ERZOFRI is indicated for the treatment of:

{ "type": "p", "children": [], "text": "ERZOFRI is indicated for the treatment of:" }

{ "type": "ul", "children": [ "Schizophrenia in adults.\n", "Schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants.\n" ], "text": "" }

For patients who have never taken oral or injectable paliperidone, or oral or injectable risperidone, establish tolerability with oral paliperidone or oral risperidone prior to initiating treatment with ERZOFRI.

ERZOFRI must be administered by a healthcare professional as an intramuscular injection. Do not administer ERZOFRI by any other route. For detailed preparation and administration instructions, see Dosage and Administration (2.7).

See Table 1 for dosage recommendations for ERZOFRI in the treatment of schizophrenia in adults or the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants.

The initial dosage of ERZOFRI is 351 mg on treatment Day 1 administered in the deltoid muscle. Following the initial dose, monthly doses can be administered in either the deltoid or gluteal muscle [see Clinical Pharmacology (12.3)].

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1: Dosage Recommendations for ERZOFRI</span> </caption> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="25%"/> <col align="center" valign="middle" width="30%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Indication</th><th align="center" class="Botrule Rrule">Initial Dose<br/> (deltoid) <br/>Day 1</th><th align="center" class="Rrule" rowspan="2">Monthly Dosage<a class="Sup" href="#footnote-4" name="footnote-reference-4">*</a> <br/>(deltoid or gluteal)</th><th align="center" class="Rrule" rowspan="2">Maximum Monthly Dosage</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>Administered 4 weeks after the first injection.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">†</a> </dt> <dd>The recommended monthly dosage for treatment of schizophrenia is 117 mg. Some patients may benefit from lower or higher monthly doses within the additional available strengths (39 mg, 78 mg, 156 mg, and 234 mg).</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">‡</a> </dt> <dd>Adjust dose based on tolerability and/or efficacy using available strengths. The 39 mg strength was not studied in the long-term schizoaffective disorder study.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">Schizophrenia</td><td align="center" class="Rrule">351 mg</td><td align="center" class="Rrule">39 mg to 234 mg<a class="Sup" href="#footnote-5" name="footnote-reference-5">†</a></td><td align="center" class="Rrule">234 mg</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Schizoaffective disorder</td><td align="center" class="Rrule">351 mg</td><td align="center" class="Rrule">78 mg to 234 mg<a class="Sup" href="#footnote-6" name="footnote-reference-6">‡</a></td><td align="center" class="Rrule">234 mg</td> </tr> </tbody> </table></div>

Adjust dosage monthly depending on clinical response and tolerability. When making dose adjustments, the pharmacokinetic profile of ERZOFRI should be considered [see Clinical Pharmacology (12.3)], as the full effect of the dose adjustment may not be apparent for several months.

Dosing Window

To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

Missed Dose

If a dose of ERZOFRI is missed, follow the dosing instructions provided in Table 2.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Management of a Missed Dose of ERZOFRI</span> </caption> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="65%"/> <thead> <tr class="Botrule First Last"> <th align="center" class="Lrule Rrule">TIMING OF MISSED DOSE</th><th align="center" class="Rrule">DOSING</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">4 to 6 weeks since last injection</span></td><td align="left" class="Rrule"><span class="Bold">Resume regular monthly dosing as soon as possible at the patient's previously stabilized dose, followed by injections at monthly intervals.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">More than 6 weeks to 6 months since last injection</span></td><td align="left" class="Rrule"><span class="Bold">Resume the same dose the patient was previously stabilized on (unless the patient was stabilized on a dose of 234 mg, then the first 2 injections should each be 156 mg) in the following manner:</span> <ol class="Arabic"> <li>Administer a deltoid injection as soon as possible.</li> <li>Administer a second deltoid injection 1 week later at the same dose.</li> <li>Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the second injection.</li> </ol> </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">More than 6 months since last injection</span></td><td align="left" class="Rrule"><span class="Bold">Restart dosing with recommended initiation</span> (<span class="Italics">see <a href="#Table1">Section 2.1, Table 1</a></span>)<span class="Italics">:</span> <ol class="Arabic"> <li>Administer a 351 mg deltoid injection on Day 1.</li> <li>Thereafter, resume administering the previously stabilized dose in the deltoid or gluteal muscle 1 month after the initial injection.</li> </ol> </td> </tr> </tbody> </table></div>

Paliperidone is the major active metabolite of risperidone. Exercise caution if ERZOFRI is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of ERZOFRI with other antipsychotics is limited.

For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), initiate ERZOFRI with a dose of 234 mg on treatment Day 1 in the deltoid muscle. Follow with the recommended monthly dosage of 78 mg, administered in either the deltoid or gluteal muscle. Adjust monthly dosage based on tolerability and/or response within the strengths of 39 mg, 78 mg, 117 mg, or 156 mg. The maximum monthly dosage is 156 mg for patients with mild renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

ERZOFRI is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Avoid using a strong inducer of CYP3A4 and/or P-gp during the one-month dosing interval for ERZOFRI, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

There are no systematically collected data to specifically address switching patients with schizophrenia or schizoaffective disorder from other antipsychotics to ERZOFRI or concerning concomitant administration with other antipsychotics.

Switching from Oral Antipsychotics

Previous oral antipsychotics can be gradually discontinued at the time of initiation of treatment with ERZOFRI. The recommended initial dosage of ERZOFRI is 351 mg on treatment Day 1, administered in the deltoid muscle [see Dosage and Administration (2.1)]. See Table 3 for subsequent monthly dosage recommendations for ERZOFRI in patients switching from oral extended-release paliperidone tablets.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: Dosage Recommendations Following Initial Dose of ERZOFRI in Patients Switching from Oral Extended-Release Paliperidone Tablets</span> </caption> <col align="center" valign="top" width="40%"/> <col align="center" valign="top" width="35%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule"></th><th align="center" class="Rrule">Paliperidone Extended-Release Tablet</th><th align="center" class="Rrule">ERZOFRI</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Dosing Frequency</th><th align="center" class="Rrule">Once Daily</th><th align="center" class="Rrule">Once every 4 weeks</th> </tr> </thead> <tbody> <tr class="First"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule">12 mg</td><td align="center" class="Rrule">234 mg</td> </tr> <tr> <td align="center" class="Lrule Rrule"><span class="Bold">Dose</span></td><td align="center" class="Rrule">9 mg</td><td align="center" class="Rrule">156 mg</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule">6 mg</td><td align="center" class="Rrule">117 mg</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule">3 mg</td><td align="center" class="Rrule">39 mg to 78 mg</td> </tr> </tbody> </table></div>

Switching from Long-Acting Injectable Antipsychotics

When switching patients currently at steady-state on a long-acting injectable antipsychotic, initiate ERZOFRI therapy in place of the next scheduled injection.

Continue ERZOFRI at monthly intervals. The initial dosing regimen as described in Section 2.1 is not required. See Table 1 for recommended monthly dosing. Based on previous clinical response and tolerability, some patients may benefit from lower or higher doses within the available strengths (39 mg, 78 mg, 117 mg, 156 mg, and 234 mg).

If ERZOFRI is discontinued, its pharmacokinetic characteristics must be considered. As recommended with other antipsychotic medications, the need for continuing existing extrapyramidal symptoms (EPS) medication should be re-evaluated periodically.

The kit contains a prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle).

ERZOFRI is for single use only.

Step 1. Select Needle

<div class="scrollingtable"><table width="85%"> <col align="left" valign="middle" width="50%"/> <col align="left" valign="middle" width="50%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">For Deltoid injection</th><th align="left" class="Rrule">For Gluteal injection</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-02.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-03.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">If the patient weighs less than 90 kg, use the 1-inch <span class="Bold">23</span> gauge needle (needle with <span class="Bold">blue</span> colored hub)</td><td align="left" class="Botrule Rrule" rowspan="2">Use the 1 ½-inch <span class="Bold">22</span> gauge needle (needle with <span class="Bold">gray</span> colored hub) regardless of patient's weight</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">If the patient weighs 90 kg or more, use the 1 ½-inch <span class="Bold">22</span> gauge needle (needle with <span class="Bold">gray</span> colored hub)</td> </tr> </tbody> </table></div>

Step 2. Prepare for Injection

<div class="scrollingtable"><table width="85%"> <col align="center" valign="top" width="33%"/> <col align="center" valign="top" width="34%"/> <col align="center" valign="top" width="33%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule"><span class="Bold">a. Open needle pouch</span></td><td align="center" class="Rrule"><span class="Bold">b. Shake vigorously for at least 10 seconds</span></td><td align="center" class="Rrule"><span class="Bold">c. Remove cap</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-04.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-05.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-06.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">First, peel the safety needle pouch half way open. Place on a clean surface.</td><td align="left" class="Rrule">Shake the syringe vigorously for a minimum of 10 seconds to ensure a homogeneous suspension.</td><td align="left" class="Rrule">While holding the syringe upright, remove the rubber tip cap with an easy counterclockwise twisting motion. Do not touch syringe tip.</td> </tr> <tr> <td align="center" class="Lrule Rrule"><span class="Bold">d. Attach needle</span></td><td align="center" class="Rrule"><span class="Bold">e. Remove needle sheath</span></td><td align="center" class="Rrule"><span class="Bold">f. Remove air bubbles</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-07.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-08.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td><td align="center" class="Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-09.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr class="Botrule Last"> <td align="left" class="Lrule Rrule">Grasp the needle sheath using the plastic peel pouch. Attach the safety needle to the luer connection of the syringe with an easy clockwise twisting motion.<br/> <span class="Bold">Do not</span> remove the pouch until the syringe and needle are securely attached.</td><td align="left" class="Rrule">Pull the needle sheath away from the needle with a straight pull. Do not twist the sheath as the needle may be loosened from the syringe.</td><td align="left" class="Rrule">Bring the syringe with the attached needle in upright position to de-aerate. De-aerate the syringe by moving the plunger rod carefully forward.</td> </tr> </tbody> </table></div>

Step 3. Inject

<div class="scrollingtable"><table width="85%"> <col align="left" valign="middle" width="47%"/> <col align="left" valign="middle" width="6%"/> <col align="left" valign="middle" width="47%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="3">Inject the entire contents intramuscularly slowly, deep into the selected deltoid or gluteal muscle of the patient. <span class="Bold">Do not administer by any other route.</span></td> </tr> <tr class="Last"> <td align="right" class="Lrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=erzofri-10.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></p> </td><td align="left"></td><td align="left" class="Rrule"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=erzofri-11.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></p> </td> </tr> </tbody> </table></div>

Step 4. After Injection

<div class="scrollingtable"><table width="85%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule"><span class="Bold">Secure Needle</span></td><td align="center" class="Rrule"><span class="Bold">Dispose properly</span></td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">a</span></td><td align="left" class="Botrule Rrule" rowspan="7"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-13.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/><br/> <p class="First">Dispose of the syringe and unused needle in an approved sharps container.</p> </td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-12.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">b</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-14.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">c</span></td> </tr> <tr> <td align="center" class="Lrule Rrule"><img alt="Image" src="/dailymed/image.cfm?name=erzofri-15.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">After the injection is complete, use either thumb or finger of one hand (a, b) or a flat surface (c) to activate the needle protection system. The needle protection system is fully activated when a 'click' is heard.</td> </tr> </tbody> </table></div>

Extended-release injectable suspension: white to off-white aqueous suspension available in dose strengths of 39 mg/0.25 mL, 78 mg/0.5 mL, 117 mg/0.75 mL, 156 mg/mL, 234 mg/1.5 mL, and 351 mg/2.25 mL paliperidone palmitate.

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Each strength is provided as a kit, which includes: one single-dose prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle).

{ "type": "p", "children": [], "text": "Each strength is provided as a kit, which includes: one single-dose prefilled syringe and 2 safety needles (a 1 ½-inch 22 gauge needle and a 1-inch 23 gauge needle)." }

ERZOFRI is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the ERZOFRI formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone [see Adverse Reactions (6.1, 6.2)].

{ "type": "p", "children": [], "text": "ERZOFRI is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the ERZOFRI formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone [see Adverse Reactions (6.1, 6.2)]." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

ERZOFRI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)].

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, 1-month or 3-month paliperidone palmitate extended-release injectable suspensions, or ERZOFRI, in elderly patients with dementia. ERZOFRI is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue ERZOFRI and provide symptomatic treatment and monitoring.

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of oral paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n=141) of oral paliperidone, the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on Day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg oral dose of immediate release paliperidone (Cmax ss = 113 ng/mL) was more than 2-fold the exposure observed with the maximum recommended 234 mg maintenance dose of another once-a-month paliperidone extended-release injectable suspension administered in the deltoid muscle (predicted median Cmax-ss = 50 ng/mL). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax-ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on Day 2 at 1.5 hours post-dose.

In the three fixed-dose efficacy studies of oral paliperidone extended release in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the oral paliperidone 12 mg group had a change exceeding 60 msec at one time- point on Day 6 (increase of 62 msec).

In the four fixed-dose efficacy studies of another once-a-month paliperidone palmitate extended-release injectable suspension in subjects with schizophrenia and in the long-term study in subjects with schizoaffective disorder, no subject experienced a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of > 500 msec at any time point. In the maintenance study in subjects with schizophrenia, no subject had a QTcLD change > 60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ERZOFRI should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on ERZOFRI, drug discontinuation should be considered. However, some patients may require treatment with ERZOFRI despite the presence of the syndrome.

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of another PP1M in subjects with schizophrenia are presented in Table 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Change in Fasting Glucose from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia</span> </caption> <col align="left" valign="middle" width="16%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" class="Botrule" colspan="6">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left" valign="top"></th><th align="center" valign="top">Placebo</th><th align="center" valign="top">39 mg</th><th align="center" valign="top">78 mg</th><th align="center" valign="top">156 mg</th><th align="center" valign="top">234/39 mg<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></th><th align="center" valign="top">234/156 mg<a class="Sup" href="#footnote-7">*</a></th><th align="center" valign="top">234/234 mg<a class="Sup" href="#footnote-7">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [<span class="Italics">see <a href="#S14.1">Clinical Studies (14.1)</a></span>].</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" colspan="8"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"></td><td align="center"><span class="Bold">n=367</span></td><td align="center"><span class="Bold">n=86</span></td><td align="center"><span class="Bold">n-244</span></td><td align="center"><span class="Bold">n=238</span></td><td align="center"><span class="Bold">n=110</span></td><td align="center"><span class="Bold">n=126</span></td><td align="center"><span class="Bold">n=115</span></td> </tr> <tr> <td align="left"><span class="Bold">Serum Glucose Change from baseline</span></td><td align="center">-1.3</td><td align="center">1.3</td><td align="center">3.5</td><td align="center">0.1</td><td align="center">3.4</td><td align="center">1.8</td><td align="center">-0.2</td> </tr> <tr> <td align="center" colspan="8"><span class="Bold">Proportion of Patients with Shifts</span></td> </tr> <tr> <td align="left"><span class="Bold">Serum Glucose Normal to High</span></td><td align="center">4.6%</td><td align="center">6.3%</td><td align="center">6.4%</td><td align="center">3.9%</td><td align="center">2.5%</td><td align="center">7.0%</td><td align="center">6.6%</td> </tr> <tr class="Last"> <td align="left"><span class="Bold">(&lt;100 mg/dL to ≥126 mg/dL)</span></td><td align="center">(11/241)</td><td align="center">(4/64)</td><td align="center">(11/173)</td><td align="center">(6/154)</td><td align="center">(2/79)</td><td align="center">(6/86)</td><td align="center">(5/76)</td> </tr> </tbody> </table></div>

