgroup>\n<col width=\"42%\"/>\n<col width=\"25%\"/>\n<col width=\"33%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"11\" valign=\"top\">† Includes any type of hypertension. 1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"bottom\">\nAdverse Event\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\nDexmedetomidine (N = 244)\n</td><td align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">\nMidazolam (N = 122)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypotension1\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n56%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n56%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypotension Requiring Intervention\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n28%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n27%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradycardia2\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n42%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n19%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradycardia Requiring Intervention\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nSystolic Hypertension3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n28%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n42%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nTachycardia4\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n25%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n44%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nTachycardia Requiring Intervention\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n10%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n10%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nDiastolic Hypertension3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n12%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n15%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypertension3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n11%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n15%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypertension Requiring Intervention†\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n19%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n30%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypokalemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n9%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n13%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPyrexia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n7%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAgitation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n7%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHyperglycemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n7%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nConstipation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n6%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypoglycemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRespiratory Failure\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRenal Failure Acute\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAcute Respiratory Distress Syndrome\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nGeneralized Edema\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n6%\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypomagnesemia\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n7%\n</td>\n</tr>\n</tbody>\n</table></div>" }

The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).

{ "type": "p", "children": [], "text": "The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%)." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 5. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex Group </caption> <colgroup> <col width="44%"/> <col width="18%"/> <col width="18%"/> <col width="19%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" class="Footnote" colspan="4">*Average maintenance dose over the entire study drug administration</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Toprule" colspan="4" valign="bottom"> Precedex mcg/kg/hr </td> </tr> <tr> <td class="Botrule Rrule" valign="bottom"> Adverse Event </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> ≤0.7* (N = 95) </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> >0.7 to ≤1.1* (N = 78) </td><td align="center" class="Botrule Lrule" valign="bottom"> >1.1* (N = 71) </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Constipation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 6% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 14% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Agitation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 8% </td><td align="center" class="Botrule Lrule" valign="bottom"> 14% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Anxiety </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 9% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Edema Peripheral </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 7% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Atrial Fibrillation </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 4% </td><td align="center" class="Botrule Lrule" valign="bottom"> 9% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Respiratory Failure </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 6% </td><td align="center" class="Botrule Lrule" valign="bottom"> 10% </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Acute Respiratory Distress Syndrome </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1% </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 9% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 5. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex Group\n</caption>\n<colgroup>\n<col width=\"44%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<col width=\"19%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" class=\"Footnote\" colspan=\"4\">*Average maintenance dose over the entire study drug administration</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Toprule\" colspan=\"4\" valign=\"bottom\">\nPrecedex mcg/kg/hr\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"bottom\">\nAdverse Event\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n≤0.7* (N = 95)\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n>0.7 to ≤1.1* (N = 78)\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n>1.1* (N = 71)\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nConstipation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n6%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n14%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAgitation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n8%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n14%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAnxiety\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n9%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nEdema Peripheral\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n7%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nAtrial Fibrillation\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n4%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n9%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRespiratory Failure\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n6%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n10%\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nAcute Respiratory Distress Syndrome\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1%\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n9%\n</td>\n</tr>\n</tbody>\n</table></div>" }

Procedural Sedation

{ "type": "p", "children": [], "text": "Procedural Sedation" }

Adverse reaction information is derived from the two trials for procedural sedation [see CLINICAL STUDIES (14.2)] in which 318 adult patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian.

{ "type": "p", "children": [], "text": "Adverse reaction information is derived from the two trials for procedural sedation [see CLINICAL STUDIES (14.2)] in which 318 adult patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian." }

Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in TABLE 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see WARNINGS AND PRECAUTIONS (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between Precedex and comparator groups in both studies.

{ "type": "p", "children": [], "text": "Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in TABLE 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see WARNINGS AND PRECAUTIONS (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between Precedex and comparator groups in both studies." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population </caption> <colgroup> <col width="38%"/> <col width="30%"/> <col width="32%"/> </colgroup> <thead> <tr class="First First Last Last"> <th align="left" class="Botrule Rrule Toprule" valign="bottom">Adverse Event</th><th align="center" class="Botrule Lrule Rrule Toprule" valign="bottom">Precedex (N = 318) (%)</th><th align="center" class="Botrule Lrule Toprule" valign="bottom">Placebo (N = 113) (%)</th> </tr> </thead> <tfoot> <tr class="First First Last Last"> <td align="left" class="Botrule" colspan="18" valign="top">1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg. 2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline. 3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value. 4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg. 5 Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. 6 Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.</td> </tr> </tfoot> <tbody> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> Hypotension1 </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="bottom"> 54% </td><td align="center" class="Botrule Lrule Toprule" valign="bottom"> 30% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Respiratory Depression2 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 37% </td><td align="center" class="Botrule Lrule" valign="bottom"> 32% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Bradycardia3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 14% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypertension4 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 13% </td><td align="center" class="Botrule Lrule" valign="bottom"> 24% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Tachycardia5 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 5% </td><td align="center" class="Botrule Lrule" valign="bottom"> 17% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Nausea </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 2% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Dry Mouth </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 3% </td><td align="center" class="Botrule Lrule" valign="bottom"> 1% </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hypoxia6 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 3% </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Bradypnea </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2% </td><td align="center" class="Botrule Lrule" valign="bottom"> 4% </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population\n</caption>\n<colgroup>\n<col width=\"38%\"/>\n<col width=\"30%\"/>\n<col width=\"32%\"/>\n</colgroup>\n<thead>\n<tr class=\"First First Last Last\">\n<th align=\"left\" class=\"Botrule Rrule Toprule\" valign=\"bottom\">Adverse Event</th><th align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">Precedex (N = 318) (%)</th><th align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">Placebo (N = 113) (%)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"18\" valign=\"top\">1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg. 2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline. 3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value. 4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg. 5 Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. 6 Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"top\">\nHypotension1\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\n54%\n</td><td align=\"center\" class=\"Botrule Lrule Toprule\" valign=\"bottom\">\n30%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRespiratory Depression2\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n37%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n32%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradycardia3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n14%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypertension4\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n13%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n24%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nTachycardia5\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n5%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n17%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nNausea\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nDry Mouth\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n3%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1%\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHypoxia6\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n3%\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nBradypnea\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2%\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n4%\n</td>\n</tr>\n</tbody>\n</table></div>" }

6.2 Postmarketing Experience

{ "type": "p", "children": [], "text": "\n6.2 Postmarketing Experience\n" }

The following adverse reactions have been identified during post approval use of Precedex. 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.

{ "type": "p", "children": [], "text": "The following adverse reactions have been identified during post approval use of Precedex. 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." }

Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex during post approval use of the drug.

{ "type": "p", "children": [], "text": "Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex during post approval use of the drug." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex </caption> <colgroup> <col width="35%"/> <col width="65%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" valign="top"> System Organ Class </td><td class="Botrule Lrule Toprule" valign="top"> Preferred Term </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Blood and Lymphatic System Disorders </td><td class="Botrule Lrule" valign="top"> Anemia </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Cardiac Disorders </td><td class="Botrule Lrule" valign="top"> Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Eye Disorders </td><td class="Botrule Lrule" valign="top"> Photopsia, visual impairment </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Gastrointestinal Disorders </td><td class="Botrule Lrule" valign="top"> Abdominal pain, diarrhea, nausea, vomiting </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> General Disorders and Administration Site Conditions </td><td class="Botrule Lrule" valign="top"> Chills, hyperpyrexia, pain, pyrexia, thirst </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Hepatobiliary Disorders </td><td class="Botrule Lrule" valign="top"> Hepatic function abnormal, hyperbilirubinemia </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Investigations </td><td class="Botrule Lrule" valign="top"> Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Metabolism and Nutrition Disorders </td><td class="Botrule Lrule" valign="top"> Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Nervous System Disorders </td><td class="Botrule Lrule" valign="top"> Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Psychiatric Disorders </td><td class="Botrule Lrule" valign="top"> Agitation, confusional state, delirium, hallucination, illusion </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Renal and Urinary Disorders </td><td class="Botrule Lrule" valign="top"> Oliguria, polyuria </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Respiratory, Thoracic and Mediastinal Disorders </td><td class="Botrule Lrule" valign="top"> Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Skin and Subcutaneous Tissue Disorders </td><td class="Botrule Lrule" valign="top"> Hyperhidrosis, pruritus, rash, urticaria </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Surgical and Medical Procedures </td><td class="Botrule Lrule" valign="top"> Light anesthesia </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Vascular Disorders </td><td class="Botrule Lrule" valign="top"> Blood pressure fluctuation, hemorrhage, hypertension, hypotension </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 7: Adverse Reactions Experienced During Post-approval Use of Precedex\n</caption>\n<colgroup>\n<col width=\"35%\"/>\n<col width=\"65%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" valign=\"top\">\nSystem Organ Class\n</td><td class=\"Botrule Lrule Toprule\" valign=\"top\">\nPreferred Term\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nBlood and Lymphatic System Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nAnemia\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nCardiac Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nArrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nEye Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nPhotopsia, visual impairment\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nGastrointestinal Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nAbdominal pain, diarrhea, nausea, vomiting\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nGeneral Disorders and Administration Site Conditions\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nChills, hyperpyrexia, pain, pyrexia, thirst\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nHepatobiliary Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nHepatic function abnormal, hyperbilirubinemia\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nInvestigations\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nAlanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nMetabolism and Nutrition Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nAcidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nNervous System Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nConvulsion, dizziness, headache, neuralgia, neuritis, speech disorder\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nPsychiatric Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nAgitation, confusional state, delirium, hallucination, illusion\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRenal and Urinary Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nOliguria, polyuria\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nRespiratory, Thoracic and Mediastinal Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nApnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nSkin and Subcutaneous Tissue Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nHyperhidrosis, pruritus, rash, urticaria\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nSurgical and Medical Procedures\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nLight anesthesia\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nVascular Disorders\n</td><td class=\"Botrule Lrule\" valign=\"top\">\nBlood pressure fluctuation, hemorrhage, hypertension, hypotension\n</td>\n</tr>\n</tbody>\n</table></div>" }

7 Drug Interactions

7.1 Anesthetics, Sedatives, Hypnotics, Opioids

{ "type": "p", "children": [], "text": "\n7.1 Anesthetics, Sedatives, Hypnotics, Opioids\n" }

Co-administration of Precedex with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between Precedex and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with Precedex, a reduction in dosage of Precedex or the concomitant anesthetic, sedative, hypnotic or opioid may be required.