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest maintenance dose available (234 mg) was evaluated, another PP1M was associated with a mean change in glucose of -0.4 mg/dL at Week 29 (n=109) and +6.8 mg/dL at Week 53 (n=100).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, another PP1M was associated with mean change in glucose of +5.3 mg/dL (n=518). At the endpoint of the subsequent 15-month double-blind period of the study, the PP1M was associated with a mean change in glucose of +0.3 mg/dL (n=131) compared with a mean change of +4.0 mg/dL in the placebo group (n=120).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of another PP1M in subjects with schizophrenia are presented in Table 5.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Change in Fasting Lipids from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia</span> </caption> <col align="left" valign="top" width="16%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="12%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" class="Botrule" colspan="6">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Placebo</th><th align="center">39 mg</th><th align="center">78 mg</th><th align="center">156 mg</th><th align="center">234/39 mg<a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a></th><th align="center">234/156 mg<a class="Sup" href="#footnote-8">*</a></th><th align="center">234/234 mg<a class="Sup" href="#footnote-8">*</a></th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. <span class="Italics">[see <a href="#S14.1">Clinical Studies (14.1)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" colspan="8"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"><span class="Bold">Cholesterol </span></td><td align="center"><span class="Bold">n=366</span></td><td align="center"><span class="Bold">n=89</span></td><td align="center"><span class="Bold">n=244</span></td><td align="center"><span class="Bold">n=232</span></td><td align="center"><span class="Bold">n=105</span></td><td align="center"><span class="Bold">n=119</span></td><td align="center"><span class="Bold">n=120</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-6.6</td><td align="center">-6.4</td><td align="center">-5.8</td><td align="center">-7.1</td><td align="center">-0.9</td><td align="center">-4.2</td><td align="center">9.4</td> </tr> <tr> <td align="left"><span class="Bold">LDL</span></td><td align="center"><span class="Bold">n=275</span></td><td align="center"><span class="Bold">n=80</span></td><td align="center"><span class="Bold">n=164</span></td><td align="center"><span class="Bold">n=141</span></td><td align="center"><span class="Bold">n=104</span></td><td align="center"><span class="Bold">n=117</span></td><td align="center"><span class="Bold">n=108</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-6.0</td><td align="center">-4.8</td><td align="center">-5.6</td><td align="center">-4.8</td><td align="center">0.9</td><td align="center">-2.4</td><td align="center">5.2</td> </tr> <tr> <td align="left"><span class="Bold">HDL</span></td><td align="center"><span class="Bold">n=286</span></td><td align="center"><span class="Bold">n=89</span></td><td align="center"><span class="Bold">n=165</span></td><td align="center"><span class="Bold">n=150</span></td><td align="center"><span class="Bold">n=105</span></td><td align="center"><span class="Bold">n=118</span></td><td align="center"><span class="Bold">n=115</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">0.7</td><td align="center">2.1</td><td align="center">0.6</td><td align="center">0.3</td><td align="center">1.5</td><td align="center">1.1</td><td align="center">0.0</td> </tr> <tr> <td align="left"><span class="Bold">Triglycerides</span></td><td align="center"><span class="Bold">n=366</span></td><td align="center"><span class="Bold">n=89</span></td><td align="center"><span class="Bold">n=244</span></td><td align="center"><span class="Bold">n=232</span></td><td align="center"><span class="Bold">n=105</span></td><td align="center"><span class="Bold">n=119</span></td><td align="center"><span class="Bold">n=120</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-16.7</td><td align="center">7.6</td><td align="center">-9.0</td><td align="center">-11.5</td><td align="center">-14.1</td><td align="center">-20.0</td><td align="center">11.9</td> </tr> <tr> <td align="center" colspan="8"><span class="Bold">Proportion of Patients with Shifts</span></td> </tr> <tr> <td align="left" valign="bottom"><span class="Bold">Cholesterol<br/> Normal to High</span></td><td align="center" valign="bottom">3.2%</td><td align="center" valign="bottom">2.0%</td><td align="center" valign="bottom">2.0%</td><td align="center" valign="bottom">2.1%</td><td align="center" valign="bottom">0%</td><td align="center" valign="bottom">3.1%</td><td align="center" valign="bottom">7.1%</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">(&lt;200 mg/dL to ≥240 mg/dL)</span></td><td align="center" valign="top">(7/222)</td><td align="center" valign="top">(1/51)</td><td align="center" valign="top">(3/147)</td><td align="center" valign="top">(3/141)</td><td align="center" valign="top">(0/69)</td><td align="center" valign="top">(2/65)</td><td align="center" valign="top">(6/84)</td> </tr> <tr> <td align="left" valign="bottom"><span class="Bold">LDL<br/> Normal to High</span></td><td align="center" valign="bottom">1.1%</td><td align="center" valign="bottom">0%</td><td align="center" valign="bottom">0%</td><td align="center" valign="bottom">0%</td><td align="center" rowspan="2" valign="middle">0% (0/41)</td><td align="center" valign="bottom">0%</td><td align="center" valign="bottom">0%</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">(&lt;100 mg/dL to ≥160 mg/dL)</span></td><td align="center" valign="top">(1/95)</td><td align="center" valign="top">(0/29)</td><td align="center" valign="top">(0/67)</td><td align="center" valign="top">(0/46)</td><td align="center" valign="top">(0/37)</td><td align="center" valign="top">(0/44)</td> </tr> <tr> <td align="left" valign="bottom"><span class="Bold">HDL<br/> Normal to Low</span></td><td align="center" valign="bottom">13.8%</td><td align="center" valign="bottom">14.8%</td><td align="center" valign="bottom">9.6%</td><td align="center" valign="bottom">14.2%</td><td align="center" valign="bottom">12.7%</td><td align="center" valign="bottom">10.5%</td><td align="center" valign="bottom">16.0%</td> </tr> <tr> <td align="left" valign="top"><span class="Bold">(≥40 mg/dL to &lt;40 mg/dL</span></td><td align="center" valign="top">(28/203)</td><td align="center" valign="top">(9/61)</td><td align="center" valign="top">(11/115)</td><td align="center" valign="top">(15/106)</td><td align="center" valign="top">(9/71)</td><td align="center" valign="top">(8/76)</td><td align="center" valign="top">(13/81)</td> </tr> <tr> <td align="left" valign="bottom"><span class="Bold">Triglycerides<br/> Normal to High</span></td><td align="center" valign="bottom">3.6%</td><td align="center" valign="bottom">6.1%</td><td align="center" valign="bottom">9.2%</td><td align="center" valign="bottom">7.2%</td><td align="center" valign="bottom">1.3%</td><td align="center" valign="bottom">3.7%</td><td align="center" valign="bottom">10.7%</td> </tr> <tr class="Last"> <td align="left" valign="top"><span class="Bold">(&lt;150 mg/dL to ≥200 mg/dL)</span></td><td align="center" valign="top">(8/221)</td><td align="center" valign="top">(3/49)</td><td align="center" valign="top">(14/153)</td><td align="center" valign="top">(10/139)</td><td align="center" valign="top">(1/79)</td><td align="center" valign="top">(3/82)</td><td align="center" valign="top">(9/84)</td> </tr> </tbody> </table></div>

In a long-term open-label pharmacokinetic and safety study in subjects with schizophrenia in which the highest maintenance dose available (234 mg) was evaluated, the mean changes from baseline in lipid values are presented in Table 6.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6: Change in Fasting Lipids from Long-term Open-label Pharmacokinetic and Safety Study in Subjects with Schizophrenia</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule" colspan="2">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension 234 mg</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Week 29</th><th align="center">Week 53</th> </tr> </thead> <tbody> <tr class="First"> <td align="left"></td><td align="center" colspan="2"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"><span class="Bold">Cholesterol</span></td><td align="center"><span class="Bold">n=112</span></td><td align="center"><span class="Bold">n=100</span></td> </tr> <tr> <td align="left">  <span class="Bold">Change from baseline</span></td><td align="center">-1.2</td><td align="center">0.1</td> </tr> <tr> <td align="left"><span class="Bold">LDL</span></td><td align="center"><span class="Bold">n=107</span></td><td align="center"><span class="Bold">n=89</span></td> </tr> <tr> <td align="left">  <span class="Bold">Change from baseline</span></td><td align="center">-2.7</td><td align="center">-2.3</td> </tr> <tr> <td align="left"><span class="Bold">HDL</span></td><td align="center"><span class="Bold">n=112</span></td><td align="center"><span class="Bold">n=98</span></td> </tr> <tr> <td align="left">  <span class="Bold">Change from baseline</span></td><td align="center">-0.8</td><td align="center">-2.6</td> </tr> <tr> <td align="left"><span class="Bold">Triglycerides</span></td><td align="center"><span class="Bold">n=112</span></td><td align="center"><span class="Bold">n=100</span></td> </tr> <tr class="Last"> <td align="left">  <span class="Bold">Change from baseline</span></td><td align="center">16.2</td><td align="center">37.4</td> </tr> </tbody> </table></div>

The mean changes from baseline in lipid values during the initial 25-week open-label period and at the endpoint of the subsequent 15-month double-blind period in a long-term study of another PP1M in subjects with schizoaffective disorder are presented in Table 7.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 7: Change in Fasting Lipids from an Open-Label and Double-Blind Periods of a Long-Term Study in Subjects with Schizoaffective Disorder</span> </caption> <col align="left" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="25%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule">Open-Label Period</th><th align="center" class="Botrule" colspan="2">Double-Blind Period</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th><th align="center">Placebo</th><th align="center">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> </thead> <tbody> <tr class="First"> <td align="left"></td><td align="center" colspan="3"><span class="Bold">Mean change from baseline (mg/dL)</span></td> </tr> <tr> <td align="left"><span class="Bold">Cholesterol</span></td><td align="center"><span class="Bold">n=198</span></td><td align="center"><span class="Bold">n=119</span></td><td align="center"><span class="Bold">n=132</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-3.9</td><td align="center">-4.2</td><td align="center">2.3</td> </tr> <tr> <td align="left"><span class="Bold">LDL</span></td><td align="center"><span class="Bold">n=198</span></td><td align="center"><span class="Bold">n=117</span></td><td align="center"><span class="Bold">n=130</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-2.7</td><td align="center">-2.8</td><td align="center">5.9</td> </tr> <tr> <td align="left"><span class="Bold">HDL</span></td><td align="center"><span class="Bold">n=198</span></td><td align="center"><span class="Bold">n=119</span></td><td align="center"><span class="Bold">n=131</span></td> </tr> <tr> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">-2.7</td><td align="center">-0.9</td><td align="center">-0.7</td> </tr> <tr> <td align="left"><span class="Bold">Triglyceride</span></td><td align="center"><span class="Bold">n=198</span></td><td align="center"><span class="Bold">n=119</span></td><td align="center"><span class="Bold">n=132</span></td> </tr> <tr class="Last"> <td align="left"><span class="Bold">Change from baseline</span></td><td align="center">7.0</td><td align="center">2.5</td><td align="center">-12.3</td> </tr> </tbody> </table></div>

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the four placebo-controlled (one 9-week and three 13-week), fixed-dose studies of another PP1M in subjects with schizophrenia are presented in Table 8.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 8: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Four Placebo-Controlled, 9- to 13-Week, Fixed-Dose Studies in Subjects with Schizophrenia</span> </caption> <col align="left" valign="middle" width="16%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <col align="center" valign="middle" width="12%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule" colspan="7">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">Placebo<br/> n=451</th><th align="center">39 mg<br/> n=116</th><th align="center">78 mg<br/> n=280</th><th align="center">156 mg<br/> n=267</th><th align="center">234/39 mg<a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a> <br/> n=137</th><th align="center">234/156 mg<a class="Sup" href="#footnote-9">*</a> <br/> n=144</th><th align="center">234/234 mg<a class="Sup" href="#footnote-9">*</a> <br/> n=145</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. <span class="Italics">[see <a href="#S14.1">Clinical Studies (14.1)</a>]</span>.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Weight (kg) Change from baseline</td><td align="center">-0.4</td><td align="center">0.4</td><td align="center">0.8</td><td align="center">1.4</td><td align="center">0.4</td><td align="center">0.7</td><td align="center">1.4</td> </tr> <tr class="Last"> <td align="left">Weight Gain ≥ 7% increase from baseline</td><td align="center">3.3 %</td><td align="center">6.0%</td><td align="center">8.9%</td><td align="center">9.0%</td><td align="center">5.8%</td><td align="center">8.3%</td><td align="center">13.1 %</td> </tr> </tbody> </table></div>

In a long-term open-label pharmacokinetic and safety study in which the highest maintenance dose available (234 mg) was evaluated, another PP1M was associated with a mean change in weight of +2.4 kg at Week 29 (n=134) and +4.3 kg at Week 53 (n=113).

During the initial 25-week open-label period of a long-term study in subjects with schizoaffective disorder, another PP1M was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, the PP1M was associated with a mean change in weight of -0.2 kg and 13.0% of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha- adrenergic blocking activity. Syncope was reported in < 1% (4/1293) of subjects treated with another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) in the recommended maintenance dose range of 39 mg to 234 mg in the four fixed- dose, double-blind, placebo-controlled trials compared with 0% (0/510) of subjects treated with placebo. In the four fixed-dose efficacy studies in subjects with schizophrenia, orthostatic hypotension was reported as an adverse event by < 1% (2/1293) of the PP1M-treated subjects compared to 0% (0/510) with placebo. Incidences of orthostatic hypotension and syncope in the long-term studies in subjects with schizophrenia and schizoaffective disorder were similar to those observed in the short-term studies.

Use ERZOFRI with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including paliperidone palmitate, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including once-a-month paliperidone palmitate extended-release injectable suspension (PP1M). Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ERZOFRI at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ERZOFRI in patients with severe neutropenia (absolute neutrophil count < 1000/mm3) and follow their WBC until recovery.

Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Prolactin data from two long-term, double-blind, placebo-controlled studies with another PP1M are presented below; one study was in a population of patients with schizophrenia; the second study was in patients with schizoaffective disorder.

Schizophrenia

In a long-term maintenance trial of another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) in schizophrenia patients (Study 5) [see Clinical Studies (14.1)], elevations of prolactin to above the reference range (> 18 ng/mL in males and > 30 ng/mL in females) relative to open-label baseline at any time during the double- blind phase were noted in a higher percentage of the patients in the PP1M group than those in the placebo group in males (51.9% versus 29.0%) and in females (50.5% versus 42.9%). During the double-blind phase, 4 females (4.2%) in the PP1M group experienced potentially prolactin-related adverse reactions (amenorrhea N=2; galactorrhea N=1; menstruation irregular N=1), while 2 females (2.2%) in the placebo group experienced potentially prolactin-related adverse reactions (amenorrhea N=1; breast pain N=1). One male (0.9%) in the PP1M group experienced erectile dysfunction and 1 male (0.9%) in placebo group experienced gynecomastia.

Prior to the double-blind phase (during the 33-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.9 (22.3) ng/mL in males (N=490) and 35.2 (39.6) ng/mL in females (N=358). At the end of the open-label phase, mean (SD) prolactin values were 24.7 (22.5) ng/mL in males (N=470) and 59.5 (38.1) ng/mL in females (N=333). During the open-label phases 49.2% of females and 47.7% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (5.3% versus 1.8%). Amenorrhea (2.5%) in females and no single potentially prolactin-related adverse reaction in males were observed with a rate greater than 2%.

Schizoaffective Disorder

In a long-term maintenance trial of another PP1M in patients with schizoaffective disorder (Study SCA-3004) see Clinical Studies (14.2), elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) relative to open-label baseline at any time during the 15-month double-blind phase were noted in a higher percentage of patients in the PP1M group than those in the placebo group in males (55.6% versus 23.2%) and in females (44.3% versus 25.0%). During the 15-month double-blind phase, 11 females (13.9%) in the PP1M group had 14 potentially prolactin-related adverse reactions (hyperprolactinemia N=3; blood prolactin increased N=4; libido decreased N=1; amenorrhea N=3; galactorrhea N=3), while 5 females (5.8%) in the placebo group had 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=2; blood prolactin increased N=1; amenorrhea N=2; galactorrhea N=1). Six males (7.1%) in the PP1M group experienced 6 potentially prolactin-related adverse reactions (hyperprolactinemia N=4; libido decreased N=1; erectile dysfunction N=1), while 1 male (1.2%) in the placebo group experienced adverse reaction of blood prolactin increased.

Prior to the 15-month double-blind phase (during the 25-week open-label phase of the long-term maintenance trial), the mean (SD) serum prolactin values at baseline were 14.6 (14.0) ng/mL in males (N=352) and 39.1 (44.6) ng/mL in females (N=302). At the end of the open-label phase, mean (SD) prolactin values were 32.8 (17.2) ng/mL in males (N=275) and 72.4 (46.5) ng/mL in females (N=239). During the open-label phase, 48.9% of females and 53.3% of males experienced elevations of prolactin above the reference range relative to baseline, and a higher proportion of females experienced potentially prolactin-related adverse reactions compared to males (10.0% versus 9.0%). Amenorrhea (5.8%) and galactorrhea (2.9%) in females and libido decrease (2.8%) and erectile dysfunction (2.5%) in males were observed with a rate greater than 2%.

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) [see Adverse Reactions (6.1)]. Antipsychotics, including ERZOFRI, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

In the four fixed-dose double-blind placebo-controlled studies in subjects with schizophrenia, <1% (1 out of 1,293) of subjects treated with another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M) in the recommended dose range of 39 mg to 234 mg experienced a convulsion compared with <1% (1 out of 510) of placebo-treated subjects who experienced a grand mal convulsion.

Like other antipsychotic drugs, ERZOFRI should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. ERZOFRI and other antipsychotic drugs should be used cautiously in patients at risk for aspiration.

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Although no cases of priapism have been reported in clinical trials with another once-a-month paliperidone palmitate extended-release injectable suspension (PP1M), priapism has been reported with oral paliperidone during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ERZOFRI to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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

The safety of ERZOFRI for the treatment of schizophrenia in adults and schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon adequate and well-controlled studies of another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). Below is a display of adverse reactions with another PP1M from those adequate and well-controlled studies.

Injection site reactions for ERZOFRI presented in this section (see "Pain and Injection Site Reactions with ERZOFRI" below) are based on pharmacokinetic studies.

Patient Exposure

The data described in this section are derived from a clinical trial database consisting of a total of 3,817 subjects (approximately 1,705 patient-years exposure) with schizophrenia who received at least one dose of PP1M in the recommended dose range of 39 mg to 234 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3,817 PP1M-treated subjects, 1,293 received PP1M in four fixed-dose, double- blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received PP1M in the maintenance trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive PP1M during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1,675 received PP1M in five non-placebo controlled trials (three noninferiority active- comparator trials, one long-term open-label pharmacokinetic and safety study, and an injection site [deltoid-gluteal] cross-over trial). One of the 13-week studies included a 234 mg PP1M initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.

The safety of PP1M was also evaluated in a 15-month, long-term study comparing the other PP1M to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received PP1M during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of PP1M was similar to that seen in previous double-blind, placebo-controlled clinical trials in adult subjects with schizophrenia.

The safety of PP1M was also evaluated in a long-term study in adult subjects with schizoaffective disorder. A total of 667 subjects PP1M during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive PP1M during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days). Adverse reactions that occurred more frequently in the PP1M group than the placebo group (a 2% difference or more between groups) were weight increased, nasopharyngitis, headache, hyperprolactinemia, and pyrexia.

Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Commonly Observed Adverse Reactions: The most common (at least 5% in any PP1M group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials in subjects with schizophrenia were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder. No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.

Discontinuation of Treatment Due to Adverse Events: The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for PP1M- and placebo-treated subjects.

The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% in PP1M- and placebo-treated subjects, respectively.

Dose-Related Adverse Reactions: Based on the pooled data from the four fixed-dose, double- blind, placebo-controlled trials in subjects with schizophrenia, among the adverse reactions that occurred with ≥ 2% incidence in the subjects treated with PP1M, only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at ≥ 2% incidence in PP1M-treated subjects from the four fixed-dose studies.