{ "type": "p", "children": [], "text": "Co-administration of Precedex with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between Precedex and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with Precedex, a reduction in dosage of Precedex or the concomitant anesthetic, sedative, hypnotic or opioid may be required." }

7.2 Neuromuscular Blockers

{ "type": "p", "children": [], "text": "\n7.2 Neuromuscular Blockers\n" }

In one study of 10 healthy adult volunteers, administration of Precedex for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.

{ "type": "p", "children": [], "text": "In one study of 10 healthy adult volunteers, administration of Precedex for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration." }

8 Use In Specific Populations Section

Risk Summary

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

{ "type": "p", "children": [], "text": "Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta." }

{ "type": "p", "children": [], "text": "In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day." }

{ "type": "p", "children": [], "text": "Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see DATA)." }

{ "type": "p", "children": [], "text": "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 2–4% and 15–20%, respectively." }

Data

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

Animal Data

{ "type": "p", "children": [], "text": "Animal Data" }

{ "type": "p", "children": [], "text": "Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported." }

{ "type": "p", "children": [], "text": "No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18)." }

{ "type": "p", "children": [], "text": "Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21)." }

In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.

{ "type": "p", "children": [], "text": "In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously." }

8.2 Lactation Risk Summary

{ "type": "p", "children": [], "text": "8.2 Lactation\nRisk Summary\n" }

Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see DATA). There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PRECEDEX and any potential adverse effects on the breastfed infant from PRECEDEX or from the underlying condition.

{ "type": "p", "children": [], "text": "Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see DATA). There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PRECEDEX and any potential adverse effects on the breastfed infant from PRECEDEX or from the underlying condition." }

Data

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

{ "type": "p", "children": [], "text": "In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2–0.7 mcg/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%." }

8.4 Pediatric Use Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated.

{ "type": "p", "children": [], "text": "\n8.4 Pediatric Use\nSafety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated." }

8.5 Geriatric Use Intensive Care Unit Sedation

{ "type": "p", "children": [], "text": "\n8.5 Geriatric Use\n\nIntensive Care Unit Sedation\n" }

A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of PRECEDEX [see WARNINGS AND PRECAUTIONS (5.2)]. Therefore, a dose reduction may be considered in patients over 65 years of age [see DOSAGE AND ADMINISTRATION (2.2, 2.3), CLINICAL PHARMACOLOGY (12.3)].

{ "type": "p", "children": [], "text": "A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of PRECEDEX [see WARNINGS AND PRECAUTIONS (5.2)]. Therefore, a dose reduction may be considered in patients over 65 years of age [see DOSAGE AND ADMINISTRATION (2.2, 2.3), CLINICAL PHARMACOLOGY (12.3)]." }

Procedural Sedation

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

A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in PRECEDEX-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.

{ "type": "p", "children": [], "text": "A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in PRECEDEX-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age." }

8.6 Hepatic ImpairmentSince PRECEDEX clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION (2.2, 2.3), CLINICAL PHARMACOLOGY (12.3)].

{ "type": "p", "children": [], "text": "8.6 Hepatic ImpairmentSince PRECEDEX clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION (2.2, 2.3), CLINICAL PHARMACOLOGY (12.3)]." }

9 Drug Abuse And Dependence

9.1 Controlled Substance

{ "type": "p", "children": [], "text": "\n9.1 Controlled Substance\n" }

Precedex (dexmedetomidine hydrochloride) is not a controlled substance.

{ "type": "p", "children": [], "text": "Precedex (dexmedetomidine hydrochloride) is not a controlled substance." }

9.3 Dependence

{ "type": "p", "children": [], "text": "\n9.3 Dependence\n" }

The dependence potential of Precedex has not been studied in humans. However, since studies in rodents and primates have demonstrated that Precedex exhibits pharmacologic actions similar to those of clonidine, it is possible that Precedex may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see WARNINGS AND PRECAUTIONS (5.5)].

{ "type": "p", "children": [], "text": "The dependence potential of Precedex has not been studied in humans. However, since studies in rodents and primates have demonstrated that Precedex exhibits pharmacologic actions similar to those of clonidine, it is possible that Precedex may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see WARNINGS AND PRECAUTIONS (5.5)]." }

10 Overdosage

The tolerability of Precedex was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute.

{ "type": "p", "children": [], "text": "The tolerability of Precedex was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute." }

Five adult patients received an overdose of Precedex in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted Precedex (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

{ "type": "p", "children": [], "text": "Five adult patients received an overdose of Precedex in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted Precedex (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated." }

11 Description

Precedex (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Precedex (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Precedex has a molecular weight of 236.7 and the empirical formula is C13H16N2 • HCl and the structural formula is:

{ "type": "p", "children": [], "text": "Precedex (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Precedex (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Precedex has a molecular weight of 236.7 and the empirical formula is C13H16N2 • HCl and the structural formula is:" }

Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89.

Precedex Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution. The solution is preservative-free and contains no additives or chemical stabilizers.

{ "type": "p", "children": [], "text": "Precedex Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution. The solution is preservative-free and contains no additives or chemical stabilizers." }

Precedex in 0.9% Sodium Chloride Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 8.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg sodium chloride in water and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers.

{ "type": "p", "children": [], "text": "Precedex in 0.9% Sodium Chloride Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 8.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg sodium chloride in water and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers." }

12 Clinical Pharmacology

12.1 Mechanism of Action

{ "type": "p", "children": [], "text": "\n12.1 Mechanism of Action\n" }

Precedex is a relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration.

{ "type": "p", "children": [], "text": "Precedex is a relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration." }

12.2 Pharmacodynamics

{ "type": "p", "children": [], "text": "\n12.2 Pharmacodynamics\n" }

In a study in healthy volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr).

{ "type": "p", "children": [], "text": "In a study in healthy volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr)." }

12.3 Pharmacokinetics

{ "type": "p", "children": [], "text": "\n12.3 Pharmacokinetics\n" }

Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.

{ "type": "p", "children": [], "text": "Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg." }

Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. TABLE 8 shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours.

{ "type": "p", "children": [], "text": "Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. TABLE 8 shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours." }

<div class="scrollingtable"><table width="97.7%"> <caption> Table 8: Mean ± SD Pharmacokinetic Parameters </caption> <colgroup> <col width="26%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> </colgroup> <tfoot> <tr class="First First Last Last"> <td align="left" class="Botrule" colspan="5" valign="top">* Presented as harmonic mean and pseudo standard deviation. # Mean Css = Average steady-state concentration of Dexmedetomidine. The mean Css was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="First"> <td class="Botrule Rrule Toprule" rowspan="4" valign="bottom"> Parameter </td><td align="center" class="Botrule Lrule Toprule" colspan="4" valign="bottom"> Loading Infusion (min)/Total Infusion Duration (hrs) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> 10 min/12 hrs </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 10 min/24 hrs </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 10 min/24 hrs </td><td align="center" class="Botrule Lrule" valign="bottom"> 35 min/24 hrs </td> </tr> <tr> <td align="center" class="Botrule Lrule" colspan="4" valign="bottom"> Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.3/0.17 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.3/0.17 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.6/0.33 </td><td align="center" class="Botrule Lrule" valign="bottom"> 1.25/0.70 </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> t1/2*, hour </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 1.78 ± 0.30 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2.22 ± 0.59 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 2.23 ± 0.21 </td><td align="center" class="Botrule Lrule" valign="bottom"> 2.50 ± 0.61 </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> CL, liter/hour </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 46.3 ± 8.3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 43.1 ± 6.5 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 35.3 ± 6.8 </td><td align="center" class="Botrule Lrule" valign="bottom"> 36.5 ± 7.5 </td> </tr> <tr> <td class="Botrule Rrule" valign="top"> Vss, liter </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 88.7 ± 22.9 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 102.4 ± 20.3 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 93.6 ± 17.0 </td><td align="center" class="Botrule Lrule" valign="bottom"> 99.6 ± 17.8 </td> </tr> <tr class="Last"> <td class="Botrule Rrule" valign="top"> Avg Css#, ng/mL </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.27 ± 0.05 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.27 ± 0.05 </td><td align="center" class="Botrule Lrule Rrule" valign="bottom"> 0.67 ± 0.10 </td><td align="center" class="Botrule Lrule" valign="bottom"> 1.37 ± 0.20 </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"97.7%\">\n<caption>\nTable 8: Mean ± SD Pharmacokinetic Parameters\n</caption>\n<colgroup>\n<col width=\"26%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First First Last Last\">\n<td align=\"left\" class=\"Botrule\" colspan=\"5\" valign=\"top\">* Presented as harmonic mean and pseudo standard deviation. # Mean Css = Average steady-state concentration of Dexmedetomidine. The mean Css was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Rrule Toprule\" rowspan=\"4\" valign=\"bottom\">\nParameter\n</td><td align=\"center\" class=\"Botrule Lrule Toprule\" colspan=\"4\" valign=\"bottom\">\nLoading Infusion (min)/Total Infusion Duration (hrs)\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n10 min/12 hrs\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n10 min/24 hrs\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n10 min/24 hrs\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n35 min/24 hrs\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule\" colspan=\"4\" valign=\"bottom\">\nDexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.3/0.17\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.3/0.17\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.6/0.33\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1.25/0.70\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nt1/2*, hour\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n1.78 ± 0.30\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2.22 ± 0.59\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n2.23 ± 0.21\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n2.50 ± 0.61\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nCL, liter/hour\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n46.3 ± 8.3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n43.1 ± 6.5\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n35.3 ± 6.8\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n36.5 ± 7.5\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Rrule\" valign=\"top\">\nVss, liter\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n88.7 ± 22.9\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n102.4 ± 20.3\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n93.6 ± 17.0\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n99.6 ± 17.8\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Rrule\" valign=\"top\">\nAvg Css#, ng/mL\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.27 ± 0.05\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.27 ± 0.05\n</td><td align=\"center\" class=\"Botrule Lrule Rrule\" valign=\"bottom\">\n0.67 ± 0.10\n</td><td align=\"center\" class=\"Botrule Lrule\" valign=\"bottom\">\n1.37 ± 0.20\n</td>\n</tr>\n</tbody>\n</table></div>" }