Adverse Reactions Occurring at an Incidence of 2% or More in a once-a-month paliperidone palmitate extended-release injectable suspension-Treated Patients: Table 9 lists the adverse reactions reported in 2% or more of PP1M -treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 9: Incidences of Adverse Reactions 2% or More of a Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension-Treated Patients (and Greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials</span> </caption> <col align="left" valign="top" width="30%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="10%"/> <thead> <tr class="First"> <th align="left"></th><th align="center"></th><th align="center" class="Botrule" colspan="6">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left">System Organ Class<br/>   Adverse Reactions</th><th align="center">Placebo<a class="Sup" href="#footnote-10" name="footnote-reference-10">*</a> <br/> (N=510)</th><th align="center">39 mg<br/> (N=130)</th><th align="center">78 mg<br/> (N=302)</th><th align="center">156 mg<br/> (N=312)</th><th align="center">234/39 mg<a class="Sup" href="#footnote-11" name="footnote-reference-11">†</a> <br/> (N=160)</th><th align="center">234/156 mg<a class="Sup" href="#footnote-11">†</a> <br/> (N=165)</th><th align="center">234/234 mg<a class="Sup" href="#footnote-11">†</a> <br/> (N=163)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="8">Percentages are rounded to whole numbers. Table includes adverse reactions that were reported in 2% or more of subjects in any of the once-a-month paliperidone palmitate extended-release injectable suspension dose groups and which occurred at greater incidence than in the placebo group.</td> </tr> <tr> <td align="left" colspan="8"> <dl class="Footnote"> <dt> <a href="#footnote-reference-10" name="footnote-10">*</a> </dt> <dd>Placebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design.</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">†</a> </dt> <dd>Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [see <span class="Italics"><a href="#S14.1"> Clinical Studies (14.1)</a></span>]</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Total percentage of subjects with adverse reactions</td><td align="center">70</td><td align="center">75</td><td align="center">68</td><td align="center">69</td><td align="center">63</td><td align="center">60</td><td align="center">63</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Gastrointestinal disorders</span></td> </tr> <tr> <td align="left">  Abdominal discomfort/abdominal pain upper</td><td align="center">2</td><td align="center">2</td><td align="center">4</td><td align="center">4</td><td align="center">1</td><td align="center">2</td><td align="center">4</td> </tr> <tr> <td align="left">  Diarrhea</td><td align="center">2</td><td align="center">0</td><td align="center">3</td><td align="center">2</td><td align="center">1</td><td align="center">2</td><td align="center">2</td> </tr> <tr> <td align="left">  Dry mouth</td><td align="center">1</td><td align="center">3</td><td align="center">1</td><td align="center">0</td><td align="center">1</td><td align="center">1</td><td align="center">1</td> </tr> <tr> <td align="left">  Nausea</td><td align="center">3</td><td align="center">4</td><td align="center">4</td><td align="center">3</td><td align="center">2</td><td align="center">2</td><td align="center">2</td> </tr> <tr> <td align="left">  Toothache</td><td align="center">1</td><td align="center">1</td><td align="center">1</td><td align="center">3</td><td align="center">1</td><td align="center">2</td><td align="center">3</td> </tr> <tr> <td align="left">  Vomiting</td><td align="center">4</td><td align="center">5</td><td align="center">4</td><td align="center">2</td><td align="center">3</td><td align="center">2</td><td align="center">2</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">General disorders and administration site conditions</span></td> </tr> <tr> <td align="left">  Asthenia</td><td align="center">0</td><td align="center">2</td><td align="center">1</td><td align="center">&lt;1</td><td align="center">0</td><td align="center">1</td><td align="center">1</td> </tr> <tr> <td align="left">  Fatigue</td><td align="center">1</td><td align="center">1</td><td align="center">2</td><td align="center">2</td><td align="center">1</td><td align="center">2</td><td align="center">1</td> </tr> <tr> <td align="left">  Injection site reactions</td><td align="center">2</td><td align="center">0</td><td align="center">4</td><td align="center">6</td><td align="center">9</td><td align="center">7</td><td align="center">10</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Infections and infestations</span></td> </tr> <tr> <td align="left">  Nasopharyngitis</td><td align="center">2</td><td align="center">0</td><td align="center">2</td><td align="center">2</td><td align="center">4</td><td align="center">2</td><td align="center">2</td> </tr> <tr> <td align="left">  Upper respiratory tract infection</td><td align="center">2</td><td align="center">2</td><td align="center">2</td><td align="center">2</td><td align="center">1</td><td align="center">2</td><td align="center">4</td> </tr> <tr> <td align="left">  Urinary tract infection</td><td align="center">1</td><td align="center">0</td><td align="center">1</td><td align="center">&lt;1</td><td align="center">1</td><td align="center">1</td><td align="center">2</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Investigations</span></td> </tr> <tr> <td align="left">  Weight increased</td><td align="center">1</td><td align="center">4</td><td align="center">4</td><td align="center">1</td><td align="center">1</td><td align="center">1</td><td align="center">2</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td> </tr> <tr> <td align="left">  Back pain</td><td align="center">2</td><td align="center">2</td><td align="center">1</td><td align="center">3</td><td align="center">1</td><td align="center">1</td><td align="center">1</td> </tr> <tr> <td align="left">  Musculoskeletal stiffness</td><td align="center">1</td><td align="center">1</td><td align="center">&lt;1</td><td align="center">&lt;1</td><td align="center">1</td><td align="center">1</td><td align="center">2</td> </tr> <tr> <td align="left">  Myalgia</td><td align="center">1</td><td align="center">2</td><td align="center">1</td><td align="center">&lt;1</td><td align="center">1</td><td align="center">0</td><td align="center">2</td> </tr> <tr> <td align="left">  Pain in extremity</td><td align="center">1</td><td align="center">0</td><td align="center">2</td><td align="center">2</td><td align="center">2</td><td align="center">3</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Nervous system disorders</span></td> </tr> <tr> <td align="left">  Akathisia</td><td align="center">3</td><td align="center">2</td><td align="center">2</td><td align="center">3</td><td align="center">1</td><td align="center">5</td><td align="center">6</td> </tr> <tr> <td align="left">  Dizziness</td><td align="center">1</td><td align="center">6</td><td align="center">2</td><td align="center">4</td><td align="center">1</td><td align="center">4</td><td align="center">2</td> </tr> <tr> <td align="left">  Extrapyramidal disorder</td><td align="center">1</td><td align="center">5</td><td align="center">2</td><td align="center">3</td><td align="center">1</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td align="left">  Headache</td><td align="center">12</td><td align="center">11</td><td align="center">11</td><td align="center">15</td><td align="center">11</td><td align="center">7</td><td align="center">6</td> </tr> <tr> <td align="left">  Somnolence/sedation</td><td align="center">3</td><td align="center">5</td><td align="center">7</td><td align="center">4</td><td align="center">1</td><td align="center">5</td><td align="center">5</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Psychiatric disorders</span></td> </tr> <tr> <td align="left">  Agitation</td><td align="center">7</td><td align="center">10</td><td align="center">5</td><td align="center">9</td><td align="center">8</td><td align="center">5</td><td align="center">4</td> </tr> <tr> <td align="left">  Anxiety</td><td align="center">7</td><td align="center">8</td><td align="center">5</td><td align="center">3</td><td align="center">5</td><td align="center">6</td><td align="center">6</td> </tr> <tr> <td align="left">  Nightmare</td><td align="center">&lt;1</td><td align="center">2</td><td align="center">0</td><td align="center">0</td><td align="center">0</td><td align="center">0</td><td align="center">0</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Respiratory, thoracic and mediastinal disorders</span></td> </tr> <tr> <td align="left">  Cough</td><td align="center">1</td><td align="center">2</td><td align="center">3</td><td align="center">1</td><td align="center">0</td><td align="center">1</td><td align="center">1</td> </tr> <tr> <td align="left" colspan="8"><span class="Bold">Vascular disorders</span></td> </tr> <tr class="Last"> <td align="left">  Hypertension</td><td align="center">1</td><td align="center">2</td><td align="center">1</td><td align="center">1</td><td align="center">1</td><td align="center">1</td><td align="center">0</td> </tr> </tbody> </table></div>

Adverse reactions for which the once-a-month paliperidone palmitate extended-release injectable suspension incidence was equal to or less than placebo are not listed in the table, but included the following: dyspepsia, psychotic disorder, schizophrenia, and tremor. The following terms were combined: somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse reactions were collapsed and are grouped under "Injection site reactions".

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension

The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.

Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: constipation, dyspepsia, flatulence, salivary hypersecretion

Immune system disorders: hypersensitivity

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite

Musculoskeletal and connective tissue disorders: arthralgia, joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, cogwheel rigidity, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope

Psychiatric disorders: insomnia, libido decreased, restlessness

Reproductive system and breast disorders: amenorrhea, breast discharge, breast enlargement/breast swelling, breast tenderness/breast pain, ejaculation disorder, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria

Demographic Differences

An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects 65 years of age and older.

Extrapyramidal Symptoms (EPS)

Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials in adult subjects with schizophrenia provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 10), and (5) incidence of spontaneous reports of EPS (Table 11).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 10: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <thead> <tr class="Botrule First"> <th align="left"></th><th align="center" colspan="4">Percentage of Subjects</th> </tr> <tr> <th align="left"></th><th align="center"></th><th align="center" class="Botrule" colspan="3">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left">Scale</th><th align="center">Placebo<br/> (N=262)</th><th align="center">39 mg<br/> (N=130)</th><th align="center">78 mg<br/> (N=223)</th><th align="center">156 mg<br/> (N=228)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>For parkinsonism, percent of subjects with Simpson-Angus Total score &gt; 0.3 at endpoint (Total score defined as total sum of items score divided by the number of items)</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at endpoint</dd> <dt> <a href="#footnote-reference-14" name="footnote-14">‡</a> </dt> <dd>For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at endpoint</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">§</a> </dt> <dd>Percent of subjects who received anticholinergic medications to treat EPS</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">  Parkinsonism<a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a></td><td align="center">9</td><td align="center">12</td><td align="center">10</td><td align="center">6</td> </tr> <tr> <td align="left">  Akathisia<a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a></td><td align="center">5</td><td align="center">5</td><td align="center">6</td><td align="center">5</td> </tr> <tr> <td align="left">  Dyskinesia<a class="Sup" href="#footnote-14" name="footnote-reference-14">‡</a></td><td align="center">3</td><td align="center">4</td><td align="center">6</td><td align="center">4</td> </tr> <tr class="Last"> <td align="left">  Use of Anticholinergic Medications<a class="Sup" href="#footnote-15" name="footnote-reference-15">§</a></td><td align="center">12</td><td align="center">10</td><td align="center">12</td><td align="center">11</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 11: Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term – Schizophrenia Studies in Adults</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule" colspan="4">Percentage of Subjects</th> </tr> <tr> <th align="left"></th><th align="center"></th><th align="center" class="Botrule" colspan="3">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left">EPS Group</th><th align="center" class="Toprule">Placebo<br/> (N=262)</th><th align="center">39 mg<br/> (N=130)</th><th align="center">78 mg<br/> (N=223)</th><th align="center">156 mg<br/> (N=228)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia<br/> Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness<br/> Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesia <br/>Dystonia group includes: Dystonia, muscle spasms</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Overall percentage of subjects with EPS-related adverse events</td><td align="center" valign="middle">10</td><td align="center" valign="middle">12</td><td align="center" valign="middle">11</td><td align="center" valign="middle">11</td> </tr> <tr> <td align="left">Parkinsonism</td><td align="center">5</td><td align="center">6</td><td align="center">6</td><td align="center">4</td> </tr> <tr> <td align="left">Hyperkinesia</td><td align="center">2</td><td align="center">2</td><td align="center">2</td><td align="center">4</td> </tr> <tr> <td align="left">Tremor</td><td align="center">3</td><td align="center">2</td><td align="center">2</td><td align="center">3</td> </tr> <tr> <td align="left">Dyskinesia</td><td align="center">1</td><td align="center">2</td><td align="center">3</td><td align="center">1</td> </tr> <tr class="Last"> <td align="left">Dystonia</td><td align="center">0</td><td align="center">1</td><td align="center">1</td><td align="center">2</td> </tr> </tbody> </table></div>

The results across all phases of the maintenance trial in subjects with schizophrenia exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of parkinsonism and akathisia assessed by incidence of rating scales were higher in the PP1M 156 mg group (18% and 11%, respectively) than in the PP1M 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).

In the 13-week study in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the PP1M 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and PP1M 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%).

In the long-term study in subjects with schizoaffective disorder, EPS reported during the 25-week open-label PP1M treatment included hyperkinesia (12.3%), parkinsonism (8.7%), tremor (3.4%), dyskinesia (2.5%), and dystonia (2.1%). During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events (> 2%) in any treatment group in the double-blind phase of the study (PP1M versus placebo) were hyperkinesia (3.7% versus 2.9%), parkinsonism (3.0% versus 1.8%), and tremor (1.2% versus 2.4%).

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Pain Assessment and Injection Site Reactions

In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials of another PP1M in subjects with schizophrenia, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.

In the 13-week study involving 234 mg initiation dosing in subjects with schizophrenia, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the PP1M and placebo groups. Investigator ratings of injection pain were similar for the placebo and PP1M groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the PP1M and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the PP1M and placebo groups.

ERZOFRI was evaluated in 281 patients with schizophrenia or schizoaffective disorder in an open-label randomized parallel arm study. The percentage of patients in the open-label study reporting injection site-related adverse reactions at the first injection for patients treated with ERZOFRI (all reported as injection site pain) was similar to the percentage of patients treated with another PP1M.

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, small intestinal obstruction

General disorders and administration site conditions: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Infections and infestations: rhinitis

Musculoskeletal and connective tissue disorders: musculoskeletal pain, torticollis, trismus

Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement

Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: hypotension, ischemia

The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were 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: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

Cases of anaphylactic reaction after injection with another once-a-month paliperidone palmitate extended-release injectable suspension product have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6) sections of the package inserts for those products.

Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)], results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.

Table 12 presents clinically significant drug interactions with ERZOFRI.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 12: Clinically Important Drug Interactions with ERZOFRI</span> </caption> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Centrally Acting Drugs and Alcohol</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Rationale:</span></td><td align="left" class="Rrule">Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of ERZOFRI.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Recommendation:</span></td><td align="left" class="Rrule">ERZOFRI should be used with caution in combination with other centrally acting drugs and alcohol <span class="Italics">[see <a href="#S6.1">Adverse Reactions (6.1</a>, <a href="#S6.2">6.2)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Drugs with Potential for Inducing Orthostatic Hypotension</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Rationale:</span></td><td align="left" class="Rrule">Because ERZOFRI has the potential for inducing orthostatic hypotension, an additive effect may occur when ERZOFRI is administered with other therapeutic agents that have this potential <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Recommendation:</span></td><td align="left" class="Rrule">Monitor orthostatic vital signs in patients who are vulnerable to hypotension <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Strong Inducers of CYP3A4 and P-gp </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Rationale:</span></td><td align="left" class="Rrule">The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Recommendation:</span></td><td align="left" class="Rrule">Avoid using CYP3A4 and/or P-gp inducers with ERZOFRI during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets <span class="Italics">[see <a href="#S2.5">Dosage and Administration (2.5)</a>]</span>.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold">Levodopa and Other Dopamine Agonists</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Rationale:</span></td><td align="left" class="Rrule">Paliperidone may antagonize the effect of levodopa and other dopamine agonists.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Italics">Clinical Recommendation:</span></td><td align="left" class="Rrule">Monitor and manage patient as clinically appropriate.</td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of ERZOFRI is required when administered with valproate [see Clinical Pharmacology (12.3)]. Additionally, no dosage adjustment is necessary for valproate when co-administered with ERZOFRI [See Clinical Pharmacology (12.3)].

Pharmacokinetic interaction between lithium and ERZOFRI is also unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [see Clinical Pharmacology (12.3)]

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ERZOFRI, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical- and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including ERZOFRI, during pregnancy (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 176 days after a single-dose administration of ERZOFRI [see Clinical Pharmacology (12.3)], and the clinical significance of ERZOFRI administered before pregnancy or anytime during pregnancy is not known.

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

In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone palmitate based on mg/m2 body surface area (BSA). There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m2 BSA. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone palmitate, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates exhibiting extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9,258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88-1.81) in a subgroup of 1,566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is 10 times MRHD of 234 mg paliperidone palmitate as a monthly maintenance dose based on body surface area (BSA).

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on BSA.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on BSA; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg risperidone based on BSA. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on BSA, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring were delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on BSA; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams (see RISPERDAL® prescribing information).

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations). Paliperidone has been detected in plasma in adult subjects up to 176 days after a single-dose administration of ERZOFRI [see Clinical Pharmacology (12.3)], and the clinical significance on the breastfed infant is not known. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ERZOFRI and any potential adverse effects on the breastfed child from ERZOFRI or from the mother's underlying condition.

Clinical Considerations

Infants exposed to ERZOFRI through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with ERZOFRI may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.10)].

Safety and effectiveness of ERZOFRI in pediatric patients have not been established.

Juvenile Animal Toxicity Data

In a study in which juvenile rats were treated with oral paliperidone from Days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at a 12 mg/day oral dose. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone, which were similar to those in children and adolescents receiving the MRHD of oral risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

The long-term effects of ERZOFRI on growth and sexual maturation have not been fully evaluated in pediatric patients.

Clinical studies of ERZOFRI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Paliperidone palmitate is substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because geriatric patients are more likely to have decreased renal function, adjust dose based on renal function [see Dosage and Administration (2.4)].

Use of ERZOFRI is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min). Dose reduction is recommended for patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

ERZOFRI has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to ERZOFRI. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Human Experience

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Refer to the OVERDOSAGE section of the risperidone prescribing information for overdose experience with risperidone.

Management of Overdosage

There is no specific antidote to paliperidone. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Consider the pharmacokinetic profile of ERZOFRI and the half-life of paliperidone when assessing treatment needs and recovery.

Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

ERZOFRI (paliperidone palmitate) extended-release injectable suspension contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:

{ "type": "p", "children": [], "text": "ERZOFRI (paliperidone palmitate) extended-release injectable suspension contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate, is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C39H57FN4O4 and its molecular weight is 664.89. The structural formula is:" }

Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in water, and slightly soluble in ethyl acetate.

{ "type": "p", "children": [], "text": "Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in water, and slightly soluble in ethyl acetate." }

ERZOFRI is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (deliverable volume) in single-dose prefilled syringes: 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1 mL), 234 mg (1.5 mL), and 351 mg (2.25 mL). The drug product hydrolyzes in vivo to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 225 mg of paliperidone, respectively.

{ "type": "p", "children": [], "text": "ERZOFRI is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in the following dose strengths of paliperidone palmitate (deliverable volume) in single-dose prefilled syringes: 39 mg (0.25 mL), 78 mg (0.5 mL), 117 mg (0.75 mL), 156 mg (1 mL), 234 mg (1.5 mL), and 351 mg (2.25 mL). The drug product hydrolyzes in vivo to the active moiety, paliperidone, resulting in dose strengths of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, and 225 mg of paliperidone, respectively. " }

The inactive ingredients are citric acid monohydrate (5 mg/mL), dibasic sodium phosphate anhydrous (5 mg/mL), monobasic sodium phosphate monohydrate (2.5 mg/mL), polyethylene glycol 4000 (30 mg/mL), polysorbate 20 (12 mg/mL), sodium hydroxide to adjust pH, and water for injection. The drug product pH is 6.5 to 7.5.

{ "type": "p", "children": [], "text": "The inactive ingredients are citric acid monohydrate (5 mg/mL), dibasic sodium phosphate anhydrous (5 mg/mL), monobasic sodium phosphate monohydrate (2.5 mg/mL), polyethylene glycol 4000 (30 mg/mL), polysorbate 20 (12 mg/mL), sodium hydroxide to adjust pH, and water for injection. The drug product pH is 6.5 to 7.5." }

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)]. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in the listed indications is unclear. However, the drug's effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism.

Paliperidone is an antagonist at the central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptors with binding affinities (Ki values) of 1.6-2.8 nM for D2 and 0.8-1.2 nM for 5HT2A receptors. Paliperidone also acts as an antagonist at the α1 and α2 adrenergic receptors and H1 histaminergic receptors. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.

The overall exposures (AUC) of paliperidone following another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section) administration was dose-proportional over a dose range of 39 mg to 234 mg, and peak plasma concentrations (Cmax) were less than dose-proportional for doses exceeding 78 mg. Steady state plasma exposures of ERZOFRI are reached 7 days after the first injection.

Absorption

After intramuscular injection, paliperidone palmitate is hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose of ERZOFRI, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 16 to 28 days. The release of the drug starts as early as day 1 and lasts for as long as 176 days.

Following multiple intramuscular injections of ERZOFRI (351 mg on day 1 and 156 mg on day 29 and every 28 days for a total of 6 consecutive injections) in patients, the geometric least square mean Cmax, trough plasma concentrations (Ctrough) and average plasma concentrations (Cavg) were 43.7 ng/mL, 28.5 ng/mL and 30.3 ng/mL, respectively, during the initial regimen period; at steady state, Cmax-ss, Ctrough,ss and AUCtau-ss were 42.6 ng/mL, 28.3 ng/mL and 909 ng*hr/mL, respectively.

Following multiple intramuscular injections of another PP1M (234 mg on day 1 and 156 mg on day 8 and every 28 days for a total of 7 consecutive injections), the geometric least square mean Cmax, Ctrough and Cavg were 58.7 ng/mL, 30.1 ng/mL and 37.8 ng/mL, respectively, during the initial regimen period; at steady state, Cmax-ss, Ctrough,ss and AUCtau-ss of another once-a-month paliperidone palmitate extended-release injectable suspension for paliperidone were 43.8 ng/mL, 30.4 ng/mL and 953 ng*hr/mL, respectively.

Following intramuscular injection of a single dose of ERZOFRI 156 mg in the deltoid muscle, the geometric mean Cmax was approximately 43% higher compared with injections of 156 mg in the gluteal muscle. Following intramuscular injection of a single dose of ERZOFRI 351 mg in the deltoid muscle, the geometric mean Cmax was approximately 21% higher compared with injections of 351 mg in the gluteal muscle. Over the dose range of 39 mg to 234 mg, the AUCinf after a single dose injection in the deltoid muscle was comparable to the AUCinf after a single dose injection in the gluteal muscle.

Following intramuscular injection of single doses (39 mg to 234 mg) of another PP1M in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle. The mean steady-state peak:trough ratio for PP1M dose of 156 mg was 1.8 following gluteal administration and 2.2 following deltoid administration.

Following administration of paliperidone palmitate, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 to 1.8.

Distribution

Based on a population analysis of data from ERZOFRI clinical trials, the apparent volume of distribution of paliperidone is 2840 L.

The plasma protein binding of racemic paliperidone is 74%.

Elimination

Metabolism

Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

The median apparent half-life of paliperidone following ERZOFRI single-dose administration at 156 mg is approximately 27 days.

Excretion

In a study with oral immediate-release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces.

Drug Interaction Studies

No specific drug interaction studies have been performed with ERZOFRI. The information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of paliperidone are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean Cmax and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration, a decrease in mean Cmax and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)]. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

Figure 1: Effects of Other Drugs on Paliperidone Pharmacokinetics

Clinically meaningful pharmacokinetic interaction between paliperidone and valproate (including valproic acid and divalproex sodium) is not expected. Oral administration of divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) with oral paliperidone extended-release tablets resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone.

After oral administration of paliperidone, the steady-state Cmax and AUC of divalproex sodium extended-release tablets were not affected in 13 patients stabilized on divalproex sodium extended- release tablets. In a clinical study, subjects on stable doses of divalproex sodium extended-release tablets had comparable valproate average plasma concentrations when oral paliperidone extended- release tablets 3-15 mg/day was added to their existing divalproex sodium extended-release tablets treatment [see Drug Interactions (7.2)].

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)].

In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.

Specific Populations

No pharmacokinetic studies have been performed with ERZOFRI in specific populations. The information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modeling of oral paliperidone and another PP1M. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 2 [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

After oral administration of paliperidone in elderly subjects, the Cmax and AUC increased 1.2-fold compared to young subjects. However, there may be age-related decreases in creatinine clearance [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)].

Figure 2 Effects of Intrinsic Factors on Paliperidone Pharmacokinetics

Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with PP1M, the trough concentrations were similar between males and females.

Lower Cmax was observed in overweight and obese subjects. At apparent steady-state PP1M, the trough concentrations were similar among normal, overweight, and obese subjects.

Carcinogenesis

The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg monthly injections, which are 0.6, 2, and 4 times, respectively, the MRHD of 234 mg of another once-a-month paliperidone palmitate extended-release injectable suspension based on body surface area (BSA). A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at 2 and 4 times the MRHD based on BSA. A carcinogenicity study in mice has not been conducted with paliperidone palmitate.

Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on BSA (see risperidone prescribing information). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.7)].

Mutagenesis

Paliperidone palmitate was not genotoxic in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay, or the in vivo rat bone marrow micronucleus test.

Impairment of Fertility

No fertility studies were conducted with paliperidone palmitate.

Paliperidone did not affect fertility in treated female rats at oral doses of up to 2.5 mg/kg/day which is 2 times the MRHD based on BSA. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the MRHD based on BSA.

Paliperidone did not affect fertility of treated male rats at oral doses of up to 2 times the MRHD of 12 mg/day based on BSA. However, studies to assess sperm count and sperm viability were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on BSA). Serum testosterone and sperm parameters partially recovered, and remained decreased after the last observation at two months after treatment was discontinued.

The efficacy of ERZOFRI for the treatment of schizophrenia in adults is based upon adequate and well-controlled studies of another once-a-month paliperidone palmitate extended-release injectable suspension (also referred to as "PP1M" in this section). The results of these adequate and well-controlled studies of another PP1M are presented below.

Short-Term Monotherapy (Studies 1, 2, 3, 4)

The efficacy of another PP1M in the acute treatment of schizophrenia was evaluated in four short-term (one 9-week and three 13-week) double-blind, randomized, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of PP1M in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on Day 64 of the 13-week studies, i.e., at a weekly interval for the initial two doses and then every 4 weeks for maintenance.

Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210.

In Study 1 (PSY-3007), a 13-week study (n=636) comparing three fixed doses of PP1M (initial deltoid injection of 234 mg followed by 3 gluteal or deltoid doses of either 39 mg/4 weeks, 156 mg/4 weeks or 234 mg/4 weeks) to placebo, all three doses of PP1M were superior to placebo in improving the PANSS total score.

In Study 2 (PSY-3003), another 13-week study (n=349) comparing three fixed doses of PP1M (78 mg/4 weeks, 156 mg/4 weeks, and 234 mg/4 weeks) to placebo, only 156 mg/4 weeks of PP1M was superior to placebo in improving the PANSS total score.

In Study 3 (PSY-3004), a third 13-week study (n=513) comparing three fixed doses of PP1M (39 mg/4 weeks, 78 mg/4 weeks, and 156 mg/4 weeks) to placebo, all three doses of PP1M were superior to placebo in improving the PANSS total score.

In Study 4 (SCH-201), the 9-week study (n=197) comparing two fixed doses of PP1M (78 mg/4 weeks and 156 mg/4 weeks) to placebo, both doses of PP1M were superior to placebo in improving PANSS total score.

A summary of the mean baseline PANSS scores along with the mean changes from baseline in the four short-term acute schizophrenia studies are provided in Table 13.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 13: Schizophrenia Short-term Studies</span> </caption> <col align="center" valign="top" width="10%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="16%"/> <col align="left" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="Botrule First"> <th align="center" valign="middle">Study Number</th><th align="center" valign="middle">Treatment Group</th><th align="center" colspan="3" valign="middle">Primary Efficacy Measure: PANSS Total Score</th> </tr> <tr class="Last"> <th align="center"></th><th align="left"></th><th align="center" valign="middle">Mean Baseline Score (SD)</th><th align="center" valign="middle">LS Mean Change from Baseline (SE)</th><th align="center" valign="middle">Placebo-subtracted Difference<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a> <br/> (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5">SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>Difference (drug minus placebo) in least-squares mean change from baseline.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>p&lt;0.05 (Doses statistically significantly superior to placebo).</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">‡</a> </dt> <dd>Because an insufficient number of subjects received the 234 mg/4 weeks dose, results from this group are not included.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">Study 1</span></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (39 mg/4 weeks)<a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a></td><td align="left">86.9 (11.99)</td><td align="left">-11.2 (1.69)</td><td align="center">-5.1 (-9.01, -1.10)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">86.2 (10.77)</td><td align="left">-14.8 (1.68)</td><td align="center">-8.7 (-12.62, -4.78)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (234 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">88.4 (11.70)</td><td align="left">-15.9 (1.70)</td><td align="center">-9.8 (-13.71, -5.85)</td> </tr> <tr class="Botrule"> <td align="center"></td><td align="left">Placebo</td><td align="left">86.8 (10.31)</td><td align="left">-6.1 (1.69)</td><td align="center">--</td> </tr> <tr> <td align="left"><span class="Bold">Study 2</span><a class="Sup" href="#footnote-18" name="footnote-reference-18">‡</a></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks)</td><td align="left">89.9 (10.78)</td><td align="left">-6.9 (2.50)</td><td align="center">-3.5 (-8.73, 1.77)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">90.1 (11.66)</td><td align="left">-10.4 (2.47)</td><td align="center">-6.9 (-12.12, -1.68)</td> </tr> <tr class="Botrule"> <td align="center"></td><td align="left">Placebo</td><td align="left">92.4 (12.55)</td><td align="left">-3.5 (2.15)</td><td align="center">--</td> </tr> <tr> <td align="left"><span class="Bold">Study 3</span></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (39 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">90.7 (12.25)</td><td align="left">-19.8 (2.19)</td><td align="center">-6.6 (-11.40, -1.73)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">91.2 (12.02)</td><td align="left">-19.2 (2.19)</td><td align="center">-5.9 (-10.76, -1.07)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">90.8 (11.70)</td><td align="left">-22.5 (2.18)</td><td align="center">-9.2 (-14.07, -4.43)</td> </tr> <tr class="Botrule"> <td align="center"></td><td align="left">Placebo</td><td align="left">90.7 (12.22)</td><td align="left">-13.3 (2.21)</td><td align="center">--</td> </tr> <tr> <td align="left"><span class="Bold">Study 4</span></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (78 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">88.0 (12.39)</td><td align="left">-4.6 (2.43)</td><td align="center">-11.2 (-16.85, -5.57)</td> </tr> <tr> <td align="center"></td><td align="left">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension (156 mg/4 weeks)<a class="Sup" href="#footnote-17">†</a></td><td align="left">85.2 (11.09)</td><td align="left">-7.4 (2.45)</td><td align="center">-14.0 (-19.51, -8.58)</td> </tr> <tr class="Last"> <td align="center"></td><td align="left">Placebo</td><td align="left">87.8 (13.90)</td><td align="left">6.6 (2.45)</td><td align="center">--</td> </tr> </tbody> </table></div>

Maintenance Monotherapy Treatment (Study 5: PSY-3001)

The efficacy of another PP1M in maintaining symptomatic control in schizophrenia was established in a longer-term double-blind, placebo-controlled, flexible-dose study involving adult subjects who met DSM-IV criteria for schizophrenia. This study included a minimum 12-week, fixed-dose stabilization phase, and a randomized, placebo-controlled phase to observe for relapse. During the double-blind phase, patients were randomized to either the same dose of PP1M they received during the stabilization phase, i.e., 39 mg, 78 mg, or 156 mg administered every 4 weeks, or to placebo. A total of 410 stabilized patients were randomized to either PP1M or to placebo until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as time to first emergence of one or more of the following: psychiatric hospitalization, ≥ 25% increase (if the baseline score was > 40) or a 10-point increase (if the baseline score was ≤ 40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation, or a score of ≥ 5 (if the maximum baseline score was ≤ 3) or ≥ 6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items. The primary efficacy variable was time to relapse. A pre-planned interim analysis showed a statistically significantly longer time to relapse in patients treated with PP1M compared to placebo, and the study was stopped early because maintenance of efficacy was demonstrated. Thirty-four percent (34%) of subjects in the placebo group and 10% of subjects in the PP1M group experienced a relapse event. There was a statistically significant difference between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 3. The time to relapse for subjects in the placebo group was statistically significantly shorter than for the PP1M group. An examination of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

Figure 3: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (Schizophrenia Study 5)

<div class="scrollingtable"><table class="Noautorules" width="75%"> <col align="left" valign="top" width="100%"/> <tfoot> <tr> <td align="left" valign="top">* median time to relapse for placebo group is 163 days</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left"> <p class="First"> <img alt="Figure 3" src="/dailymed/image.cfm?name=erzofri-19.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></p> </td> </tr> </tbody> </table></div>

Long-Term Comparative Monotherapy Treatment versus Oral Antipsychotic Therapy (Study 6: SCH-3006)

The efficacy of another PP1M in delaying time to treatment failure compared with selected oral antipsychotic medications was established in a long-term, randomized, flexible-dose study in subjects with schizophrenia and a history of incarceration. Subjects were screened for up to 14 days followed by a 15-month treatment phase during which they were observed for treatment failure.

The primary endpoint was time to first treatment failure. Treatment failure was defined as one of the following: arrest and/or incarceration; psychiatric hospitalization; discontinuation of antipsychotic treatment because of safety or tolerability; treatment supplementation with another antipsychotic because of inadequate efficacy; need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization; discontinuation of antipsychotic treatment because of inadequate efficacy; or suicide. Treatment failure was determined by an Event Monitoring Board (EMB) that was blinded to treatment assignment. A total of 444 subjects were randomly assigned to either PP1M (N = 226; median dose 156 mg) or one of up to seven pre-specified, flexibly-dosed, commonly prescribed oral antipsychotic medications (N = 218; aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, or risperidone). The selection of the oral antipsychotic medication was determined to be appropriate for the patient by the investigator. A statistically significantly longer time to first treatment failure was seen for PP1M compared with oral antipsychotic medications. The median time to treatment failure was 416 days and 226 days for PP1M and antipsychotic medications, respectively. A Kaplan-Meier plot of time to first treatment failure is shown in Figure 4. The frequencies of first treatment failure events by type are shown in Table 14. The time to first arrest and/or incarceration or psychiatric hospitalization was also statistically significantly longer for the PP1M group compared to the oral antipsychotic group.

Figure 4: Kaplan-Meier Plot of Time to First Treatment Failure in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6)

<div class="scrollingtable"><table class="Noautorules" width="80%"> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left" valign="top">* Median time to first treatment failure: 416 days with once-a-month paliperidone palmitate extended-release injectable suspension; 226 days with oral antipsychotics</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="center"><img alt="Figure 4" src="/dailymed/image.cfm?name=erzofri-20.jpg&amp;setid=492bf9dd-868e-421a-92db-8cca8973aac1"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 14: Components of Composite Endpoint in a Long-Term, Randomized, Flexible-Dose Study in Subjects with Schizophrenia and a History of Incarceration (Schizophrenia Study 6)</span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="14%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" valign="middle">Event Type</th><th align="center" class="Rrule">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension<br/> N=226<br/> frequency (%)</th><th align="center" class="Rrule">Oral Antipsychotics<br/> N=218<br/> frequency (%)</th><th align="center" class="Rrule">Hazard Ratio<a class="Sup" href="#footnote-19" name="footnote-reference-19">*</a> <br/> [95% CI]</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-19" name="footnote-19">*</a> </dt> <dd>Hazard ratio of once-a-month paliperidone palmitate extended-release injectable suspension to Oral Antipsychotics based on Cox regression model for time-to-event analysis. Note that the hazard ratio did not appear constant throughout the trial.</dd> <dt> <a href="#footnote-reference-20" name="footnote-20">†</a> </dt> <dd>Analysis results, which incorporated relevant events collected after discontinuation for those who discontinued, were consistent with the results from the pre-specified analysis of this secondary endpoint.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule"><span class="Bold">First Treatment Failures</span></td><td align="center" class="Rrule">90 (39.8%)</td><td align="center" class="Rrule">117 (53.7%)</td><td align="center" class="Rrule">0.70<br/> [0.53, 0.92]</td> </tr> <tr> <td align="left" class="Lrule Rrule"><span class="Bold">First Treatment Failure Component Events</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Arrest and/or incarceration</li> </ul> </td><td align="center" class="Rrule">48 (21.2%)</td><td align="center" class="Rrule">64 (29.4%)</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Psychiatric hospitalization</li> </ul> </td><td align="center" class="Rrule">18 (8.0%)</td><td align="center" class="Rrule">26 (11.9%)</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Discontinuation of antipsychotic treatment because of safety or tolerability</li> </ul> </td><td align="center" class="Rrule" valign="middle">15 (6.6%)</td><td align="center" class="Rrule" valign="middle">8 (3.7%)</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Treatment supplementation with another antipsychotic because of inadequate efficacy</li> </ul> </td><td align="center" class="Rrule" valign="middle">5 (2.2%)</td><td align="center" class="Rrule" valign="middle">6 (2.8%)</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Need for increase in level of psychiatric services to prevent an imminent psychiatric hospitalization</li> </ul> </td><td align="center" class="Rrule" valign="middle">3 (1.3%)</td><td align="center" class="Rrule" valign="middle">4 (1.8%)</td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Discontinuation of antipsychotic treatment because of inadequate efficacy</li> </ul> </td><td align="center" class="Rrule" valign="middle">1 (0.4%)</td><td align="center" class="Rrule" valign="middle">9 (4.1%)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"> <ul class="Square"> <li>Suicide</li> </ul> </td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="Bold">Arrest and/or Incarceration or Psychiatric Hospitalization Events, regardless of whether they were first events<a class="Sup" href="#footnote-20" name="footnote-reference-20">†</a></span></td><td align="center" class="Rrule">76 (33.6%)</td><td align="center" class="Rrule">98 (45.0%)</td><td align="center" class="Rrule">0.70<br/> [0.52, 0.94]</td> </tr> </tbody> </table></div>

The efficacy of ERZOFRI for the treatment of schizoaffective disorder in adults as monotherapy and as an adjunct to mood stabilizers or antidepressants is based upon an adequate and well-controlled study of another PP1M. The results of the adequate and well-controlled study is presented below.

Maintenance Treatment – Monotherapy and as Adjunct to Mood Stabilizer or Antidepressant (SAff Study 1: SCA-3004)

The efficacy of PP1M in maintaining symptom control in schizoaffective disorder was established in a long-term double-blind, placebo-controlled, flexible-dose randomized-withdrawal study designed to delay relapse in adult subjects who met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders. The population included subjects with schizoaffective bipolar and depressive types. Subjects received PP1M either as monotherapy or as an adjunct to stable doses of antidepressant or mood stabilizers.

This study included a 13-week, open-label, flexible-dose (PP1M 78 mg, 117 mg, 156 mg, or 234 mg) lead-in period which enrolled a total of 667 subjects who had 1) acute exacerbation of psychotic symptoms; 2) score ≥4 on ≥3 PANSS items of delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, tension, and poor impulse control; and 3) prominent mood symptoms ≥16 on the Young Mania Rating Scale (YMRS) and/or the Hamilton Rating Scale for Depression, 21-item version (HAM-D-21). Subjects were 19 to 66 years old (mean 39.5 years) and 53.5% were male. The mean scores at open-label enrollment of PANSS total was 85.8 (range 42 to 128), HAM-D- 21 was 20.4 (range 3 to 43), YMRS was 18.6 (range 0 to 50), and CGI-S-SCA was 4.4 (range 2 to 6).