The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.

{ "type": "p", "children": [], "text": "The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively." }

Dexmedetomidine pharmacokinetic parameters after Precedex maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the PK parameters after Precedex maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.

{ "type": "p", "children": [], "text": "Dexmedetomidine pharmacokinetic parameters after Precedex maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the PK parameters after Precedex maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively." }

Distribution

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

The steady-state volume of distribution (Vss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.

{ "type": "p", "children": [], "text": "The steady-state volume of distribution (Vss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects." }

The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex.

{ "type": "p", "children": [], "text": "The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex." }

Metabolism

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

Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.

{ "type": "p", "children": [], "text": "Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide." }

Elimination

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

The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.

{ "type": "p", "children": [], "text": "The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified." }

Specific Populations

{ "type": "p", "children": [], "text": "Specific Populations" }

Male and Female Patients

{ "type": "p", "children": [], "text": "Male and Female Patients" }

There was no observed difference in PRECEDEX pharmacokinetics due to sex.

{ "type": "p", "children": [], "text": "There was no observed difference in PRECEDEX pharmacokinetics due to sex." }

Geriatric Patients

{ "type": "p", "children": [], "text": "Geriatric Patients" }

The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects.

{ "type": "p", "children": [], "text": "The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects." }

Patients with Hepatic Impairment

{ "type": "p", "children": [], "text": "Patients with Hepatic Impairment" }

In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for PRECEDEX were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively.

{ "type": "p", "children": [], "text": "In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for PRECEDEX were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively." }

Although PRECEDEX is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.8)].

{ "type": "p", "children": [], "text": "Although PRECEDEX is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.8)]." }

Patients with Renal Impairment

{ "type": "p", "children": [], "text": "Patients with Renal Impairment" }

Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.

{ "type": "p", "children": [], "text": "Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects." }

Drug Interaction Studies

{ "type": "p", "children": [], "text": "\nDrug Interaction Studies\n" }

In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.

{ "type": "p", "children": [], "text": "In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance." }

13 Nonclinical Toxicology

Carcinogenesis

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

Animal carcinogenicity studies have not been performed with dexmedetomidine.

{ "type": "p", "children": [], "text": "Animal carcinogenicity studies have not been performed with dexmedetomidine." }

Mutagenesis

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

Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.

{ "type": "p", "children": [], "text": "Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice." }

Impairment of Fertility

{ "type": "p", "children": [], "text": "\nImpairment of Fertility\n" }

Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

{ "type": "p", "children": [], "text": "Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females." }

13.2 Animal Toxicology and/or Pharmacology There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.

{ "type": "p", "children": [], "text": "\n13.2 Animal Toxicology and/or Pharmacology\nThere were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression." }

14 Clinical Studies

The safety and efficacy of Precedex has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 adult patients.

{ "type": "p", "children": [], "text": "The safety and efficacy of Precedex has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 adult patients." }

14.1 Intensive Care Unit Sedation

{ "type": "p", "children": [], "text": "\n14.1 Intensive Care Unit Sedation\n" }

Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of Precedex by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between Precedex and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in TABLE 9.

{ "type": "p", "children": [], "text": "Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of Precedex by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between Precedex and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in TABLE 9." }

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive PRECEDEX by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to PRECEDEX (see TABLE 13).

{ "type": "p", "children": [], "text": "In the first study, 175 adult patients were randomized to receive placebo and 178 to receive PRECEDEX by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive \"rescue\" midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to PRECEDEX (see TABLE 13)." }

A second prospective primary analysis assessed the sedative effects of PRECEDEX by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the PRECEDEX group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see TABLE 13).

{ "type": "p", "children": [], "text": "A second prospective primary analysis assessed the sedative effects of PRECEDEX by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the PRECEDEX group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see TABLE 13)." }

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Precedex patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.

{ "type": "p", "children": [], "text": "A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Precedex patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group." }

In a second study, 198 adult patients were randomized to receive placebo and 203 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated.

{ "type": "p", "children": [], "text": "In a second study, 198 adult patients were randomized to receive placebo and 203 to receive Precedex by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive \"rescue\" propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated." }

Patients randomized to placebo received significantly more propofol than patients randomized to Precedex (see TABLE 11).

{ "type": "p", "children": [], "text": "Patients randomized to placebo received significantly more propofol than patients randomized to Precedex (see TABLE 11)." }

A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see TABLE 11).

{ "type": "p", "children": [], "text": "A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see TABLE 11)." }

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.

{ "type": "p", "children": [], "text": "A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group." }

In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Precedex was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of Precedex for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see ADVERSE REACTIONS (6.1)].

{ "type": "p", "children": [], "text": "In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Precedex was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of Precedex for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see ADVERSE REACTIONS (6.1)]." }

14.2 Procedural Sedation

{ "type": "p", "children": [], "text": "\n14.2 Procedural Sedation\n" }

The safety and efficacy of Precedex for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of Precedex in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Precedex in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.

{ "type": "p", "children": [], "text": "The safety and efficacy of Precedex for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of Precedex in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Precedex in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure." }

In Study 1, the sedative properties of Precedex were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer's Assessment of Alertness/Sedation Scale (see TABLE 12).

{ "type": "p", "children": [], "text": "In Study 1, the sedative properties of Precedex were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer's Assessment of Alertness/Sedation Scale (see TABLE 12)." }

Patients were randomized to receive a loading infusion of either Precedex 1 mcg/kg, Precedex 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer's Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer's Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the Precedex and comparator groups. Efficacy results showed that Precedex was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see TABLE 13).

{ "type": "p", "children": [], "text": "\nPatients were randomized to receive a loading infusion of either Precedex 1 mcg/kg, Precedex 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer's Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer's Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the Precedex and comparator groups. Efficacy results showed that Precedex was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see TABLE 13).\n" }

In Study 2, the sedative properties of Precedex were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see TABLE 9). Patients were randomized to receive a loading infusion of Precedex 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the Precedex and comparator groups. For efficacy results see TABLE 13.

{ "type": "p", "children": [], "text": "In Study 2, the sedative properties of Precedex were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see TABLE 9). Patients were randomized to receive a loading infusion of Precedex 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the Precedex and comparator groups. For efficacy results see TABLE 13." }

How Supplied/Storage And Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 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 between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]" }

Do not use if product is discolored or if precipitate matter is present.

{ "type": "p", "children": [], "text": "Do not use if product is discolored or if precipitate matter is present." }

PRECEDEX (dexmedetomidine hydrochloride) injection 200 mcg/2 mL (100 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion.

{ "type": "p", "children": [], "text": "PRECEDEX (dexmedetomidine hydrochloride) injection 200 mcg/2 mL (100 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion." }

PRECEDEX (dexmedetomidine hydrochloride in 0.9% Sodium Chloride) injection (4 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion.

{ "type": "p", "children": [], "text": "PRECEDEX (dexmedetomidine hydrochloride in 0.9% Sodium Chloride) injection (4 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion." }

<div class="scrollingtable"><table width="100%"> <caption> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 </caption> <tbody class="Headless"> <tr class="First"> <td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit </td> </tr> <tr class="Last"> <td>NDC 0409-1638-02 Tray of 25 single-dose clear glass vials</td><td>NDC 0404-9938-02 1 2 mL single-dose clear glass vial in a bag (Vial bears NDC 0409-1638-32)</td><td>200 mcg/2 mL (100 mcg/mL)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<caption>\n Product repackaged by: Henry Schein, Inc., Bastian, VA 24314\n</caption>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td>From Original Manufacturer/Distributor's NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale</td><td>Total Strength/Total Volume (Concentration) per unit </td>\n</tr>\n<tr class=\"Last\">\n<td>NDC 0409-1638-02 Tray of 25 single-dose clear glass vials</td><td>NDC 0404-9938-02 1 2 mL single-dose clear glass vial in a bag (Vial bears NDC 0409-1638-32)</td><td>200 mcg/2 mL (100 mcg/mL)</td>\n</tr>\n</tbody>\n</table></div>" }

17 Patient Counseling Information

PRECEDEX is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of PRECEDEX and as clinically appropriate after discontinuation.