After the 13-week open-label flexible-dose PP1M treatment, 432 subjects met stabilization criteria (PANSS total score ≤70, YMRS ≤12, and HAM-D-21 ≤12) and continued into the 12-week open-label fixed-dose stabilization period.

A total of 334 subjects who met stabilization criteria for 12 consecutive weeks were randomized (1:1) to continue the same dose of PP1M or to placebo in the 15-month, double- blind, maintenance period. For the 164 subjects who were randomized to PP1M, dose distribution was 78 mg (4.9%), 117 mg (9.8%), 156 mg (47.0%), and 234 mg (38.4%). The primary efficacy variable was time to relapse. Relapse was defined as the first occurrence of one or more of the following: 1) psychiatric hospitalization; 2) intervention employed to avert hospitalization; 3) clinically significant self-injury, suicidal or homicidal ideation or violent behavior; 4) a score of ≥6 (if the score was ≤4 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; 5) on two consecutive assessments within 7 days: ≥ 25% increase (if the score at randomization was > 45) or ≥ 10-point increase (if the score at randomization was ≤ 45) in total PANSS score; a score of ≥ 5 (if the score was ≤ 3 at randomization) of any of the individual PANSS items: delusions, conceptual disorganization, hallucinatory behavior, excitement, suspiciousness/persecution, hostility, uncooperativeness, or poor impulse control; an increase of ≥ 2 points (if the score was 1 [not ill] to 3 [mildly ill] at randomization) or increase of ≥ 1 point (if the score was ≥ 4 [moderately ill or worse] at randomization) in CGI-S-SCA overall score.

There was a statistically significant difference in time to relapse between the treatment groups in favor of PP1M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 5.

Figure 5: Kaplan-Meier Plot of Cumulative Proportion of Subjects with Relapse Over Time (SAff Study 1)

Table 15 summarizes the number of subjects with relapse in the overall population, by subgroup (monotherapy versus adjunctive therapy), and by symptom type at the first occurrence of relapse.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 15: Summary of Relapse Rates (SAff Study 1).</span> </caption> <col align="left" valign="top" width="40%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" class="Botrule" colspan="2">Number (Percent) of Subjects Who Relapsed</th> </tr> <tr> <th align="left"></th><th align="center">Placebo</th><th align="center">Once-a-Month Paliperidone Palmitate Extended-Release Injectable Suspension</th> </tr> <tr class="Last"> <th align="left"></th><th align="center">N=170</th><th align="center">N=164</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-21" name="footnote-21">*</a> </dt> <dd>8 subjects experienced a relapse without psychotic symptoms.</dd> <dt> <a href="#footnote-reference-22" name="footnote-22">†</a> </dt> <dd>16 subjects experienced a relapse without any mood symptoms.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left"><span class="Bold">All Subjects</span></td><td align="center">57 (33.5%)</td><td align="center">25 (15.2%)</td> </tr> <tr> <td align="left">  <span class="Bold">Monotherapy subset</span></td><td align="center">N=73<br/> 24 (32.9%)</td><td align="center">N=78<br/> 9 (11.5%)</td> </tr> <tr class="Botrule"> <td align="left">  <span class="Bold">Adjunct to Antidepressants or Mood Stabilizer subset</span></td><td align="center">N=97<br/> 33 (34.0%)</td><td align="center">N=86<br/> 16 (18.6%)</td> </tr> <tr class="Botrule"> <td align="left"><span class="Bold">Psychotic Symptoms<a class="Sup" href="#footnote-21" name="footnote-reference-21">*</a></span></td><td align="center">53 (31.2%)</td><td align="center">21 (12.8%)</td> </tr> <tr> <td align="left"><span class="Bold">Mood Symptoms<a class="Sup" href="#footnote-22" name="footnote-reference-22">†</a></span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  <span class="Bold">Any Mood Symptoms</span></td><td align="center">48 (28.2%)</td><td align="center">18 (11.0%)</td> </tr> <tr> <td align="left">    <span class="Bold">Manic</span></td><td align="center">16 (9.4%)</td><td align="center">5 (3.0%)</td> </tr> <tr> <td align="left">    <span class="Bold">Depressive</span></td><td align="center">23 (13.5%)</td><td align="center">8 (4.9%)</td> </tr> <tr class="Last"> <td align="left">    <span class="Bold">Mixed</span></td><td align="center">9 (5.3%)</td><td align="center">5 (3.0%)</td> </tr> </tbody> </table></div>

How Supplied

ERZOFRI® is provided as a single-use kit containing a single-dose prefilled syringe with a plunger stopper and tip cap. The kit also contains 2 safety needles (a 1 ½-inch 22 gauge safety needle and a 1-inch 23 gauge safety needle).

ERZOFRI is available as a white to off-white aqueous suspension in the following strengths:

<div class="scrollingtable"><table class="Noautorules" width="65%"> <col align="left" valign="top" width="60%"/> <col align="center" valign="top" width="40%"/> <tbody class="Headless"> <tr> <td align="left">39 mg/0.25 mL paliperidone palmitate kit</td><td align="center">(NDC 72526-105-11)</td> </tr> <tr> <td align="left">78 mg/0.5 mL paliperidone palmitate kit</td><td align="center">(NDC 72526-106-11)</td> </tr> <tr> <td align="left">117 mg/0.75 mL paliperidone palmitate kit</td><td align="center">(NDC 72526-107-11)</td> </tr> <tr> <td align="left">156 mg/mL paliperidone palmitate kit</td><td align="center">(NDC 72526-108-11)</td> </tr> <tr> <td align="left">234 mg/1.5 mL paliperidone palmitate kit</td><td align="center">(NDC 72526-109-11)</td> </tr> <tr> <td align="left">351 mg/2.25 mL paliperidone palmitate kit</td><td align="center">(NDC 72526-110-11)</td> </tr> </tbody> </table></div>

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not mix with any other product or diluent.

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)].

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia that they should have their CBC monitored while taking ERZOFRI [see Warnings and Precautions (5.9)].

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of ERZOFRI. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.10)].

Potential for Cognitive and Motor Impairment

As ERZOFRI has the potential to impair judgement, thinking or motor skills, caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ERZOFRI therapy does not affect them adversely [see Warnings and Precautions (5.11)].

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.14)].

Heat Exposure and Dehydration

Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.15)].

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take any prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drug Interactions (7)].

Alcohol

Advise patients to avoid alcohol during treatment with ERZOFRI [see Drug Interactions (7.1)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with ERZOFRI. Advise patients that ERZOFRI may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to ERZOFRI during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using ERZOFRI to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential that ERZOFRI may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

ERZOFRI® (paliperidone palmitate) extended-release injectable suspension

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Product of China.

{ "type": "p", "children": [], "text": "Product of China." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Shandong Luye Pharmaceutical Co., Ltd. No.15 Chuangye Road Yantai, Shandong Province, China 264003

{ "type": "p", "children": [], "text": "Shandong Luye Pharmaceutical Co., Ltd. No.15 Chuangye Road Yantai, Shandong Province, China 264003" }

Manufactured for: Luye Innomind Pharma Shijiazhuang Co., Ltd. Shijiazhuang, Hebei Province, China 050000

{ "type": "p", "children": [], "text": "Manufactured for: Luye Innomind Pharma Shijiazhuang Co., Ltd. Shijiazhuang, Hebei Province, China 050000" }

For patent information: www.luyeusa.com/patents

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© 2024 Luye Innomind Pharma Shijiazhuang Co., Ltd.

{ "type": "p", "children": [], "text": "© 2024 Luye Innomind Pharma Shijiazhuang Co., Ltd." }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="54%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="7">PATIENT INFORMATION<br/> ERZOFRI<span class="Sup">®</span> (er-ZOH-free)<br/> (paliperidone palmitate)<br/> extended-release injectable suspension</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="6">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="right">Revised: 3/2025</td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold"><a name="important"></a>What is the most important information I should know about ERZOFRI?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">ERZOFRI may cause serious side effects, including:</span> <ul class="Disc"> <li> <span class="Bold">Increased risk of death in elderly people with dementia-related psychosis. ERZOFRI increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia).</span> ERZOFRI is not for the treatment of people with dementia-related psychosis.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What is ERZOFRI?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7">ERZOFRI is a prescription medicine given by injection by a healthcare provider and used to treat:</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li>schizophrenia in adults</li> <li>schizoaffective disorder in adults either alone or with other medicines such as mood stabilizers or antidepressants</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7">It is not known if ERZOFRI is safe and effective in children.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Who should not receive ERZOFRI?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Do not receive ERZOFRI if you</span> are allergic to paliperidone, risperidone, or any of the ingredients in ERZOFRI. See the end of this Patient Information leaflet for a complete list of ingredients in ERZOFRI. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Before receiving ERZOFRI, tell your healthcare provider about all your medical conditions, including if you:</span> <ul class="Disc"> <li>have never taken paliperidone or risperidone before</li> <li>have had Neuroleptic Malignant Syndrome (NMS)</li> <li>have or had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome</li> <li>have or had low levels of potassium or magnesium in your blood</li> <li>have or had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)</li> <li>have or had kidney or liver problems</li> <li>have or had high blood sugar, diabetes or have a family history of diabetes</li> <li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li> <li>have Parkinson's disease or a type of dementia called Lewy Body Dementia</li> <li>have or had problems with dizziness or fainting or are being treated for high blood pressure</li> <li>have or had a low white blood cell count</li> <li>have or had seizures or epilepsy</li> <li>are pregnant or plan to become pregnant. It is not known if ERZOFRI will harm your unborn baby.<ul class="Circle"> <li>If you become pregnant during treatment with ERZOFRI, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li> <li>Babies born to women who are treated with ERZOFRI during their third trimester of pregnancy may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. ERZOFRI can pass into your breast milk.<ul class="Circle"> <li>Talk to your healthcare provider about the best way to feed your baby if you receive ERZOFRI.</li> </ul> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. ERZOFRI and certain other medicines may affect each other causing possible serious side effects or affect the way each other works. Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">How will I receive ERZOFRI?</span> <ul class="Disc"> <li>Follow your ERZOFRI treatment schedule exactly as your healthcare provider tells you to.</li> <li>Your healthcare provider will tell you how much ERZOFRI you will receive and when you will receive it.</li> <li>ERZOFRI is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks 1 time every month. Your first ERZOFRI injection will be in your arm.</li> <li>If you miss a dose of ERZOFRI, call your healthcare provider right away to schedule your next injection.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold"><a name="avoid"></a>What should I avoid while receiving ERZOFRI?</span> <ul class="Disc"> <li> <span class="Bold">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how ERZOFRI affects you. ERZOFRI may affect your ability to make decisions, think clearly, or react quickly.</li> <li>Avoid getting too hot or becoming dehydrated.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="5"> <ul class="Circle"> <li>Do not exercise too much.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun.</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>Do not wear too much clothing or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li>Avoid alcohol during treatment with ERZOFRI.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What are the possible side effects of ERZOFRI?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">ERZOFRI may cause serious side effects, including:</span> <ul class="Disc"> <li>See <span class="Bold">"<a href="#important">What is the most important information I should know about ERZOFRI</a>"</span> </li> <li> <span class="Bold">Cardiovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.</span> </li> <li> <span class="Bold">Neuroleptic Malignant Syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider right away or go to your nearest emergency room right away if you get any of the following signs or symptoms:</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Circle"> <li>high fever</li> <li>stiff muscles</li> <li>confusion</li> </ul> </td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li>sweating</li> <li>changes in your breathing, pulse, heart rate, or blood pressure</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li> <span class="Bold">Problems with your heartbeat.</span> These heart problems can cause death. Call your healthcare provider right away if you get any of these symptoms:<ul class="Circle"> <li>passing out or feeling like you will pass out</li> <li>dizziness</li> <li>feeling as if your heart is pounding or missing beats</li> </ul> </li> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia).</span> ERZOFRI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking ERZOFRI. Tardive dyskinesia may also start after you stop taking ERZOFRI.</li> <li> <span class="Bold">Problems with your metabolism such as:</span> <ul class="Circle"> <li> <span class="Bold">High blood sugar (hyperglycemia) and diabetes.</span> Increases in blood sugar can happen in some people who are treated with ERZOFRI. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes such as being overweight, or a family history of diabetes, your healthcare provider should check your blood sugar before you start treatment and during your treatment with ERZOFRI. <br/> <span class="Bold">Call your healthcare provider if you get any of these symptoms of high blood sugar during treatment with ERZOFRI:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule" colspan="2"></td><td align="left" colspan="2"> <ul class="Square"> <li>feel very thirsty</li> <li>feel very hungry</li> <li>feel sick to your stomach</li> </ul> </td><td align="left" class="Rrule" colspan="3"> <ul class="Square"> <li>need to urinate more than usual</li> <li>feel weak or tired</li> <li>feel confused, or your breath smells fruity</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="6"> <ul class="Circle"> <li> <span class="Bold">Increased fat levels (cholesterol and triglycerides) in your blood.</span> Your healthcare provider may check your cholesterol and triglyceride levels during treatment with ERZOFRI.</li> <li> <span class="Bold">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ERZOFRI.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"> <ul class="Disc"> <li> <span class="Bold">Decreased blood pressure (orthostatic hypotension) and fainting.</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li> <li> <span class="Bold">Falls.</span> ERZOFRI may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li> <li> <span class="Bold">Low white blood cell counts.</span> Your healthcare provider may do blood tests during treatment with ERZOFRI.</li> <li> <span class="Bold">Increased prolactin levels in your blood (hyperprolactinemia).</span> ERZOFRI may cause a rise in the blood levels of a hormone called prolactin that may cause side effects including missed menstrual periods, a reversible reduction in fertility in females who are able to become pregnant, leakage of milk from the breasts, development of breasts in men, or problems with erection.</li> <li> <span class="Bold">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class="Bold">"<a href="#avoid">What should I avoid while receiving ERZOFRI?</a>"</span> </li> <li> <span class="Bold">Seizures (convulsions).</span> </li> <li> <span class="Bold">Difficulty swallowing</span> that can cause food or liquid to get into your lungs.</li> <li> <span class="Bold">Prolonged or painful erection lasting more than 4 hours (priapism).</span> Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours.</li> <li> <span class="Bold">Problems with control of your body temperature so that you feel too warm.</span> See <span class="Bold">"<a href="#avoid">What should I avoid while receiving ERZOFRI?</a>"</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">The most common side effects of ERZOFRI include:</span></td> </tr> <tr> <td align="left" class="Lrule" colspan="3"> <ul class="Disc"> <li>injection site reactions</li> <li>sleepiness or drowsiness</li> <li>dizziness</li> </ul> </td><td align="left" class="Rrule" colspan="4"> <ul class="Disc"> <li>feeling restless or like you need to move</li> <li>abnormal muscle movements including tremor (shaking), shuffling, uncontrolled involuntary movements, and abnormal movements of your eyes</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7">Tell your healthcare provider if you have any side effect that bothers you or does not go away.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7">These are not all of the possible side effects of ERZOFRI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">General information about the safe and effective use of ERZOFRI.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ERZOFRI that is written for health professionals.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">What are the ingredients in ERZOFRI?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Active ingredient</span>: paliperidone palmitate</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="7"><span class="Bold">Inactive ingredients:</span> citric acid monohydrate, dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, polyethylene glycol 4000, polysorbate 20, sodium hydroxide, and water for injection.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="7">Manufactured by: Shandong Luye Pharmaceutical Co., Ltd., No.15 Chuangye Road, Yantai, Shandong Province, China 264003</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="7">Manufactured for: Luye Innomind Pharma Shijiazhuang Co., Ltd., Shijiazhuang, Hebei Province, China 050000<br/> For more information call 1-800-548-9765.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"5%\"/>\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"5%\"/>\n<col align=\"left\" valign=\"top\" width=\"54%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"7\">PATIENT INFORMATION<br/> ERZOFRI<span class=\"Sup\">®</span> (er-ZOH-free)<br/> (paliperidone palmitate)<br/> extended-release injectable suspension</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"6\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"right\">Revised: 3/2025</td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\"><a name=\"important\"></a>What is the most important information I should know about ERZOFRI?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">ERZOFRI may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Increased risk of death in elderly people with dementia-related psychosis. ERZOFRI increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia).</span> ERZOFRI is not for the treatment of people with dementia-related psychosis.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What is ERZOFRI?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">ERZOFRI is a prescription medicine given by injection by a healthcare provider and used to treat:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>schizophrenia in adults</li>\n<li>schizoaffective disorder in adults either alone or with other medicines such as mood stabilizers or antidepressants</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">It is not known if ERZOFRI is safe and effective in children.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Who should not receive ERZOFRI?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Do not receive ERZOFRI if you</span> are allergic to paliperidone, risperidone, or any of the ingredients in ERZOFRI. See the end of this Patient Information leaflet for a complete list of ingredients in ERZOFRI. \t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Before receiving ERZOFRI, tell your healthcare provider about all your medical conditions, including if you:</span>\n<ul class=\"Disc\">\n<li>have never taken paliperidone or risperidone before</li>\n<li>have had Neuroleptic Malignant Syndrome (NMS)</li>\n<li>have or had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome</li>\n<li>have or had low levels of potassium or magnesium in your blood</li>\n<li>have or had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)</li>\n<li>have or had kidney or liver problems</li>\n<li>have or had high blood sugar, diabetes or have a family history of diabetes</li>\n<li>have or had high levels of total cholesterol, LDL cholesterol, or triglycerides, or low levels of HDL cholesterol</li>\n<li>have Parkinson's disease or a type of dementia called Lewy Body Dementia</li>\n<li>have or had problems with dizziness or fainting or are being treated for high blood pressure</li>\n<li>have or had a low white blood cell count</li>\n<li>have or had seizures or epilepsy</li>\n<li>are pregnant or plan to become pregnant. It is not known if ERZOFRI will harm your unborn baby.<ul class=\"Circle\">\n<li>If you become pregnant during treatment with ERZOFRI, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li>\n<li>Babies born to women who are treated with ERZOFRI during their third trimester of pregnancy may experience symptoms such as tremors, irritability, excessive sleepiness, eye twitching, muscle spasms, decreased appetite, difficulty breathing, or abnormal movement of arms and legs. Let your healthcare provider know if these symptoms occur.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. ERZOFRI can pass into your breast milk.<ul class=\"Circle\">\n<li>Talk to your healthcare provider about the best way to feed your baby if you receive ERZOFRI.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. ERZOFRI and certain other medicines may affect each other causing possible serious side effects or affect the way each other works. Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">How will I receive ERZOFRI?</span>\n<ul class=\"Disc\">\n<li>Follow your ERZOFRI treatment schedule exactly as your healthcare provider tells you to.</li>\n<li>Your healthcare provider will tell you how much ERZOFRI you will receive and when you will receive it.</li>\n<li>ERZOFRI is given as an injection by your healthcare provider into the muscle (intramuscularly) of your arm or your buttocks 1 time every month. Your first ERZOFRI injection will be in your arm.</li>\n<li>If you miss a dose of ERZOFRI, call your healthcare provider right away to schedule your next injection.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\"><a name=\"avoid\"></a>What should I avoid while receiving ERZOFRI?</span>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> drive, operate heavy machinery, or do other dangerous activities until you know how ERZOFRI affects you. ERZOFRI may affect your ability to make decisions, think clearly, or react quickly.</li>\n<li>Avoid getting too hot or becoming dehydrated.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"5\">\n<ul class=\"Circle\">\n<li>Do not exercise too much.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>Do not wear too much clothing or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>Avoid alcohol during treatment with ERZOFRI.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What are the possible side effects of ERZOFRI?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">ERZOFRI may cause serious side effects, including:</span>\n<ul class=\"Disc\">\n<li>See <span class=\"Bold\">\"<a href=\"#important\">What is the most important information I should know about ERZOFRI</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Cardiovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.</span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic Malignant Syndrome (NMS), a serious condition that can lead to death.</span> Call your healthcare provider right away or go to your nearest emergency room right away if you get any of the following signs or symptoms:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>high fever</li>\n<li>stiff muscles</li>\n<li>confusion</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>sweating</li>\n<li>changes in your breathing, pulse, heart rate, or blood pressure</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Problems with your heartbeat.</span> These heart problems can cause death. Call your healthcare provider right away if you get any of these symptoms:<ul class=\"Circle\">\n<li>passing out or feeling like you will pass out</li>\n<li>dizziness</li>\n<li>feeling as if your heart is pounding or missing beats</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia).</span> ERZOFRI may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking ERZOFRI. Tardive dyskinesia may also start after you stop taking ERZOFRI.</li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">High blood sugar (hyperglycemia) and diabetes.</span> Increases in blood sugar can happen in some people who are treated with ERZOFRI. Extremely high blood sugar can lead to coma or death. If you have diabetes or risk factors for diabetes such as being overweight, or a family history of diabetes, your healthcare provider should check your blood sugar before you start treatment and during your treatment with ERZOFRI. <br/>\n<span class=\"Bold\">Call your healthcare provider if you get any of these symptoms of high blood sugar during treatment with ERZOFRI:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"2\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Square\">\n<li>feel very thirsty</li>\n<li>feel very hungry</li>\n<li>feel sick to your stomach</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"3\">\n<ul class=\"Square\">\n<li>need to urinate more than usual</li>\n<li>feel weak or tired</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"6\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Increased fat levels (cholesterol and triglycerides) in your blood.</span> Your healthcare provider may check your cholesterol and triglyceride levels during treatment with ERZOFRI.</li>\n<li>\n<span class=\"Bold\">Weight gain.</span> You and your healthcare provider should check your weight regularly during treatment with ERZOFRI.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Decreased blood pressure (orthostatic hypotension) and fainting.</span> You may feel lightheaded or faint when you rise too quickly from a sitting or lying position.</li>\n<li>\n<span class=\"Bold\">Falls.</span> ERZOFRI may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.</li>\n<li>\n<span class=\"Bold\">Low white blood cell counts.</span> Your healthcare provider may do blood tests during treatment with ERZOFRI.</li>\n<li>\n<span class=\"Bold\">Increased prolactin levels in your blood (hyperprolactinemia).</span> ERZOFRI may cause a rise in the blood levels of a hormone called prolactin that may cause side effects including missed menstrual periods, a reversible reduction in fertility in females who are able to become pregnant, leakage of milk from the breasts, development of breasts in men, or problems with erection.</li>\n<li>\n<span class=\"Bold\">Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities.</span> See <span class=\"Bold\">\"<a href=\"#avoid\">What should I avoid while receiving ERZOFRI?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Seizures (convulsions).</span>\n</li>\n<li>\n<span class=\"Bold\">Difficulty swallowing</span> that can cause food or liquid to get into your lungs.</li>\n<li>\n<span class=\"Bold\">Prolonged or painful erection lasting more than 4 hours (priapism).</span> Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours.</li>\n<li>\n<span class=\"Bold\">Problems with control of your body temperature so that you feel too warm.</span> See <span class=\"Bold\">\"<a href=\"#avoid\">What should I avoid while receiving ERZOFRI?</a>\"</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">The most common side effects of ERZOFRI include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" colspan=\"3\">\n<ul class=\"Disc\">\n<li>injection site reactions</li>\n<li>sleepiness or drowsiness</li>\n<li>dizziness</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Disc\">\n<li>feeling restless or like you need to move</li>\n<li>abnormal muscle movements including tremor (shaking), shuffling, uncontrolled involuntary movements, and abnormal movements of your eyes</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Tell your healthcare provider if you have any side effect that bothers you or does not go away.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">These are not all of the possible side effects of ERZOFRI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">General information about the safe and effective use of ERZOFRI.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about ERZOFRI that is written for health professionals.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">What are the ingredients in ERZOFRI?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Active ingredient</span>: paliperidone palmitate</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\"><span class=\"Bold\">Inactive ingredients:</span> citric acid monohydrate, dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, polyethylene glycol 4000, polysorbate 20, sodium hydroxide, and water for injection.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Manufactured by: Shandong Luye Pharmaceutical Co., Ltd., No.15 Chuangye Road, Yantai, Shandong Province, China 264003</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"7\">Manufactured for: Luye Innomind Pharma Shijiazhuang Co., Ltd., Shijiazhuang, Hebei Province, China 050000<br/> For more information call 1-800-548-9765.</td>\n</tr>\n</tbody>\n</table></div>" }