{ "type": "p", "children": [], "text": "PRECEDEX is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of PRECEDEX and as clinically appropriate after discontinuation." }

• When PRECEDEX is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.• Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of PRECEDEX such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness.• Advise breastfeeding mothers who were exposed to PRECEDEX to monitor breastfed neonates for irritability [see USE IN SPECIFIC POPULATIONS (8.2)].

{ "type": "p", "children": [], "text": "• When PRECEDEX is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.• Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of PRECEDEX such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness.• Advise breastfeeding mothers who were exposed to PRECEDEX to monitor breastfed neonates for irritability [see USE IN SPECIFIC POPULATIONS (8.2)]." }

Distributed by Hospira, Inc. Lake Forest, IL 60045

{ "type": "p", "children": [], "text": "Distributed by Hospira, Inc. Lake Forest, IL 60045" }

LAB-1346-3.0

{ "type": "p", "children": [], "text": "LAB-1346-3.0" }

Sample Package Label

99476e8c-2527-4cb0-9d67-9f9cd91343c6

IGALMI- dexmedetomidine film

1 Indications And Usage

Limitations of Use

The safety and effectiveness of IGALMI have not been established beyond 24 hours from the first dose [see Warnings and Precautions (5.4, 5.5)].

2 Dosage And Administration

2.1 Important Recommendations Prior To Initiating Igalmi And During Therapy

IGALMI should be administered under the supervision of a healthcare provider. A healthcare provider should monitor vital signs and alertness after IGALMI administration to prevent falls and syncope [see Warnings and Precautions (5.5)].

IGALMI is for sublingual or buccal administration. Do not chew or swallow IGALMI. Do not eat or drink for at least 15 minutes after sublingual administration, or at least one hour after buccal administration.

2.2 Recommended Dosage

Table 1 includes dosage recommendations for IGALMI based on agitation severity for adults, patients with hepatic impairment, and geriatric patients. Lower dosages are recommended for patients with hepatic impairment and geriatric patients [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].

If agitation persists after the initial dose, up to two additional doses may be administered at least two hours apart. The dosage recommendations for additional doses vary depending upon the patient population and agitation severity (see Table 1). Assess vital signs including orthostatic measurements prior to the administration of any subsequent doses.

Due to risk of hypotension, additional half-doses are not recommended in patients with systolic blood pressure (SBP) less than 90 mmHg, diastolic blood pressure (DBP) less than 60 mmHg, heart rate (HR) less than 60 beats per minute, or postural decrease in SBP ≥ 20 mmHg or in DBP ≥ 10 mmHg.

<div class="scrollingtable"><table width="75%"> <caption> Table 1: Dosage Recommendations for IGALMI in Adults, Adult Patients with Hepatic Impairment, and Geriatric Patients with Agitation Associated with Schizophrenia or Bipolar I or II Disorder </caption> <col align="left" valign="middle" width="25%"/> <col align="left" valign="middle" width="16%"/> <col align="left" valign="middle" width="17%"/> <col align="left" valign="middle" width="17%"/> <col align="left" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Patient Population</th><th align="center" class="Rrule">Agitation Severity</th><th align="center" class="Rrule">Initial Dose<a class="Sup" href="#footnote-2" name="footnote-reference-2">*</a></th><th align="center" class="Rrule">Optional 2nd/3rd Doses<a class="Sup" href="#footnote-2">*</a></th><th align="center" class="Rrule">Maximum Recommended Total Daily Dosage </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-2" name="footnote-2">*</a> </dt> <dd>IGALMI 120 mcg and 180 mcg dosage strengths may be cut in half to obtain the 60 mcg and 90 mcg doses, respectively [see <a href="#S2.3">Dosage and Administration (2.3)</a>].</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">†</a> </dt> <dd>Hepatic impairment: Mild (Child-Pugh Class A); Moderate (Child-Pugh Class B); Severe (Child-Pugh Class C)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" rowspan="2">Adults</td><td align="left" class="Rrule">Mild or Moderate</td><td align="left" class="Rrule">120 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">240 mcg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Severe</td><td align="left" class="Rrule">180 mcg</td><td align="left" class="Rrule">90 mcg</td><td align="left" class="Rrule">360 mcg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Patients with Mild or Moderate Hepatic Impairment<a class="Sup" href="#footnote-3" name="footnote-reference-3">†</a></td><td align="left" class="Rrule">Mild or Moderate</td><td align="left" class="Rrule">90 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">210 mcg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Severe</td><td align="left" class="Rrule">120 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">240 mcg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">Patients with Severe Hepatic Impairment<a class="Sup" href="#footnote-3">†</a></td><td align="left" class="Rrule">Mild or Moderate</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">180 mcg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Severe</td><td align="left" class="Rrule">90 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">210 mcg</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Geriatric Patients (≥ 65 years old)</td><td align="left" class="Rrule">Mild, Moderate, or Severe</td><td align="left" class="Rrule">120 mcg</td><td align="left" class="Rrule">60 mcg</td><td align="left" class="Rrule">240 mcg</td> </tr> </tbody> </table></div>

2.3 Preparation And Administration Instructions

Keep IGALMI in the foil pouch until ready to administer. IGALMI should be immediately administered once the pouch is opened and the dose prepared.

Prepare and administer IGALMI under the supervision of a healthcare provider as follows:

<div class="scrollingtable"><table width="95%"> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="45%"/> <col align="left" valign="top" width="25%"/> <col align="left" valign="top" width="25%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="4">Healthcare Professional: Prepare IGALMI Dose for Patient</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">1</td><td align="left" class="Rrule">Open the sealed foil pouch by tearing straight across at the notch.</td><td align="left"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-01.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=igalmi-02.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="4"> <ul class="Disc"> <li> Perform Steps 2a, 2b, 2c and 2d only if a 60 mcg or 90 mcg dose (half of a film) is needed, then proceed to Step 3. </li> <li> If administering a full dose (1 film), proceed directly to Step 3. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">2a</td><td align="left" class="Rrule">Remove the film from the pouch with clean dry hands.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-03.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">2b</td><td align="left" class="Rrule">Cut the film in half between the dots with clean, dry scissors.</td><td align="left"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-04.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td><td align="left" class="Rrule"><img alt="Figure" src="/dailymed/image.cfm?name=igalmi-05.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">2c</td><td align="left" class="Rrule" colspan="3">Discard unused half in waste container.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">2d</td><td align="left" class="Rrule">Place the half film for administration to the patient back into the pouch.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-06.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">3</td><td align="left" class="Rrule">Immediately give the pouch to the patient.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-07.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">4</td><td align="left" class="Rrule">Instruct patient to remove the film from the pouch with clean dry hands.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-08.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" rowspan="2">5</td><td align="left" class="Rrule">For sublingual administration: Instruct patient to place film under the tongue. The film will stick in place. Note: Patient may not eat or drink for 15 minutes after sublingual administration.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-09.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">For buccal administration: Instruct patient to place film behind lower lip. The film will stick in place. Note: Patient may not eat or drink for one hour after buccal administration.</td><td align="left" class="Rrule" colspan="2"> <img alt="Figure" src="/dailymed/image.cfm?name=igalmi-10.jpg&setid=99476e8c-2527-4cb0-9d67-9f9cd91343c6"/> </td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">6</td><td align="left" class="Rrule" colspan="3">Instruct patient to:<ul class="Disc"> <li>Close their mouth.</li> <li>Allow the film to dissolve.</li> <li>Do not chew or swallow the film.</li> </ul> </td> </tr> </tbody> </table></div>

3 Dosage Forms And Strengths

IGALMI is a blue rectangular sublingual film containing on its surface two darker blue spots in dose strengths of 120 mcg and 180 mcg.

{ "type": "p", "children": [], "text": "IGALMI is a blue rectangular sublingual film containing on its surface two darker blue spots in dose strengths of 120 mcg and 180 mcg. " }

4 Contraindications

None.

{ "type": "p", "children": [], "text": "None." }

5 Warnings And Precautions

5.1 Hypotension, Orthostatic Hypotension, And Bradycardia

IGALMI causes dose-dependent hypotension, orthostatic hypotension, and bradycardia. In clinical studies, 18%, 16%, and 9% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced orthostatic hypotension (defined as SBP decrease ≥ 20 mmHg or DBP decrease ≥ 10 mmHg after 1, 3, or 5 minutes of standing) at 2 hours post-dose. In those studies, 7%, 6%, and 1% of patients treated with 180 mcg of IGALMI, 120 mcg of IGALMI, and placebo, respectively, experienced HR ≤ 50 beats per minute within 2 hours of dosing [see Adverse Reactions (6.1)]. In clinical studies with IGALMI, patients were excluded if they had treatment with alpha-1 noradrenergic blockers, benzodiazepines, other hypnotics or antipsychotic drugs four hours prior to study drug administration; had a history of syncope or syncopal attacks; SBP < 110 mmHg; DBP < 70 mmHg; HR < 55 beats per minute; or had evidence of hypovolemia or orthostatic hypotension.

Reports of hypotension and bradycardia, including some resulting in fatalities, have been associated with the use of another dexmedetomidine product given intravenously (IGALMI is for sublingual or buccal use and is not approved for intravenous use). Clinically significant episodes of bradycardia and sinus arrest have been reported after administration of this other dexmedetomidine product to young, healthy adult volunteers with high vagal tone and when this product was given by rapid intravenous or bolus administration.

Because IGALMI decreases sympathetic nervous system activity, hypotension and/or bradycardia may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in geriatric patients [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].