NDC 72526-105-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-105-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

39 mg/0.25 mL

{ "type": "p", "children": [], "text": "39 mg/0.25 mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

NDC 72526-106-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-106-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

78 mg/0.5 mL

{ "type": "p", "children": [], "text": "78 mg/0.5 mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

NDC 72526-107-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-107-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

117 mg/0.75 mL

{ "type": "p", "children": [], "text": "117 mg/0.75 mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

NDC 72526-108-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-108-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

156 mg/mL

{ "type": "p", "children": [], "text": "156 mg/mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

NDC 72526-109-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-109-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

234 mg/1.5 mL

{ "type": "p", "children": [], "text": "234 mg/1.5 mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

NDC 72526-110-11 Rx Only

{ "type": "p", "children": [], "text": "NDC 72526-110-11 Rx Only" }

Erzofri® (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "Erzofri®\n (paliperidone palmitate) extended-release injectable suspension" }

351 mg/2.25 mL

{ "type": "p", "children": [], "text": "351 mg/2.25 mL" }

For Single Use Only. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "For Single Use Only. Use entire contents of syringe." }

FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional.

{ "type": "p", "children": [], "text": "FOR INTRAMUSCULAR INJECTION ONLY. Shake before using. Each injection must be administered by a healthcare professional." }

INVEGA HAFYERA, an every-six-month injection, is indicated for the treatment of schizophrenia in adults after they have been adequately treated with:

{ "type": "p", "children": [], "text": "INVEGA HAFYERA, an every-six-month injection, is indicated for the treatment of schizophrenia in adults after they have been adequately treated with:" }

{ "type": "ul", "children": [ "A once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA) for at least four months, or", "An every-three-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA TRINZA) for at least one three-month cycle." ], "text": "" }

Switching to INVEGA HAFYERA from a PP1M Product

The recommended initial INVEGA HAFYERA dose is based on the previous PP1M dose (see Table 1). Initiate INVEGA HAFYERA when the next PP1M dose is scheduled. INVEGA HAFYERA may be administered up to 1 week before or 1 week after the next scheduled PP1M dose. When switching from PP1M to INVEGA HAFYERA, the two injection cycles immediately preceding the switch should be the same dosage strength before starting INVEGA HAFYERA.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP1M <a class="Sup" href="#footnote-3" name="footnote-reference-3">*</a>Product </span> </caption> <col align="center" valign="top" width="45%"/> <col align="center" valign="top" width="55%"/> <thead> <tr class="Botrule First Last"> <th align="center" class="Rrule">Last Dose of PP1M <a class="Sup" href="#footnote-4" name="footnote-reference-4">†</a></th><th align="center">Initial Dose of INVEGA HAFYERA</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-3" name="footnote-3">*</a> </dt> <dd>PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">†</a> </dt> <dd>There are no equivalent doses of INVEGA HAFYERA for 39 mg, 78 mg, or 117 mg doses of a PP1M product, which were not studied [see Clinical Studies (14)] . </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Rrule">156 mg</td><td align="center">1,092 mg</td> </tr> <tr class="Last"> <td align="center" class="Rrule">234 mg</td><td align="center">1,560 mg</td> </tr> </tbody> </table></div>

Switching to INVEGA HAFYERA from a PP3M Product

The recommended initial INVEGA HAFYERA dose is based on the previous PP3M dose (see Table 2). Initiate INVEGA HAFYERA when the next PP3M dose is scheduled. INVEGA HAFYERA may be administered up to 2 weeks before or 2 weeks after the next scheduled PP3M dose.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2. Initial INVEGA HAFYERA Dose for Adult Patients Switching from a PP3M <a class="Sup" href="#footnote-5" name="footnote-reference-5">*</a>Product </span> </caption> <col align="center" valign="top" width="45%"/> <col align="center" valign="top" width="55%"/> <thead> <tr class="Botrule First Last"> <th align="center" class="Rrule">Last Dose of PP3M <a class="Sup" href="#footnote-6" name="footnote-reference-6">†</a></th><th align="center">Initial Dose of INVEGA HAFYERA</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-5" name="footnote-5">*</a> </dt> <dd>PP3M: Every-three-month paliperidone palmitate extended-release injectable suspension</dd> <dt> <a href="#footnote-reference-6" name="footnote-6">†</a> </dt> <dd>There are no equivalent doses of INVEGA HAFYERA for the 273 mg or 410 mg doses of a PP3M product, which were not studied [see Clinical Studies (14)] . </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Rrule">546 mg</td><td align="center">1,092 mg</td> </tr> <tr class="Last"> <td align="center" class="Rrule">819 mg</td><td align="center">1,560 mg</td> </tr> </tbody> </table></div>

Dosing Interval and Dosage Adjustments of INVEGA HAFYERA

Following the initial dose, administer INVEGA HAFYERA once every 6 months.

If needed, dosage adjustment can be made every 6 months between the dose of 1,092 mg to 1,560 mg based on individual response and tolerability. Because of the potential longer duration of INVEGA HAFYERA, the patient's response to an adjusted dose may not be apparent for several months [see Clinical Pharmacology (12.3)] .

Dosing Window

To avoid a missed dose, patients may be given the injection up to 2 weeks before or 3 weeks after the scheduled 6-month dose.

Missed Dose

If a dose of INVEGA HAFYERA is missed, re-initiate with a PP1M product using the re-initiation regimens described in Tables 3 and 4.

More than 6 Months and 3 Weeks, up to but Less than 8 Months Since Last Dose

If more than 6 months and 3 weeks but less than 8 months have elapsed since the last dose of INVEGA HAFYERA, do not administer the next dose of INVEGA HAFYERA. Instead, use the re-initiation regimen shown in Table 3:

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3. Re-initiation Regimen for Missed Dose (more than 6 months and 3 weeks, but less than 8 months since last dose)</span> </caption> <col align="center" valign="bottom" width="25%"/> <col align="center" valign="bottom" width="35%"/> <col align="center" valign="bottom" width="40%"/> <thead> <tr class="Botrule First"> <th align="center" class="Rrule">Last Dose of INVEGA HAFYERA</th><th align="center" class="Rrule">Administer PP1M Product <a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a>into deltoid muscle </th><th align="center">Administer INVEGA HAFYERA into gluteal muscle</th> </tr> <tr class="Last"> <th align="center" class="Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center">1 month after Day 1</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Rrule">1,092 mg</td><td align="center" class="Rrule">156 mg</td><td align="center">1,092 mg</td> </tr> <tr class="Last"> <td align="center" class="Rrule">1,560 mg</td><td align="center" class="Rrule">234 mg</td><td align="center">1,560 mg</td> </tr> </tbody> </table></div>

8 Months Up to and including 11 Months Since Last Dose

If 8 months but up to and including 11 months have elapsed since the last dose of INVEGA HAFYERA, do not administer the next dose of INVEGA HAFYERA. Instead, use the re-initiation regimen shown in Table 4:

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4. Re-initiation Regimen for Missed Dose (8 months up to and including 11 months since last dose)</span> </caption> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="15%"/> <col align="center" valign="bottom" width="40%"/> <thead> <tr class="Botrule First"> <th align="center" class="Rrule">Last dose of INVEGA HAFYERA</th><th align="center" class="Rrule" colspan="2">Administer PP1M Product <a class="Sup" href="#footnote-8" name="footnote-reference-8">*</a>into deltoid muscle </th><th align="center">Administer INVEGA HAFYERA into gluteal muscle</th> </tr> <tr class="Last"> <th align="center" class="Rrule"></th><th align="center" class="Rrule">Day 1</th><th align="center" class="Rrule">Day 8</th><th align="center">1 month after Day 8</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-8" name="footnote-8">*</a> </dt> <dd>PP1M: Once-a-month paliperidone palmitate extended-release injectable suspension</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Rrule">1,092 mg</td><td align="center" class="Rrule">156 mg</td><td align="center" class="Rrule">156 mg</td><td align="center">1,092 mg</td> </tr> <tr class="Last"> <td align="center" class="Rrule">1,560 mg</td><td align="center" class="Rrule">156 mg</td><td align="center" class="Rrule">156 mg</td><td align="center">1,560 mg</td> </tr> </tbody> </table></div>

More than 11 Months Since Last Dose

If more than 11 months have elapsed since the last dose of INVEGA HAFYERA, re-initiate treatment with a PP1M product as described in the prescribing information for that product. INVEGA HAFYERA can then be resumed after the patient has been adequately treated with a PP1M product for at least 4 months.

INVEGA HAFYERA has not been systematically studied in patients with renal impairment [see Clinical Pharmacology (12.3)] . For patients with mild renal impairment (creatinine clearance ≥50 mL/min to < 80 mL/min [Cockcroft-Gault Formula]), adjust dosage and stabilize the patient using PP1M before transitioning from PP1M to INVEGA HAFYERA, or from PP1M to PP3M before transitioning to INVEGA HAFYERA (see Table 1) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)]. Refer to the Prescribing Information of PP1M or PP3M product for the recommended PP1M or PP3M dosage in patients with mild renal impairment.

INVEGA HAFYERA is not recommended in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) [see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)] .

Incomplete Administration

<div class="scrollingtable"><table class="Noautorules" width="90%"> <colgroup> <col align="left" valign="top" width="40%"/> <col align="left" valign="top" width="60%"/> </colgroup> <tbody class="Headless"> <tr> <td align="center"> <p class="First"> <span class="Bold">Administer every 6 months</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-01.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td><td align="left"><span class="Bold">INVEGA HAFYERA (paliperidone palmitate) Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds. <br/> For Gluteal Intramuscular injection only. </span></td> </tr> <tr> <td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-02.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"></td> </tr> <tr> <td align="center"><span class="Bold">Preparation</span></td><td align="left">INVEGA HAFYERA requires <span class="Bold">longer and faster shaking </span>than once-a-month paliperidone palmitate extended-release injectable suspension (e.g., INVEGA SUSTENNA). <br/> INVEGA HAFYERA must be administered by a healthcare professional as a single injection. Do not divide dose into multiple injections. <br/> INVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel. </td> </tr> <tr> <td align="left"><span class="Bold">Dosing</span></td><td align="left">Administer INVEGA HAFYERA <span class="Bold">once every 6 months</span>. </td> </tr> <tr> <td align="left"><span class="Bold">Thin Wall Safety Needle</span></td><td align="left">Thin wall safety needle is designed to be used with INVEGA HAFYERA. Therefore, it is important to <span class="Bold">only use the needle provided in the INVEGA HAFYERA suspension kit.</span></td> </tr> <tr> <td align="left"><span class="Bold">Dose pack contents Prefilled Syringe</span></td><td align="left"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=invega-03.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td> </tr> <tr> <td align="center"> <p class="First"> <span class="Bold">Thin Wall Safety Needle</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-04.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><br/> <span class="Bold">20G × 1½" <br/> Only use the needle included in this kit </span> </p> </td><td align="left"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=invega-05.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td> </tr> <tr> <td align="left" colspan="2"><span class="Bold">1. Prepare for the injection: this highly concentrated product requires specific steps to resuspend</span></td> </tr> <tr> <td align="left"><span class="Bold">Hold syringe with the tip cap pointing up</span></td><td align="center"> <p class="First">Syringe tip cap pointing up <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-06.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td> </tr> <tr> <td align="left"> <p class="First"> <span class="Bold">Shake syringe VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds</span> <br/> To ensure complete resuspension shake syringe with: </p> <ul> <li> <span class="Bold">Short, VERY FAST up and down motion</span> </li> <li> <span class="Bold">Loose wrist</span> </li> </ul> <p> <img alt="Image" src="/dailymed/image.cfm?name=invega-07.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td><td align="center" rowspan="2"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=invega-08.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td> </tr> <tr> <td align="center">Proceed to the next step immediately after shaking.</td> </tr> <tr> <td align="center" colspan="2"><span class="Bold">Check suspension for solid product</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-09.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="center"><span class="Bold">Mixed well</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-10.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="center"> <p class="First"> <span class="Bold">Not mixed well</span> <br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-11.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><br/> <img alt="Image" src="/dailymed/image.cfm?name=invega-12.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><span class="Bold">STOP</span> </p> </td> </tr> <tr> <td align="left"> <ul> <li>Uniform, thick and milky white</li> <li>It is normal to see air bubbles</li> </ul> </td><td align="left"> <ul> <li>Solid product on sides and top of syringe</li> <li>Uneven mix</li> <li>Thin liquid</li> </ul> <span class="Bold">Product may clog.</span></td> </tr> <tr> <td align="left"></td><td align="center">Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds.</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="90%"> <colgroup> <col align="left" valign="top" width="33%"/> <col align="left" valign="top" width="17%"/> <col align="left" valign="top" width="17%"/> <col align="left" valign="top" width="33%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Open needle pouch</span></td><td align="center" colspan="2">Peel off the pouch cover. <br/> Place pouch with the needle inside on a clean surface. </td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-13.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left">Remove syringe tip cap and attach needle</td><td align="left">Hold the syringe with the tip cap pointing up. Twist and pull off the cap. <br/> Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration. </td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-14.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-15.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table class="Noautorules" width="90%"> <colgroup> <col align="left" valign="top" width="60%"/> <col align="center" valign="top" width="40%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Pull back plunger</span> <br/> Hold the syringe upright. <br/> <span class="Bold">Gently pull back the plunger to clear the syringe tip of any solid product. </span>This will make pressing the plunger easier during the injection. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-16.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left"><span class="Bold">Remove air bubbles</span> <br/> Press the plunger carefully until a drop of liquid comes out of the needle tip. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-17.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left" colspan="2"><span class="Bold">2. Slowly inject entire content and confirm</span></td> </tr> <tr> <td align="left"><span class="Bold">Select and clean a gluteal injection site</span> <br/> Wipe the gluteal site with an alcohol swab and allow it to dry. <br/> <span class="Bold">Do not touch</span>, fan or blow on the injection site after you have cleaned it. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-18.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left" valign="middle"><span class="Bold">Remove needle sheath</span> <br/> Pull the needle sheath away from the needle in a straight motion. <br/> <span class="Bold">Do not </span>twist the sheath, as this may loosen the needle from the syringe. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-19.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left"><span class="Bold">Slowly inject and confirm</span> <br/> Use slow, firm, consistent pressure to press the plunger <span class="Bold">completely</span>. This should take approximately 30 seconds. <br/> <span class="Bold">Continue to press the plunger if you feel resistance. This is normal.</span></td><td align="center"></td> </tr> <tr> <td align="center"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=invega-20.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></p> </td><td align="center" rowspan="2"><img alt="Image" src="/dailymed/image.cfm?name=invega-21.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left">Remove needle from the muscle.</td> </tr> <tr> <td align="left"><span class="Bold">3. After the injection</span></td><td align="center"></td> </tr> <tr> <td align="left"><span class="Bold">Secure needle</span> <br/> After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device. <br/> The needle is secure when you hear a "click" sound. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-22.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> <tr> <td align="left"><span class="Bold">Dispose of properly and check injection site</span> <br/> Dispose of the syringe in an approved sharps container. <br/> There may be a small amount of blood or liquid at the injection site. Hold pressure over the skin with a cotton ball or gauze pad until any bleeding stops. <br/> Do not rub the injection site. <br/> If needed, cover injection site with a bandage. </td><td align="center"><img alt="Image" src="/dailymed/image.cfm?name=invega-23.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td> </tr> </tbody> </table></div>

INVEGA HAFYERA is a white to off-white aqueous extended-release injectable suspension for gluteal intramuscular injection in dose strengths of 1,092 mg/3.5 mL and 1,560 mg/5 mL paliperidone palmitate in single-dose prefilled syringes.