Avoid use of IGALMI in patients with hypotension, orthostatic hypotension, advanced heart block, severe ventricular dysfunction, or history of syncope. After IGALMI administration, patients should be adequately hydrated and should sit or lie down until vital signs are within normal range. If a patient is unable to remain seated or lying down, precautions should be taken to reduce the risk of falls. Ensure that a patient is alert and not experiencing orthostatic hypotension or symptomatic hypotension prior to allowing them to resume ambulation [see Dosage and Administration (2.1)].

5.2 Qt Interval Prolongation

IGALMI prolongs the QT interval. Avoid use of IGALMI in patients at risk of torsades de pointes or sudden death including those with known QT prolongation, a history of other arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, and in patients receiving other drugs known to prolong the QT interval [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].

5.3 Somnolence

IGALMI can cause somnolence. In placebo-controlled clinical studies in adults with agitation associated with schizophrenia or bipolar I or II disorder, somnolence (including fatigue and sluggishness) was reported in 23% and 22% of patients treated with IGALMI 180 mcg and 120 mcg, respectively, compared to 6% of placebo-treated patients. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or operating hazardous machinery, for at least eight hours after taking IGALMI [see Adverse Reactions (6.1)].

5.4 Risk Of Withdrawal Reactions

Symptoms of withdrawal have been observed after procedural sedation with another dexmedetomidine product administered intravenously. In this study, 12 (5%) adult patients who received intravenous dexmedetomidine up to 7 days (regardless of dose) experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing dexmedetomidine and 7 (3%) adult patients who received intravenous dexmedetomidine experienced at least 1 event related with withdrawal 24 to 48 hours after discontinuing dexmedetomidine. The most common withdrawal reactions were nausea, vomiting, and agitation. In these subjects, tachycardia and hypertension requiring intervention occurred at a frequency of <5% in the 48 hours following intravenous dexmedetomidine discontinuation.

IGALMI was not studied for longer than 24 hours after the first dose. There may be a risk of physical dependence and a withdrawal syndrome if IGALMI is used in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3)].

5.5 Tolerance And Tachyphylaxis

Use of another dexmedetomidine product administered intravenously beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions.

IGALMI was not studied for longer than 24 hours after the first dose. There may be a risk of tolerance and tachyphylaxis if IGALMI is used in a manner other than indicated [see Dosage and Administration (2.2) and Drug Abuse and Dependence (9.3)].

6 Adverse Reactions

6.1 Clinical Studies Experience

The safety of IGALMI was evaluated in 507 adult patients with agitation associated with schizophrenia (N=255) or bipolar I or II disorder (N=252) in two randomized, placebo-controlled studies (Studies 1 and 2) [see Clinical Studies (14)]. In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment. Patients were 18 to 71 years of age (mean age was 46 years old); 45% were female and 55% were male; 66% were Black, 31% were White, 2% were multiracial, and 1% were other.

In these studies, patients received an initial dose of IGALMI 180 mcg (N=252), IGALMI 120 mcg (N=255), or placebo (N=252). Patients who were hemodynamically stable (i.e., those with systolic blood pressure (SBP) > 90 mmHg, diastolic blood pressure (DBP) > 60 mmHg, and heart rate (HR) > 60 beats per minute) and without orthostatic hypotension (i.e., reduction in SBP < 20 mmHg or DBP < 10 mmHg upon standing) were eligible for an additional dose after 2 hours. An additional half dose (90 mcg, 60 mcg, or placebo) was given to 7.1% (18/252), 22.7% (58/255) and 44.0% (111/252) of patients in the IGALMI 180 mcg, IGALMI 120 mcg or placebo arms, respectively. After at least an additional 2 hours, an additional second half dose (total IGALMI dose of 360 mcg, total IGALMI dose of 240 mcg, or placebo, respectively) was given to 3.2% (8/252), 9.4% (24/255), and 21.0% (53/252) of patients in the IGALMI 180 mcg, IGALMI 120 mcg or placebo arms, respectively.

In these studies, one patient discontinued treatment due to an adverse reaction of oropharyngeal pain.

The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) were: somnolence, oral paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension.

Table 2 presents the adverse reactions that occurred in IGALMI-treated patients at a rate of at least 2% and at a higher rate than in placebo-treated patients in Studies 1 and 2.

<div class="scrollingtable"><table width="75%"> <caption> Table 2: Adverse Reactions Reported in ≥2% of IGALMI-Treated Patients and Greater than Placebo in Two Placebo-Controlled Studies of Agitated Adult Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) </caption> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="24%"/> <col align="center" valign="top" width="23%"/> <col align="center" valign="top" width="23%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">IGALMI 180 mcg N=252 %</th><th align="center" class="Rrule">IGALMI 120 mcg N=255 %</th><th align="center" class="Rrule">Placebo N=252 %</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-4" name="footnote-4">*</a> </dt> <dd>Somnolence includes the terms fatigue and sluggishness</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>Abdominal discomfort includes dyspepsia, gastroesophageal reflux disease</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Somnolence<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a></td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">22</td><td align="center" class="Rrule">6</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Paresthesia oral or hypoesthesia oral</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">6</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Hypotension</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">0</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Orthostatic hypotension</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule"><1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Dry mouth</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Nausea</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Bradycardia</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Abdominal discomfort<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1</td> </tr> </tbody> </table></div>

Hypotension, Orthostatic Hypotension, and Bradycardia in Two Placebo-Controlled Studies

In clinical studies, patients were excluded if they were treated with alpha-1 noradrenergic blockers, benzodiazepines, antipsychotic drugs, or other hypnotics four hours prior to study drug administration; had a history of syncope or syncopal attacks; their SBP was less than 110 mmHg; their DBP was less than 70 mmHg; their HR was less than 55 beats per minute; or they had evidence of hypovolemia or orthostatic hypotension. In these studies, vital signs were monitored (at 30 minutes, 1-, 2-, 4-, 6-, and 8-hours post-dose), including orthostatic vital signs at 2-, 4-, and 8-hours post-dose. Maximum positional decreases in SBP and DBP after standing were observed at two hours post-dose. Maximal reductions on BP and HR were observed two hours post-dose.

Table 3 presents the mean BP and HR decrease across all patients from both studies at 2 hours post dose.

<div class="scrollingtable"><table width="75%"> <caption> Table 3: Mean Blood Pressure and Heart Rate Decrease At 2 Hours Post-Dose </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">IGALMI 180 mcg N=252</th><th align="center" class="Rrule">IGALMI 120 mcg N=255</th><th align="center" class="Rrule">Placebo N=252</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Mean SBP Decrease (mmHg)</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">13</td><td align="center" class="Rrule">1</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Mean DBP Decrease (mmHg)</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule"><1</td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Mean Heart Rate Decrease (bpm)</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">3</td> </tr> </tbody> </table></div>

In the clinical studies:

At 8 hours post-dose, 2% of patients in the IGALMI 180 mcg group experienced a SBP ≤ 90 mmHg and decrease ≥ 20 mmHg compared with one patient (<1%) in the IGALMI 120 mcg group and none in the placebo group. At 24 hours, none of the patients in the IGALMI 180 mcg group experienced a SBP ≤90 mmHg and decrease ≥ 20 mmHg compared with one patient (<1%) in the IGALMI 120 mcg group and none in the placebo group. At 8 hours post-dose, none of the patients in the IGALMI 180 mcg group had a HR ≤ 50 beats per minute and a HR decrease ≥ 20 beats per minute compared with one patient in the 120 mcg group (<1%) and none in the placebo group.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of another dexmedetomidine product given intravenously (IGALMI is not approved for intravenous use). 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.

7 Drug Interactions

7.1 Drugs That Prolong The Qt Interval

Concomitant use of drugs that prolong the QT interval may add to the QT-prolonging effects of IGALMI and increase the risk of cardiac arrhythmia. Avoid the use of IGALMI in combination with other drugs known to prolong the QT interval [see Warnings and Precautions (5.2)].

7.2 Anesthetics, Sedatives, Hypnotics, And Opioids

Concomitant use of IGALMI with anesthetics, sedatives, hypnotics, or opioids is likely to lead to enhanced CNS depressant effects. Specific studies with another dexmedetomidine product given intravenously have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. Due to possible enhanced CNS effects when given concomitantly with IGALMI, consider a reduction in dosage of IGALMI or the concomitant anesthetic, sedative, hypnotic, or opioid.

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

There are no available data on IGALMI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal effects. Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects or miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta.

In animal reproductive studies fetal toxicity occurred in the presence of maternal toxicity with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 5 times the maximum recommended human dose [MRHD] of 360 mcg/day based on mg/m2 body surface area. Adverse developmental effects, including early implantation loss and decreased viability of second generation offspring, occurred when pregnant rats were subcutaneously administered doses less than or equal to the MRHD based on mg/m2 from late pregnancy through lactation and weaning (see Data).

Data

Animal Data

Increased post-implantation losses and reduced live pups in the presence of maternal toxicity (decreased body weight) occurred in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine of 200 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m2) during the period of organogenesis (Gestation Day (GD) 5 to 16). No embryo-fetal toxicity was observed at 20 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m2). No malformations were reported at any dose level.

No malformation or embryo-fetal toxicity were observed in a rabbit embryo-fetal developmental study in which pregnant dams were administered dexmedetomidine intravenously at doses up to 96 mcg/kg/day (equivalent to 5 times the MRHD of 360 mcg/day based on mg/m2) during the period of organogenesis (GD 6 to 18).

Reduced pup and adult offspring weights and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at 8 mcg/kg/day (less than the MRHD of 360 mcg/day based on mg/m2) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred at 32 mcg/kg/day (equivalent to the MRHD of 360 mcg/day based on mg/m2) when first generation offspring were mated. This study limited dosing to hard palate closure (GD 15-18) through weaning instead of standard dosing from implantation (GD 6-7) to weaning (PND 21).

8.2 Lactation

Risk Summary

Available published literature report the presence of dexmedetomidine in human milk following intravenous administration. There is no information regarding the effects of dexmedetomidine on the breastfed child or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for IGALMI and any potential adverse effects on the breastfed child from IGALMI or from the underlying maternal condition.

8.4 Pediatric Use

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

8.5 Geriatric Use

Fifteen geriatric patients (≥ 65 years of age) were enrolled (no patients were 75 years of age and older) in the clinical studies for acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. Of the total number of IGALMI-treated patients in these clinical studies, 11/507 (2.2%) were 65 years of age and older [see Clinical Studies (14)].

Dosage reduction of IGALMI is recommended in geriatric patients [see Dosage and Administration (2.2)]. A higher incidence of bradycardia and hypotension was observed in geriatric patients compared to younger adult patients after intravenous administration of another dexmedetomidine product [see Warnings and Precautions (5.1)]. The pharmacokinetic profile of intravenous dexmedetomidine was not altered in geriatric subjects [see Clinical Pharmacology (12.3)].

Clinical studies of IGALMI did not include sufficient numbers of patients 65 years of age and older to determine whether there were differences in the effectiveness of IGALMI in the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder compared to younger adult patients.

8.6 Hepatic Impairment

Dexmedetomidine clearance was decreased in patients with hepatic impairment (Child-Pugh Class A, B, or C). Thus, a dosage reduction of IGALMI is recommended in patients with hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

9 Drug Abuse And Dependence

9.1 Controlled Substance

IGALMI contains dexmedetomidine, which is not a controlled substance.

9.3 Dependence

Physical Dependence

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. The dependence potential of dexmedetomidine has not been studied in humans. However, because studies in rodents and primates have demonstrated that intravenous dexmedetomidine exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation.

IGALMI was not studied for longer than 24 hours after the first dose. There may be risk of physical dependence and a withdrawal syndrome if IGALMI is used in a manner other than indicated [see Dosage and Administration (2.1, 2.2) and Warnings and Precautions (5.4)].

Tolerance

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).

IGALMI has not been studied for longer than 24 hours after the first dose. There may be a risk for tolerance if IGALMI is administered in a manner other than indicated [see Dosage and Administration (2.1, 2.2) and Warnings and Precautions (5.5)].

10 Overdosage

In a tolerability study of intravenous dexmedetomidine in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hour, the maximum blood concentration was approximately 13 times the upper boundary of the therapeutic range for the intravenous dexmedetomidine (IGALMI is not approved for intravenous use). The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block.

{ "type": "p", "children": [], "text": "In a tolerability study of intravenous dexmedetomidine in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hour, the maximum blood concentration was approximately 13 times the upper boundary of the therapeutic range for the intravenous dexmedetomidine (IGALMI is not approved for intravenous use). The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block." }

Five adult patients received an overdose of intravenous dexmedetomidine in intensive care unit sedation studies. Two patients who received a 2 mcg/kg loading dose (twice the recommended loading dose) over 10 minutes, experienced bradycardia and/or hypotension.

{ "type": "p", "children": [], "text": "Five adult patients received an overdose of intravenous dexmedetomidine in intensive care unit sedation studies. Two patients who received a 2 mcg/kg loading dose (twice the recommended loading dose) over 10 minutes, experienced bradycardia and/or hypotension." }

One patient who received a loading intravenous bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

{ "type": "p", "children": [], "text": "One patient who received a loading intravenous bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated." }

Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for overdosage management recommendations for IGALMI.

{ "type": "p", "children": [], "text": "Consider contacting a Poison Center (1-800-222-1222) or a medical toxicologist for overdosage management recommendations for IGALMI." }

11 Description

IGALMI contains dexmedetomidine, an alpha-2 adrenergic receptor agonist, present as dexmedetomidine hydrochloride, the S-enantiomer of medetomidine chemically described as 4-[(1S)-1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride. The empirical formula is C13H16N2∙HCl with a molecular weight of 236.7 g/mol. The structural formula of dexmedetomidine hydrochloride is:

{ "type": "p", "children": [], "text": "IGALMI contains dexmedetomidine, an alpha-2 adrenergic receptor agonist, present as dexmedetomidine hydrochloride, the S-enantiomer of medetomidine chemically described as 4-[(1S)-1-(2, 3-dimethylphenyl) ethyl]-1H-imidazole hydrochloride. The empirical formula is C13H16N2∙HCl with a molecular weight of 236.7 g/mol. The structural formula of dexmedetomidine hydrochloride is:" }

Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in octanol/water at pH 7.4 is 2.89.

IGALMI is for sublingual or buccal use. Each IGALMI sublingual film contains 120 mcg or 180 mcg of dexmedetomidine equivalent to 141.8 mcg and 212.7 mcg of dexmedetomidine hydrochloride, respectively.

{ "type": "p", "children": [], "text": "IGALMI is for sublingual or buccal use. Each IGALMI sublingual film contains 120 mcg or 180 mcg of dexmedetomidine equivalent to 141.8 mcg and 212.7 mcg of dexmedetomidine hydrochloride, respectively. " }

IGALMI contains the following inactive ingredients: FD&C Blue #1 colorant, hydroxypropyl cellulose, peppermint oil, polyethylene oxide, and sucralose.

{ "type": "p", "children": [], "text": "IGALMI contains the following inactive ingredients: FD&C Blue #1 colorant, hydroxypropyl cellulose, peppermint oil, polyethylene oxide, and sucralose." }

12 Clinical Pharmacology

12.1 Mechanism Of Action

Dexmedetomidine is an alpha-2 adrenergic receptor agonist. The mechanism of action of IGALMI in the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder is thought to be due to activation of presynaptic alpha-2 adrenergic receptors.

12.2 Pharmacodynamics

Dexmedetomidine acts as an agonist at alpha-2 adrenergic receptors with binding affinities (Ki values) of 4 to 6 nM at the alpha-2 adrenergic receptor subtypes.

Cardiac Electrophysiology

IGALMI exhibits a concentration dependent QT prolongation. Table 4 shows the mean (upper 90% confidence interval) QTcF increase from baseline for respective dosing regimens [see Warnings and Precautions (5.2)].

<div class="scrollingtable"><table width="75%"> <caption> Table 4: QTcF Increase from Baseline by Dosage of IGALMI </caption> <col align="left" valign="top" width="65%"/> <col align="center" valign="top" width="35%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">IGALMI Dosage</th><th align="center" class="Rrule" valign="middle">Mean QTcF Increase from Baseline (upper 90% confidence interval)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">120 mcg single use</td><td align="center" class="Rrule">6 (7) msec</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">120 mcg + 2 additional doses of 60 mcg 2 hours apart (total 3 doses)</td><td align="center" class="Rrule">8 (9) msec</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">180 mcg single use</td><td align="center" class="Rrule">8 (11) msec</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">180 mcg + 2 additional doses of 90 mcg 2 hours apart (total 3 doses)</td><td align="center" class="Rrule">11 (14) msec</td> </tr> </tbody> </table></div>

12.3 Pharmacokinetics

Dexmedetomidine exposure (Cmax and AUC) increased in a dose proportional manner in the dose range of 20 mcg (0.17 times the lowest recommended initial dose of 120 mcg) to 180 mcg after single sublingual administration of IGALMI.

The mean time for film to dissolve in the mouth was about 6 to 8 minutes and 18 minutes following sublingual and buccal administration, respectively. Dexmedetomidine was quantifiable in plasma generally after 5 to 20 minutes post dosing.

Absorption

The absolute bioavailability of dexmedetomidine was about 72% and 82% following sublingual and buccal administration of IGALMI, respectively. When water was taken at two hours post dose, comparable exposures of dexmedetomidine were observed when IGALMI was administered by both routes.

Mean maximal plasma concentrations of dexmedetomidine were reached approximately two hours after sublingual or buccal administration of IGALMI. Following sublingual administration of 40 mcg of IGALMI (0.33 times the lowest recommended initial dose) with water drinking at two hours post dose and 20 mcg dexmedetomidine intravenous infusion for 90 minutes in healthy volunteers:

Effect of Drinking Water on Absorption

Compared to drinking water at two hours post sublingual administration of IGALMI, early water intake (as early as 15 minutes post dose) had minimal effects on the rate or extent of absorption of dexmedetomidine.

Effects of early water intake (i.e., before two hours post dose) on the absorption of dexmedetomidine has not been evaluated following buccal administration.

Distribution

The steady-state volume of distribution (Vss) of dexmedetomidine following intravenous administration was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.

The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of dexmedetomidine IV were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine hydrochloride injection was explored in vitro and none of these compounds appeared to be significantly displaced by intravenous dexmedetomidine.

Elimination

Metabolism

Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.

Excretion

The mean terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2.8 hours following sublingual or buccal administration of IGALMI. Clearance is estimated to be approximately 39 L/h following intravenous administration.

A mass balance study demonstrated that after nine days, an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.

Specific Populations

Male and Female Patients

There was no observed difference in the pharmacokinetics of intravenous dexmedetomidine due to sex.

Geriatric Patients

The pharmacokinetic profile of intravenous dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of intravenous dexmedetomidine in young (18–40 years), middle age (41–65 years), and geriatric (>65 years) subjects.

Patients with Hepatic Impairment

In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for intravenous dexmedetomidine were lower than in subjects with normal hepatic function [see Dosage and Administration (2.2)]. After an intravenous infusion of 0.6 mcg/kg of this dexmedetomidine product over 10 minutes the mean clearance values for subjects with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in subjects with normal hepatic function, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in subjects with normal hepatic function, respectively.