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INVEGA HAFYERA is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA HAFYERA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone.

{ "type": "p", "children": [], "text": "INVEGA HAFYERA is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA HAFYERA formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA HAFYERA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.2)] .

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. No studies have been conducted with oral paliperidone, the 1-month paliperidone palmitate extended-release injectable suspension, the 3-month paliperidone extended-release injectable suspension or INVEGA HAFYERA in elderly patients with dementia. These medications are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)] .

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, discontinue INVEGA HAFYERA and provide symptomatic treatment and monitoring.

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter Thorough QT study with oral paliperidone in adult patients, and in four fixed-dose efficacy studies and one maintenance study of the 1-month paliperidone palmitate injectable product.

In the Thorough QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD (QT interval corrected for heart rate using the population specified linear derived method) of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate release (C max ss=113 ng/mL) was approximately 1.3-fold the exposure with the maximum recommended 1,560 mg dose of INVEGA HAFYERA administered in the gluteal muscle (mean C max md=89.3 ng/mL). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which C max ss=35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose.

In the four fixed-dose efficacy studies of the 1-month paliperidone palmitate injectable product, no subject had a change in QTcLD exceeding 60 msec and no subject had a QTcLD value of >500 msec at any time point. In the maintenance study, no subject had a QTcLD change >60 msec, and one subject had a QTcLD value of 507 msec (Bazett's QT corrected interval [QTcB] value of 483 msec); this latter subject also had a heart rate of 45 beats per minute.

In the INVEGA HAFYERA randomized double-blind active controlled study in subjects with schizophrenia, during the double-blind Phase, QTcLD exceeding 60 msec was observed in 2 subjects (0.4%) in the INVEGA HAFYERA treatment group and in 2 subjects (0.9%) in the PP3M treatment group. No subject had a QTcLD value of >480 msec at any point in the study.

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus mask the underlying process. The effect of symptomatic suppression on the long-term course of the syndrome is unknown.

Given these considerations, INVEGA HAFYERA should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA HAFYERA, drug discontinuation should be considered. Consideration should be given to the long-acting nature of INVEGA HAFYERA. However, some patients may require treatment with INVEGA HAFYERA despite the presence of the syndrome.

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials. Hyperglycemia and diabetes have been reported in trial subjects treated with INVEGA HAFYERA. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Data from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia are presented in Table 5.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 5. Change in Fasting Glucose from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="Botrule First Last"> <th align="left">Total no. of patients <a class="Sup" href="#footnote-9" name="footnote-reference-9">*</a></th><th align="center">PP3M <a class="Sup" href="#footnote-10" name="footnote-reference-10">†</a> <br/> N=195 </th><th align="center">INVEGA HAFYERA <br/> N=423 </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-9" name="footnote-9">*</a> </dt> <dd>The number of subjects with paired fasting data (baseline and any post baseline assessment). Using the conversion factor (1 mg/dL=0.05551 mmol/L) the ADA specified limits are as follows: Normal: &lt;100 mg/dL (&lt;5.551 mmol/L) Impaired: ≥100 mg/dL (≥5.551 mmol/L) to &lt;126 mg/dL (&lt;6.994 mmol/L) High: ≥126 mg/dL (≥6.994 mmol/L) 126 mg/dL=6.994 mmol/L; 140 mg/dL=7.771 mmol/L; 200 mg/dL=11.102 mmol/L; 300 mg/dL=16.653 mmol/L </dd> <dt> <a href="#footnote-reference-10" name="footnote-10">†</a> </dt> <dd>PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Normal to high</td><td align="center">3%</td><td align="center">4%</td> </tr> <tr> <td align="left">Impaired glucose tolerance to high</td><td align="center">4%</td><td align="center">5%</td> </tr> <tr> <td align="left">Normal/impaired glucose tolerance to high</td><td align="center">7%</td><td align="center">9%</td> </tr> <tr> <td align="left">&lt;126 mg/dL to &gt;=140 mg/dL</td><td align="center">4%</td><td align="center">5%</td> </tr> <tr> <td align="left">&lt;126 mg/dL to &gt;=200 mg/dL</td><td align="center">0</td><td align="center">1%</td> </tr> <tr class="Last"> <td align="left">&lt;126 mg/dL to &gt;=300 mg/dL</td><td align="center">0</td><td align="center">&lt;1%</td> </tr> </tbody> </table></div>

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Shifts in lipid parameters from the randomized double-blind active controlled study with INVEGA HAFYERA in patients with schizophrenia are presented in Table 6.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 6. Shifts in Fasting Lipids in the Double-Blind Phase from the randomized active controlled study with INVEGA HAFYERA in patients with schizophrenia</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="First Last"> <th align="left"></th><th align="center">PP3M <a class="Sup" href="#footnote-11" name="footnote-reference-11">*</a> <br/> N=194 </th><th align="center">INVEGA HAFYERA <br/> N=423 </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">For each fasting parameter, subjects with both Baseline (DB) record and any post baseline (DB) record during Double-Blind Phase are included in the denominator.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-11" name="footnote-11">*</a> </dt> <dd>PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension.</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Fasting Cholesterol (mg/dL)</td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  &lt;200 mg/dL to &gt;=240 mg/dL</td><td align="center">2 (1%)</td><td align="center">3 (0.7%)</td> </tr> <tr> <td align="left">Fasting HDL Cholesterol (mg/dL)</td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  &gt;=40 mg/dL to &lt;40 mg/dL</td><td align="center">28 (14%)</td><td align="center">55 (13%)</td> </tr> <tr> <td align="left">Fasting LDL Cholesterol (mg/dL)</td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">  &lt;100 mg/dL to &gt;=160 mg/dL</td><td align="center">1 (0.5%)</td><td align="center">2 (0.5%)</td> </tr> <tr> <td align="left">Fasting Triglycerides (mg/dL)</td><td align="center"></td><td align="center"></td> </tr> <tr class="Last"> <td align="left">  &lt;150 mg/dL to &gt;=200 mg/dL</td><td align="center">22 (11%)</td><td align="center">22 (5%)</td> </tr> </tbody> </table></div>

Change in Body Weight

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In the randomized active controlled clinical study of INVEGA HAFYERA, the overall mean weight change during the double-blind Phase was similar to PP3M.

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-adrenergic blocking activity.

Use INVEGA HAFYERA with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including paliperidone palmitate, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trial and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including INVEGA HAFYERA. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA HAFYERA at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue INVEGA HAFYERA in patients with severe neutropenia (absolute neutrophil count <1000/mm 3) and follow their WBC until recovery.

Like other drugs that antagonize dopamine D 2receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)] . Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Median prolactin levels remained relatively stable throughout the open-label and double-blind phases in male subjects, whereas in female subjects, median prolactin levels increased. During the double-blind phase, median prolactin levels continued to increase after dosing in both the INVEGA HAFYERA and PP3M groups, returning to baseline level at Month 6 and at Month 12 (end of double-blind phase).

During the double-blind phase, prolactin levels relative to reference range (>13.13 ng/mL in males and >26.72 ng/mL in females) from maintenance baseline were noted in a similar percentage of subjects in the INVEGA HAFYERA and PP3M groups in both males (35% vs 36%) and females (29% vs. 30%). In the INVEGA HAFYERA group, 14 females (2.9%) and 4 males (0.8%) experienced potentially prolactin-related adverse reactions, while 6 females (2.7%) and 1 male (0.4%) in the PP3M experienced potentially prolactin-related adverse reactions.

Somnolence and sedation were reported as adverse reactions in patients treated with INVEGA HAFYERA [see Adverse Reactions (6.1)] . Antipsychotics, including INVEGA HAFYERA, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

In the 6-month paliperidone palmitate extended-release injectable suspension double-blind active controlled trial there were no reports of seizures or convulsions, nor were any reports made in the long-term maintenance trial of PP3M. In the pivotal clinical studies with PP1M which included four fixed-dose, double-blind, placebo-controlled studies in subjects with schizophrenia, <1% (1/1293) of subjects treated with the PP1M experienced an adverse event of convulsion compared with <1% (1/510) of placebo-treated subjects who experienced an adverse event of grand mal convulsion.

Like other antipsychotic drugs, INVEGA HAFYERA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. INVEGA HAFYERA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

A case (0.2%) of priapism was reported in the clinical trial with INVEGA HAFYERA. Priapism has been reported with oral paliperidone during postmarketing surveillance. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Severe priapism may require surgical intervention.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA HAFYERA to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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

Patient Exposure

The data described in this section is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 (86.97) days in the INVEGA HAFYERA group and 336.4 (80.89) days in the PP3M group during the double-blind phase:

Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.

Discontinuation of Treatment Due to Adverse Reactions: In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate extended-release injectable suspension group discontinued due to adverse reactions.

Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients: Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 7. Incidences of Adverse Reactions 2% or More of INVEGA HAFYERA-Treated Patients for the Double-Blind Phase of the Randomized Double-blind Active Controlled Trial in Patients with Schizophrenia</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Double Blind</th> </tr> <tr class="Botrule Last"> <th align="left">System Organ Class</th><th align="center">PP3M <a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a> <br/> (N=224) <br/> % </th><th align="center">INVEGA HAFYERA <br/> (N=478) <br/> % </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>The following terms were combined: Diarrhea includes: Diarrhea, Diarrhea infectious. Injection site reaction: includes Injection site reaction, Injection site discomfort, Injection site erythema, Injection site hemorrhage, Injection site induration, Injection site nodule, Injection site oedema, Injection site pain, Injection site swelling. Weight increased includes: Weight increased, Body mass index increased, Obesity, Waist circumference increased. Upper respiratory tract infection includes: Upper respiratory tract infection, Nasopharyngitis, Pharyngitis, Rhinitis, Viral pharyngitis, Viral upper respiratory tract infection. Back pain includes: Back pain, Neck pain, Spinal pain. Musculoskeletal pain includes: Musculoskeletal pain, Musculoskeletal chest pain, Myalgia, Pain in extremity. Akathisia includes: Akathisia, Restless legs syndrome, Restlessness. Extrapyramidal symptoms includes: blepharospasms, bradykinesia, drooling, dyskinesia, dystonia, hypokinesia, musculoskeletal stiffness, muscle rigidity, muscle spasms, oculogyric crisis, Parkinsonism, Parkinsonism rest tremor, reduced facial expression, tardive dyskinesia. Insomnia includes: Insomnia, Initial insomnia, Middle insomnia. Psychosis includes: acute psychosis, delusion, delusion of reference, hallucination (auditory), psychotic disorder, psychotic symptom, and schizophrenia. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" colspan="3">Adverse Reaction</td> </tr> <tr> <td align="left"><span class="Bold">Gastrointestinal disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Diarrhea <a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a></td><td align="center">1</td><td align="center">2</td> </tr> <tr> <td align="left"><span class="Bold">General disorders and administration site conditions</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Injection site reaction <a class="Sup" href="#footnote-13">†</a></td><td align="center">5</td><td align="center">11</td> </tr> <tr> <td align="left"><span class="Bold">Infections and infestations</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Upper respiratory tract infection <a class="Sup" href="#footnote-13">†</a></td><td align="center">13</td><td align="center">12</td> </tr> <tr> <td align="left">Urinary tract infection</td><td align="center">1</td><td align="center">3</td> </tr> <tr> <td align="left"><span class="Bold">Metabolism and nutrition disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Weight increased</td><td align="center">8</td><td align="center">9</td> </tr> <tr> <td align="left"><span class="Bold">Musculoskeletal and connective tissue disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Back pain <a class="Sup" href="#footnote-13">†</a></td><td align="center">1</td><td align="center">3</td> </tr> <tr> <td align="left">Musculoskeletal pain <a class="Sup" href="#footnote-13">†</a></td><td align="center">1</td><td align="center">3</td> </tr> <tr> <td align="left"><span class="Bold">Nervous system disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Akathisia <a class="Sup" href="#footnote-13">†</a></td><td align="center">4</td><td align="center">4</td> </tr> <tr> <td align="left">Headache</td><td align="center">5</td><td align="center">7</td> </tr> <tr> <td align="left">Extrapyramidal symptoms <a class="Sup" href="#footnote-13">†</a></td><td align="center">5</td><td align="center">7</td> </tr> <tr> <td align="left"><span class="Bold">Psychiatric disorders</span></td><td align="center"></td><td align="center"></td> </tr> <tr> <td align="left">Psychosis <a class="Sup" href="#footnote-13">†</a></td><td align="center">3</td><td align="center">3</td> </tr> <tr> <td align="left">Anxiety</td><td align="center">0</td><td align="center">3</td> </tr> <tr class="Last"> <td align="left">Insomnia <a class="Sup" href="#footnote-13">†</a></td><td align="center">2</td><td align="center">3</td> </tr> </tbody> </table></div>

Demographic Differences

An examination of population subgroups in the INVEGA HAFYERA trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone.

Extrapyramidal Symptoms (EPS)

Data from the randomized double-blind active controlled study provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus Rating Scale Global Score which broadly evaluates parkinsonism, (2) the Barnes Akathisia Rating Scale Global Clinical Rating Score which evaluates akathisia, (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and (4) use of anticholinergic medications to treat EPS (Table 8) and (5) incidence of spontaneous reports of EPS (Table 9).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 8. Extrapyramidal Symptoms (EPS) Assessed by Rating Scales Incidence and Use of Anticholinergic Medication During the Double-blind Phase</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="Botrule First Last"> <th align="left"></th><th align="center">PP3M <a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a> <br/> (N=224) <br/> % </th><th align="center">INVEGA HAFYERA <br/> (N=478) <br/> % </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="3" valign="top">Note: Percentages are calculated based on number of subjects in the DB Safety analysis set per treatment group.</td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>PP3M - Every-three-month paliperidone palmitate extended-release injectable suspension</dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>Use of Anti-EPS Medication During the Double-blind Phase</dd> <dt> <a href="#footnote-reference-16" name="footnote-16">‡</a> </dt> <dd>Percent of subjects with Simpson-Angus Scale Global Score &gt;0.3(Global Score defined as total sum of items score divided by the number of items).</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">§</a> </dt> <dd>Percent of subjects with Barnes Akathisia Rating Scale Global Clinical Rating Score ≥2</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">¶</a> </dt> <dd>Percent of subjects with a score ≥3 on any of the first seven items or a score ≥2 on two or more of any of the first seven items of the Abnormal Involuntary Movement Scale</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left">Use of Anticholinergic Medication <a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a></td><td align="center">13</td><td align="center">15</td> </tr> <tr> <td align="left">Parkinsonism <a class="Sup" href="#footnote-16" name="footnote-reference-16">‡</a></td><td align="center">6</td><td align="center">7</td> </tr> <tr> <td align="left">Akathisia <a class="Sup" href="#footnote-17" name="footnote-reference-17">§</a></td><td align="center">3</td><td align="center">3</td> </tr> <tr class="Last"> <td align="left">Dyskinesia <a class="Sup" href="#footnote-18" name="footnote-reference-18">¶</a></td><td align="center">1</td><td align="center">1</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 9. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="center" valign="bottom" width="30%"/> <col align="center" valign="bottom" width="30%"/> <thead> <tr class="First"> <th align="left"></th><th align="center" colspan="2">Double-blind Phase</th> </tr> <tr class="Last"> <th align="left">EPS Group</th><th align="center">PP3M <a class="Sup" href="#footnote-19" name="footnote-reference-19">*</a> <br/> (N=224) <br/> % </th><th align="center">INVEGA HAFYERA <br/> (N=478) <br/> % </th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-19" name="footnote-19">*</a> </dt> <dd>PP3M – Every-three-month paliperidone palmitate extended-release injectable suspension Parkinsonism group includes: Bradykinesia, drooling, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism, parkinsonian rest tremor, reduced facial expression Hyperkinesia group includes: Akathisia, restlessness, restless legs syndrome Dyskinesia group includes: Dyskinesia, muscle twitching, tardive dyskinesia Dystonia group includes: Blepharospasm, dystonia, muscle spasms, oculogyric crisis </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" valign="middle"><span class="Bold">Overall percentage of subjects with EPS-related adverse events</span></td><td align="center" valign="middle">9</td><td align="center" valign="middle">10</td> </tr> <tr> <td align="left">Parkinsonism</td><td align="center">4</td><td align="center">5</td> </tr> <tr> <td align="left">Hyperkinesia</td><td align="center">4</td><td align="center">4</td> </tr> <tr> <td align="left">Tremor</td><td align="center">0</td><td align="center">&lt;1</td> </tr> <tr> <td align="left">Dyskinesia</td><td align="center">1</td><td align="center">2</td> </tr> <tr class="Last"> <td align="left">Dystonia</td><td align="center">1</td><td align="center">1</td> </tr> </tbody> </table></div>

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Pain Assessment and Local Injection Site Reactions

Investigator ratings of injection site. Induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the PP3M group during the double-blind Phase. Investigator evaluation of tenderness was higher for subjects in the INVEGA HAFYERA group versus the 3-month paliperidone palmitate extended-release injectable suspension group (31% vs. 19%) during the double-blind Phase. Active INVEGA HAFYERA medication was given at double-blind baseline and Month 6, while placebo medication was given at the other injection times.