Patients with Renal Impairment

Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and V) were not significantly different in patients with creatinine clearance <30 mL/minute compared to subjects with normal renal function.

Drug Interactions Studies

In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Animal carcinogenicity studies have not been performed with dexmedetomidine.

Mutagenesis

Dexmedetomidine was not mutagenic in the in vitro Ames bacterial reverse mutation test or mammalian mouse lymphoma cell forward mutation assay. Dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test in the absence or presence of human liver S9 metabolic activation, however, a weak clastogenic response was noted in the presence of rat liver S9 metabolic activation. Dexmedetomidine was not clastogenic in the in vivo bone marrow micronucleus test in CD-1 mice, although there was some evidence for clastogenicity in NMRI mice.

Impairment of Fertility

Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (1.5 times the MRHD of 360 mcg/day on a mg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

13.2 Animal Toxicology And/Or Pharmacology

Twice daily sublingual administration of 120 to 320 mcg/day of dexmedetomidine to dogs for 28 days caused decreased heart rate and moderate sedation up to 3.5 hours post dose. A single male dog (out of 32 treated dogs) dosed 320 mcg/day (equivalent to the MRHD of 360 mcg/day) exhibited inflammation, necrosis, myofiber degeneration, and hemorrhage at the sublingual treatment site. No adverse effects were noted at 240 mcg/day (less than the MRHD of 360 mcg/day).

14 Clinical Studies

The effectiveness of IGALMI for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose studies (Studies 1 and 2):

{ "type": "p", "children": [], "text": "The effectiveness of IGALMI for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose studies (Studies 1 and 2): " }

{ "type": "ul", "children": [ "Study 1 (NCT04268303) included 380 patients who met DSM-5 criteria for schizophrenia, schizoaffective or schizophreniform disorder. The population was 18 to 71 years of age (mean age was 46 years old); 37% female and 63% male; 78% Black, 20% White, 1% multiracial, and 1% Asian.", "Study 2 (NCT04276883) included 378 patients who met DSM-5 criteria for bipolar I or II disorder. The population was 18 to 70 years of age (mean age was 47 years old); 55% female and 45% male; 56% Black, 41% White, 1% Asian, 1% multiracial, and 1% other." ], "text": "" }

The Positive and Negative Syndrome Scale-Excited Component (PEC) is an investigator-rated instrument consisting of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate-severe, 6=severe, 7=extremely severe). The total PEC score ranges from 5 to 35, with higher scores reflecting greater overall symptom severity. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PEC score of ≥ 14, with at least one individual item score ≥ 4. In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment.

{ "type": "p", "children": [], "text": "The Positive and Negative Syndrome Scale-Excited Component (PEC) is an investigator-rated instrument consisting of 5 items: poor impulse control, tension, hostility, uncooperativeness, and excitement. Each item is scored on a scale from 1 to 7 (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate-severe, 6=severe, 7=extremely severe). The total PEC score ranges from 5 to 35, with higher scores reflecting greater overall symptom severity. For enrollment in the studies, patients had to be judged to be clinically agitated with a total PEC score of ≥ 14, with at least one individual item score ≥ 4. In both studies, patients were admitted to a clinical research unit or a hospital and remained under medical supervision for at least 24 hours following treatment." }

Patients were randomized to receive a single sublingual dose of 180 mcg of IGALMI, 120 mcg of IGALMI, or placebo. The primary efficacy endpoint in both studies was the change from baseline in the PEC score, assessed two hours following the initial dose. The key secondary endpoint was the time to effect onset, assessed by measuring the change from baseline in PEC score at 10, 20, 30, 45, 60, and 90 minutes after the initial dose administration.

{ "type": "p", "children": [], "text": "Patients were randomized to receive a single sublingual dose of 180 mcg of IGALMI, 120 mcg of IGALMI, or placebo. The primary efficacy endpoint in both studies was the change from baseline in the PEC score, assessed two hours following the initial dose. The key secondary endpoint was the time to effect onset, assessed by measuring the change from baseline in PEC score at 10, 20, 30, 45, 60, and 90 minutes after the initial dose administration. " }

In both studies, mean baseline PEC scores were similar in all treatment groups (Table 5). The mean change from baseline in the PEC total score at two hours after the first dose in patients treated with 180 mcg and 120 mcg of IGALMI was statistically greater than patients who received placebo (Table 5).

{ "type": "p", "children": [], "text": "In both studies, mean baseline PEC scores were similar in all treatment groups (Table 5). The mean change from baseline in the PEC total score at two hours after the first dose in patients treated with 180 mcg and 120 mcg of IGALMI was statistically greater than patients who received placebo (Table 5). " }

Examination of population subsets (race and sex) on the primary endpoint did not show evidence for differential responsiveness between White and Black or female and male patients. The clinical studies did not include enough patients of other races or patients ≥65 years of age to determine whether there were differences in effectiveness for those groups.

{ "type": "p", "children": [], "text": "Examination of population subsets (race and sex) on the primary endpoint did not show evidence for differential responsiveness between White and Black or female and male patients. The clinical studies did not include enough patients of other races or patients ≥65 years of age to determine whether there were differences in effectiveness for those groups." }

<div class="scrollingtable"><table width="75%"> <caption> Table 5: Primary Efficacy Results for Change from Baseline in the PEC Score at Two Hours in Agitated Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) </caption> <col align="center" valign="middle" width="10%"/> <col align="center" valign="middle" width="15%"/> <col align="center" valign="middle" width="13%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="bottom">Study</th><th align="center" class="Rrule" valign="bottom">Treatment Group</th><th align="center" class="Rrule" valign="bottom">Number of Patients</th><th align="center" class="Rrule" valign="bottom">Mean Baseline PEC Score (SD)</th><th align="center" class="Rrule" valign="bottom">LS Mean Change from Baseline to 2 hour Post First Dose (SE)</th><th align="center" class="Rrule" valign="bottom">LS Mean Difference (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6">SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=unadjusted confidence interval; PEC=Positive and Negative Syndrome Scale-Excited Component</td> </tr> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-6" name="footnote-6">*</a> </dt> <dd>IGALMI doses that were statistically significantly superior to placebo after adjusting for multiplicity.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="3">Study 1</td><td align="left" class="Rrule">IGALMI 180 mcg<a class="Sup" href="#footnote-6" name="footnote-reference-6">*</a></td><td align="center" class="Rrule">125</td><td align="center" class="Rrule">17.6 (2.7)</td><td align="center" class="Rrule">-10.3 (0.4)</td><td align="center" class="Rrule">-5.5 (-6.5, -4.4)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">IGALMI 120 mcg<a class="Sup" href="#footnote-6">*</a></td><td align="center" class="Rrule">129</td><td align="center" class="Rrule">17.5 (2.5)</td><td align="center" class="Rrule">-8.5 (0.4)</td><td align="center" class="Rrule">-3.7 (-4.8, -2.7)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">126</td><td align="center" class="Rrule">17.6 (2.3)</td><td align="center" class="Rrule">-4.8 (0.4)</td><td align="center" class="Rrule">-</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="3">Study 2</td><td align="left" class="Rrule">IGALMI 180 mcg<a class="Sup" href="#footnote-6">*</a></td><td align="center" class="Rrule">126</td><td align="center" class="Rrule">18.0 (3.0)</td><td align="center" class="Rrule">-10.4 (0.4)</td><td align="center" class="Rrule">-5.4 (-6.5, -4.3)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">IGALMI 120 mcg<a class="Sup" href="#footnote-6">*</a></td><td align="center" class="Rrule">126</td><td align="center" class="Rrule">18.0 (2.7)</td><td align="center" class="Rrule">-9.1 (0.4)</td><td align="center" class="Rrule">-4.1 (-5.1, -3.0)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Placebo</td><td align="center" class="Rrule">126</td><td align="center" class="Rrule">17.9 (2.9)</td><td align="center" class="Rrule">-5.0 (0.4)</td><td align="center" class="Rrule">-</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"75%\">\n<caption>\nTable 5: Primary Efficacy Results for Change from Baseline in the PEC Score at Two Hours in Agitated Patients with Schizophrenia or Bipolar I or II Disorder (Studies 1 and 2) \n</caption>\n<col align=\"center\" valign=\"middle\" width=\"10%\"/>\n<col align=\"center\" valign=\"middle\" width=\"15%\"/>\n<col align=\"center\" valign=\"middle\" width=\"13%\"/>\n<col align=\"center\" valign=\"middle\" width=\"12%\"/>\n<col align=\"center\" valign=\"middle\" width=\"25%\"/>\n<col align=\"center\" valign=\"middle\" width=\"25%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" valign=\"bottom\">Study</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">Treatment Group</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">Number of Patients</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">Mean Baseline PEC Score (SD)</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">LS Mean Change from Baseline to 2 hour Post First Dose (SE)</th><th align=\"center\" class=\"Rrule\" valign=\"bottom\">LS Mean Difference (95% CI)</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"6\">SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=unadjusted confidence interval; PEC=Positive and Negative Syndrome Scale-Excited Component</td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"6\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-6\" name=\"footnote-6\">*</a>\n</dt>\n<dd>IGALMI doses that were statistically significantly superior to placebo after adjusting for multiplicity.</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" rowspan=\"3\">Study 1</td><td align=\"left\" class=\"Rrule\">IGALMI 180 mcg<a class=\"Sup\" href=\"#footnote-6\" name=\"footnote-reference-6\">*</a></td><td align=\"center\" class=\"Rrule\">125</td><td align=\"center\" class=\"Rrule\">17.6 (2.7)</td><td align=\"center\" class=\"Rrule\">-10.3 (0.4)</td><td align=\"center\" class=\"Rrule\">-5.5 (-6.5, -4.4)</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">IGALMI 120 mcg<a class=\"Sup\" href=\"#footnote-6\">*</a></td><td align=\"center\" class=\"Rrule\">129</td><td align=\"center\" class=\"Rrule\">17.5 (2.5)</td><td align=\"center\" class=\"Rrule\">-8.5 (0.4)</td><td align=\"center\" class=\"Rrule\">-3.7 (-4.8, -2.7)</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">Placebo</td><td align=\"center\" class=\"Rrule\">126</td><td align=\"center\" class=\"Rrule\">17.6 (2.3)</td><td align=\"center\" class=\"Rrule\">-4.8 (0.4)</td><td align=\"center\" class=\"Rrule\">-</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"center\" class=\"Lrule Rrule\" rowspan=\"3\">Study 2</td><td align=\"left\" class=\"Rrule\">IGALMI 180 mcg<a class=\"Sup\" href=\"#footnote-6\">*</a></td><td align=\"center\" class=\"Rrule\">126</td><td align=\"center\" class=\"Rrule\">18.0 (3.0)</td><td align=\"center\" class=\"Rrule\">-10.4 (0.4)</td><td align=\"center\" class=\"Rrule\">-5.4 (-6.5, -4.3)</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">IGALMI 120 mcg<a class=\"Sup\" href=\"#footnote-6\">*</a></td><td align=\"center\" class=\"Rrule\">126</td><td align=\"center\" class=\"Rrule\">18.0 (2.7)</td><td align=\"center\" class=\"Rrule\">-9.1 (0.4)</td><td align=\"center\" class=\"Rrule\">-4.1 (-5.1, -3.0)</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\">Placebo</td><td align=\"center\" class=\"Rrule\">126</td><td align=\"center\" class=\"Rrule\">17.9 (2.9)</td><td align=\"center\" class=\"Rrule\">-5.0 (0.4)</td><td align=\"center\" class=\"Rrule\">-</td>\n</tr>\n</tbody>\n</table></div>" }

Figures 1 and 2 show the changes from baseline in PEC score at each time point assessed up to two hours following the initial dose. In Study 1, the decrease in agitation with IGALMI, compared to placebo, was statistically significant beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose. In Study 2, the decrease in agitation with IGALMI, compared to placebo, was statistically significant beginning at 20 minutes after treatment with both 120 mcg and 180 mcg doses.

{ "type": "p", "children": [], "text": "Figures 1 and 2 show the changes from baseline in PEC score at each time point assessed up to two hours following the initial dose. In Study 1, the decrease in agitation with IGALMI, compared to placebo, was statistically significant beginning at 20 minutes following dosing with the 180 mcg dose and 30 minutes after the 120 mcg dose. In Study 2, the decrease in agitation with IGALMI, compared to placebo, was statistically significant beginning at 20 minutes after treatment with both 120 mcg and 180 mcg doses." }

Figure 1: Mean Change from Baseline in PEC Score Through Two Hours after a Single Dose in Agitated Patients with Schizophrenia (Study 1)

{ "type": "p", "children": [], "text": "\nFigure 1: Mean Change from Baseline in PEC Score Through Two Hours after a Single Dose in Agitated Patients with Schizophrenia (Study 1)\n" }

Figure 2: Mean Change from Baseline in PEC Score Through Two Hours after a Single Dose in Agitated Patients with Bipolar I or II Disorder (Study 2)

{ "type": "p", "children": [], "text": "\nFigure 2: Mean Change from Baseline in PEC Score Through Two Hours after a Single Dose in Agitated Patients with Bipolar I or II Disorder (Study 2)\n" }

16 How Supplied/Storage And Handling

How Supplied

IGALMI (dexmedetomidine) sublingual film is supplied as a blue rectangular sublingual film, containing on its surface two darker blue spots in dose strengths of 120 mcg and 180 mcg and is packaged as individual films in heat-sealed foil pouches in 10-count and 30-count films per carton. The NDC number for each packaging configuration is:

Storage and Handling

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.

Keep IGALMI in the foil pouch until ready to administer.

17 Patient Counseling Information

Administration Information

Advise patients to place IGALMI under the tongue, close to the base of the tongue, on the left or right side (sublingual) or behind the lower lip (buccal).

Advise patients not to chew or swallow IGALMI. Also, advise patients not to eat or drink for at least 15 minutes after sublingual administration, or at least 1 hour after buccal administration [see Dosage and Administration (2.3)].

Hypotension, Orthostatic Hypotension, and Bradycardia

Advise patients that IGALMI can cause dose-dependent hypotension, orthostatic hypotension, and bradycardia. Inform patients to remain sitting or lying down after receiving IGALMI and to inform the healthcare provider if they have any symptoms of hypotension or bradycardia [see Warnings and Precautions (5.1)].

QT Interval Prolongation

Inform patients to consult their physician immediately if they feel faint or have heart palpitations [see Warnings and Precautions (5.2)].

Somnolence

Advise patients that IGALMI can cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that they should avoid doing activities that require them to be alert, such as driving a car or operating machinery for at least eight hours after receiving IGALMI [see Warnings and Precautions (5.3)].

Lactation

Advise patients exposed to IGALMI to monitor breastfed infants for irritability [see Use in Specific Populations (8.2)].

Spl Unclassified Section

Distributed by: BioXcel Therapeutics, Inc. 555 Long Wharf Drive 12th Floor New Haven, CT 06511

{ "type": "p", "children": [], "text": "Distributed by: BioXcel Therapeutics, Inc. 555 Long Wharf Drive 12th Floor New Haven, CT 06511" }

{ "type": "p", "children": [], "text": "IGALMI is a trademark of BioXcel Therapeutics, Inc. All other trademarks are the properties of their respective owners. Copyright © 2022, BioXcel Therapeutics, Inc. All rights reserved.MFG-0028v3.0" }

Principal Display Panel - 120 Mcg Film Pouch Carton

Rx Only

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

Igalmi™ (dexmedetomidine) sublingual film

{ "type": "p", "children": [], "text": "Igalmi™\n(dexmedetomidine) sublingual film" }

For sublingual or buccal useKeep IGALMI in pouch until administrationDo not chew or swallow the film

{ "type": "p", "children": [], "text": "For sublingual or buccal useKeep IGALMI in pouch until administrationDo not chew or swallow the film" }

120 mcg

{ "type": "p", "children": [], "text": "120 mcg" }

10 pouches Each containing 1 film

{ "type": "p", "children": [], "text": "10 pouches Each containing 1 film" }

NDC 81092-1120-1

{ "type": "p", "children": [], "text": "NDC 81092-1120-1" }

Principal Display Panel - 180 Mcg Film Pouch Carton

Rx Only

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

Igalmi™ (dexmedetomidine) sublingual film

{ "type": "p", "children": [], "text": "Igalmi™\n(dexmedetomidine) sublingual film" }

For sublingual or buccal useKeep IGALMI in pouch until administrationDo not chew or swallow the film

{ "type": "p", "children": [], "text": "For sublingual or buccal useKeep IGALMI in pouch until administrationDo not chew or swallow the film" }

180 mcg

{ "type": "p", "children": [], "text": "180 mcg" }

10 pouches Each containing 1 film

{ "type": "p", "children": [], "text": "10 pouches Each containing 1 film" }

NDC 81092-1180-1

{ "type": "p", "children": [], "text": "NDC 81092-1180-1" }

dexmedetomidine

dexmedetomidine

PRECEDEX

PRECEDEX

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION, USP

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION, USP

DEXMEDETOMIDINE HYDROCHLORIDE FOR INJECTION

DEXMEDETOMIDINE HYDROCHLORIDE INJECTION

1 Indications And Usage

1.1 Intensive Care Unit Sedation

1.2 Procedural Sedation

2 Dosage And Administration

2.1 Administration Instructions

2.2 Recommended Dosage

2.3 Dosage Adjustment

2.4 Preparation Of Solution

2.5 Administration With Other Fluids

2.6 Compatibility With Natural Rubber

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Drug Administration

5.2 Hypotension, Bradycardia, And Sinus Arrest

5.3 Transient Hypertension

5.4 Arousability

5.5 Withdrawal

5.6 Tolerance And Tachyphylaxis

5.7 Hyperthermia Or Pyrexia

5.8 Hepatic Impairment

6 Adverse Reactions

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 Drug Interactions

7.1 Anesthetics, Sedatives, Hypnotics, Opioids

7.2 Neuromuscular Blockers

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

9 Drug Abuse And Dependence

9.1 Controlled Substance

9.3 Dependence

10 Overdosage

11 Description

12 Clinical Pharmacology

12.1 Mechanism Of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

13.2 Animal Toxicology And/Or Pharmacology

14 Clinical Studies

14.1 Intensive Care Unit Sedation

14.2 Procedural Sedation

16 How Supplied/Storage And Handling

17 Patient Counseling Information

Package/Label Principal Display Panel

1 Indications And Usage

﻿2 Dosage And Administration

﻿3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

6 Adverse Reactions

7 Drug Interactions

8 Use In Specific Populations Section

﻿9 Drug Abuse And Dependence

10 Overdosage

11 Description

12 Clinical Pharmacology

13 Nonclinical Toxicology

14 Clinical Studies

How Supplied/Storage And Handling

17 Patient Counseling Information

Sample Package Label

2 Dosage And Administration

3 Dosage Forms And Strengths

9 Drug Abuse And Dependence