Subject ratings of injection site pain. The average score for the subject's evaluation of injection pain on a scale of 0 to 100 was approximately 16 at the open-label Phase end point and approximately 5 in both groups at the double-blind Phase end point.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA HAFYERA

The following additional adverse reactions were identified in the randomized double-blind active controlled study. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications.

Blood and lymphatic system disorders: anemia

Cardiac disorders: bradycardia, tachycardia

Ear and labyrinth disorders: vertigo

Gastrointestinal disorders: constipation, nausea, vomiting

General disorders and administration site conditions: fatigue

Hepatobiliary disorders: transaminases increased

Infections and infestations: cystitis, respiratory tract infection, tonsillitis

Metabolism and nutritional disorders: decreased appetite, increased appetite, weight decreased

Psychiatric disorders: depression

Reproductive system and breast disorders: breast pain, menstrual disorder

Skin and subcutaneous tissue disorders: rash

Vascular disorders: hypertension

Additional Adverse Reactions Reported in Clinical Trials with the 1-Month and 3-Month Paliperidone Palmitate Extended-Release Injectable Suspension

The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month and 3-month paliperidone palmitate extended-release injectable suspensions that are not listed elsewhere:

Cardiac disorders: atrioventricular block first degree, bundle branch block, palpitations, postural orthostatic tachycardia syndrome

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache

General disorders and administration site conditions: asthenia, chest discomfort

Immune system disorders: hypersensitivity

Investigations: electrocardiogram abnormal

Metabolism and nutrition disorders: hyperinsulinemia

Musculoskeletal and connective tissue disorders: myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness, dizziness postural, dysarthria, hypertonia, lethargy, oromandibular dystonia, psychomotor hyperactivity, syncope

Psychiatric disorders: agitation, nightmare

Reproductive system and breast disorders: breast discharge, erectile dysfunction, gynecomastia, sexual dysfunction

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: drug eruption, eczema, pruritus, pruritus generalized, urticaria

Vascular disorders: hypotension, orthostatic hypotension

Additional Adverse Reactions Reported in Clinical Trials with Oral Paliperidone

The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction

General disorders and administration site conditions: edema, edema peripheral

Immune system disorders: anaphylactic reaction

Musculoskeletal and connective tissue disorders: arthralgia, torticollis, trismus

Nervous system disorders: grand mal convulsion, parkinsonian gait, transient ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement, breast tenderness, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: ischemia

The following adverse reactions have been identified during post-approval use of paliperidone; because these reactions were 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: angioedema, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the Adverse Reactions (6)section of the Prescribing Information for those products.

Because paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 6-month dosing interval and the half-life of INVEGA HAFYERA [see Clinical Pharmacology (12.3)] .

Table 10 presents clinically significant drug interactions with INVEGA HAFYERA.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 10. Clinically Important Drug Interactions with INVEGA HAFYERA</span> </caption> <col align="left" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" colspan="2"><span class="Bold">Centrally acting Drugs and Alcohol</span></td> </tr> <tr> <td align="left" class="Rrule">Clinical Rationale</td><td align="left">Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of INVEGA HAFYERA.</td> </tr> <tr class="Botrule"> <td align="left" class="Rrule">Clinical Recommendation</td><td align="left">INVEGA HAFYERA should be used with caution with other centrally acting drugs and alcohol.</td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Drugs with Potential for Inducing Orthostatic Hypotension</span></td> </tr> <tr> <td align="left" class="Rrule">Clinical Rationale</td><td align="left">Because INVEGA HAFYERA has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA HAFYERA is administered with other therapeutic agents that have this potential <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>] </span>. </td> </tr> <tr class="Botrule"> <td align="left" class="Rrule">Clinical Recommendation</td><td align="left">Monitor orthostatic vital signs in patients who are vulnerable to hypotension <span class="Italics">[see <a href="#S5.7">Warnings and Precautions (5.7)</a>] </span>. </td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Strong Inducers of CYP3A4 and P-gp</span></td> </tr> <tr> <td align="left" class="Rrule">Clinical Rationale</td><td align="left">The concomitant use of INVEGA HAFYERA and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone <span class="Italics">[see <a href="#S12.3">Clinical Pharmacology (12.3)</a>] </span>. </td> </tr> <tr> <td align="left" class="Rrule">Clinical Recommendation</td><td align="left">Avoid using CYP3A4 and/or P-gp inducers with INVEGA HAFYERA during the 6-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets <span class="Italics">[see <a href="#S2.1">Dosage and Administration (2.1)</a>] </span>. </td> </tr> <tr class="Botrule"> <td align="left">Examples</td><td align="left">carbamazepine, rifampin, or St. John's Wort</td> </tr> <tr class="Botrule"> <td align="left" colspan="2"><span class="Bold">Levodopa and Other Dopamine Agonists</span></td> </tr> <tr> <td align="left" class="Rrule">Clinical Rationale</td><td align="left">Paliperidone may antagonize the effect of levodopa and other dopamine agonists.</td> </tr> <tr class="Last"> <td align="left" class="Rrule">Clinical Recommendation</td><td align="left">Monitor and manage patient as clinically appropriate.</td> </tr> </tbody> </table></div>

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of INVEGA HAFYERA is required when administered concomitantly with valproate [see Clinical Pharmacology (12.3)] . Additionally, no dosage adjustment is necessary for valproate when co-administered with INVEGA HAFYERA [see Clinical Pharmacology (12.3)] .

Pharmacokinetic interaction between lithium and INVEGA HAFYERA is unlikely.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely [see Clinical Pharmacology (12.3)].

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including INVEGA HAFYERA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) . Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA HAFYERA during pregnancy (see Clinical Considerations) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate extended-release injectable suspension. [See Clinical Pharmacology (12.3)] . The clinical significance of INVEGA HAFYERA administered before pregnancy or anytime during pregnancy is not known.

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

In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate or when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal Data) .

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including INVEGA HAFYERA, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

No developmental toxicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension.

There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate extended-release injectable suspension during the period of organogenesis at doses up to 250 mg/kg, which is ~10 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release injectable suspension based on mg/m 2 body surface area.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the oral MRHD of 12 mg based on mg/m 2 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the MRHD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m 2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or, to effects on the dams.

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations) . Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate extended-release injectable suspension. The clinical significance on the breastfed infant is not known [see Clinical Pharmacology (12.3)] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INVEGA HAFYERA and any potential adverse effects on the breastfed child from INVEGA HAFYERA or from the mother's underlying condition.

Clinical Considerations

Infants exposed to INVEGA HAFYERA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of paliperidone (D 2 receptor antagonism), treatment with INVEGA HAFYERA may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.10)] .

Safety and effectiveness of INVEGA HAFYERA in patients less than 18 years of age have not been established. Use of INVEGA HAFYERA is not recommended in pediatric patients because of the potential longer duration of an adverse event. In clinical trials of oral paliperidone, there were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies.

Juvenile Animal Studies

No juvenile animal studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension.

In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents dosed at 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2–3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

The clinical study of INVEGA HAFYERA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

This drug is substantially excreted by the kidney and clearance is decreased in patients with renal impairment [see Clinical Pharmacology (12.3)] . Because elderly patients are more likely to have decreased renal function, INVEGA HAFYERA is not recommended to be used in elderly patients with mild, moderate or severe renal impairment [see Use in Specific Populations (8.6)] .

Use of INVEGA HAFYERA is not recommended for use in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min). Use of INVEGA HAFYERA in patients with mild renal impairment (creatinine clearance ≥50 mL/min to <80 mL/min) is based on the patient’s previous dose of PP1M or PP3M before transitioning to INVEGA HAFYERA [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

INVEGA HAFYERA has not been studied in patients with hepatic impairment. Based on a study with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)] .

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA HAFYERA. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

INVEGA HAFYERA contains paliperidone, which is not a controlled substance.

Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Human Experience

No cases of overdose were reported in premarketing studies with paliperidone palmitate injection.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsades de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Refer to the OVERDOSAGE section of the risperidone prescribing information for overdose experience with risperidone.

Management of Overdosage

Contact a Certified Poison Control Center for the most up to date information on the management of paliperidone and INVEGA HAFYERA overdosage (1-800-222-1222 or www.poison.org). Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. There is no specific antidote to paliperidone.

Consider the extended-release characteristics of INVEGA HAFYERA and the half-life of paliperidone when assessing treatment needs and recovery.

INVEGA HAFYERA ® contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9 RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 H-pyrido[1,2- a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C 39H 57FN 4O 4 and its molecular weight is 664.89. The structural formula is:

{ "type": "p", "children": [], "text": "INVEGA HAFYERA\n ® contains a racemic mixture of (+)- and (-)- paliperidone palmitate. Paliperidone palmitate is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical name is (9 \n RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4 \n H-pyrido[1,2- \n a]pyrimadin-9-yl hexadecanoate. Its molecular formula is C\n 39H\n 57FN\n 4O\n 4 and its molecular weight is 664.89. The structural formula is:\n " }

Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate.

{ "type": "p", "children": [], "text": "Paliperidone palmitate is very slightly soluble in ethanol and methanol, practically insoluble in polyethylene glycol 400 and propylene glycol, and slightly soluble in ethyl acetate." }

INVEGA HAFYERA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 1,092 mg and 1,560 mg paliperidone palmitate. The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 700 mg, and 1,000 mg of paliperidone, respectively. The inactive ingredients are polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate (6 mg/mL), sodium hydroxide (5.4 mg/mL), and water for injection.

{ "type": "p", "children": [], "text": "INVEGA HAFYERA is available as a white to off-white sterile aqueous extended-release suspension for intramuscular injection in dose strengths of 1,092 mg and 1,560 mg paliperidone palmitate. The drug product hydrolyzes to the active moiety, paliperidone, resulting in dose strengths of 700 mg, and 1,000 mg of paliperidone, respectively. The inactive ingredients are polysorbate 20 (10 mg/mL), polyethylene glycol 4000 (75 mg/mL), citric acid monohydrate (7.5 mg/mL), sodium dihydrogen phosphate monohydrate (6 mg/mL), sodium hydroxide (5.4 mg/mL), and water for injection." }

INVEGA HAFYERA is provided in a single-dose prefilled syringe (cyclic-olefin-copolymer) prefilled with either 700 mg (3.5 mL), or 1,000 mg (5.0 mL) paliperidone (as 1,092 mg, or 1,560 mg paliperidone palmitate) suspension with a tip cap, plunger rod, backstop and a thin walled 20G, 1½-inch safety needle.

{ "type": "p", "children": [], "text": "INVEGA HAFYERA is provided in a single-dose prefilled syringe (cyclic-olefin-copolymer) prefilled with either 700 mg (3.5 mL), or 1,000 mg (5.0 mL) paliperidone (as 1,092 mg, or 1,560 mg paliperidone palmitate) suspension with a tip cap, plunger rod, backstop and a thin walled 20G, 1½-inch safety needle." }

Paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3)] . Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone is unclear. However, its efficacy in the treatment of schizophrenia could be mediated through a combination of central dopamine D 2 and serotonin 5HT 2A receptor antagonism.

In vitro, paliperidone acts as an antagonist at the central dopamine D 2 and serotonin 5HT 2A receptors with binding affinities (Ki values) of 1.6–2.8 nM and 0.8–1.2 nM, respectively. Paliperidone also acts as an antagonist at histamine H 1 and α 1 and α 2 adrenergic receptors with binding affinities of 32 nM, 4 nM, and 17 nM, respectively. Paliperidone has no appreciable affinity for cholinergic muscarinic or β 1- and β 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar.

The pharmacokinetics for INVEGA HAFYERA presented below are based on gluteal administration only.

INVEGA HAFYERA delivers paliperidone over a 6-month period, compared to the 1-month or 3-month products which are administered every month or every three months, respectively. INVEGA HAFYERA doses of 1,092 mg and 1,560 mg result in paliperidone total exposure ranges that are encompassed within the exposure range for corresponding doses of 1-month paliperidone palmitate injections (PP1M) (156 mg and 234 mg) or corresponding doses of 3-month paliperidone palmitate (PP3M) injections (546 mg and 819 mg, respectively) or to corresponding once daily doses of paliperidone extended-release tablets. However, mean trough concentrations (C trough) at the end of the dosing interval were approximately 20 – 25% lower for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate. The mean peak concentration (C max) was higher (1.4 to 1.5-fold) for INVEGA HAFYERA as compared to corresponding doses of 3-month paliperidone palmitate.

Inter-subject variability in paliperidone PK parameters for INVEGA HAFYERA ranged from 42 to 48% for AUC 6months and ranged from 56 to 103% for C max. Because of the difference in pharmacokinetic profiles among the four paliperidone products, caution should be exercised when making a direct comparison of their pharmacokinetic properties.

Absorption

Due to its extremely low water solubility, the 6-month formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The release of the drug starts as early as day 1 and is predicted to last longer than 18 months.

Following gluteal injection(s) of INVEGA HAFYERA at doses of 1,092 or 1,560 mg plasma concentrations of paliperidone rise to reach maximum concentrations at a median T max of 29 to 32 days. The release profile and dosing regimen of INVEGA HAFYERA results in sustained concentrations over 6 months. The total and peak dose-normalized exposures of paliperidone following INVEGA HAFYERA administration were comparable between 1,092 mg and 1,560 mg dose levels. The median steady-state peak:trough ratio for an INVEGA HAFYERA dose is 3.1 and 3.0 following gluteal administration of 1,092 and 1,560 mg respectively.

Distribution

Following administration of INVEGA HAFYERA, the apparent volume of distribution of paliperidone is 1,960 L.

The plasma protein binding of racemic paliperidone is 74%.

Elimination

Metabolism

In a study with oral immediate-release 14C-paliperidone, one week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone, 59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensively metabolized in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four metabolic pathways have been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

Excretion

The median apparent half-life of paliperidone following a single INVEGA HAFYERA of either 1,092 or 1,560 mg was 148 and 159 days respectively. the concentration of paliperidone remaining in the circulation 18 months after dosing of 1,560 mg 6-month paliperidone palmitate extended-release injectable suspension stopped is estimated to be 18% of the average steady-state levels.

Drug Interaction Studies

No specific drug interaction studies have been performed with INVEGA HAFYERA. The information below is obtained from studies with oral paliperidone.

Effects of other drugs on the exposures of INVEGA HAFYERA are summarized in Figure 1. After oral administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor), an increase in mean C max and AUC values at steady-state was observed (see Figure 1). Higher doses of paroxetine have not been studied. The clinical relevance is unknown. After oral administration of paliperidone, a decrease in mean C max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp [see Drug Interactions (7.1)] . This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

Figure 1: Effects of Other Drugs on INVEGA HAFYERA Pharmacokinetics

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism, however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone; they contribute to only a small fraction of total body clearance. In vitro studies demonstrated that paliperidone is a substrate of P-glycoprotein (P-gp) [see Drug Interactions (7.2)] .

Co-administration of a single dose of an oral paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Since no significant effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium extended-release tablets and INVEGA HAFYERA. This interaction has not been studied with INVEGA HAFYERA.

In vitro studies in human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-gp at high concentrations. No in vivo data are available, and the clinical relevance is unknown.

The effects of INVEGA HAFYERA on the exposures of other drugs are summarized in Figure 2.

After oral administration of paliperidone, the steady-state C max and AUC of valproate were not affected in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when oral paliperidone extended-release tablets 3–15 mg/day was added to their existing valproate treatment [see Drug Interactions (7.1)] .

Figure 2: Effects of INVEGA HAFYERA on Pharmacokinetics of Other Drugs

Specific Populations

No specific pharmacokinetic studies have been performed with INVEGA HAFYERA in specific populations. All the information is obtained from studies with oral paliperidone or is based on the population pharmacokinetic modelling of oral paliperidone and INVEGA HAFYERA. Exposures of paliperidone in specific populations (renal impairment, hepatic impairment and elderly) are summarized in Figure 3 [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)] .

Patients with Hepatic Impairment

After oral administration of paliperidone in patients with moderate hepatic impairment, the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Paliperidone has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)] .

Geriatric Patients

After oral administration of paliperidone in elderly subjects, the C max and AUC increased 1.2-fold compared to young subjects. This may be attributable to age-related decreases in creatinine clearance [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)] .

Figure 3: Effects of Intrinsic factors on Paliperidone Pharmacokinetics

Smokers

Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Male and Female Patients

Slower absorption was observed in females in a population pharmacokinetic analysis. At apparent steady-state with 6-month paliperidone palmitate extended-release injectable suspension the trough concentrations were similar between males and females.

Obese Patients

Lower C max was observed in overweight and obese subjects. At apparent steady state with INVEGA HAFYERA, the trough concentrations were similar among normal, overweight, and obese subjects.

Carcinogenesis

No carcinogenicity studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension.

The carcinogenic potential of intramuscularly injected 1-month paliperidone palmitate extended-release injectable suspension was assessed in rats. There was an increase in mammary gland adenocarcinomas in female rats at 16, 47, and 94 mg/kg/month, which are ~0.7, 2 and 4 times, respectively, the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A no-effect dose was not established. Male rats showed an increase in mammary gland adenomas, fibroadenomas, and carcinomas at ~2 and 4 times the MRHD of 234 mg of the 1-month paliperidone palmitate extended-release suspension based on mg/m 2 body surface area. A carcinogenicity study in mice has not been conducted with paliperidone palmitate.

Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the maximum recommended human dose of risperidone based on mg/m 2body surface area (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D 2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.10)] .

Mutagenesis

Paliperidone palmitate showed no genotoxicity in the in vitro Ames bacterial reverse mutation test or the mouse lymphoma assay. Paliperidone was not genotoxic in the in vitro Ames bacterial reverse mutation test, the mouse lymphoma assay or the in vivo rat bone marrow micronucleus test.

Impairment of Fertility

No fertility studies were conducted with the 6-month paliperidone palmitate extended-release injectable suspension.

In an oral paliperidone study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the oral MRHD of 12 mg based on mg/m 2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at an oral dose of 0.63 mg/kg, which is half of the oral MRHD of 12 mg based on mg/m 2 body surface area.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the oral MRHD of 12 mg/day based on mg/m 2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg – 5.0 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m 2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

Injection site toxicity was assessed in minipigs injected intramuscularly with the 6-month paliperidone palmitate extended-release injectable suspension at doses up to 2,115 mg, which is slightly above the MRHD. Injection site inflammatory reactions were greater and more advanced than reactions to the 1-month paliperidone palmitate extended-release injectable suspension. Reversibility of these findings was not examined.

The efficacy of INVEGA HAFYERA for the treatment of schizophrenia in patients who had previously been stably treated with either PP1M for at least 4 months or PP3M for at least one 3-month injection cycle was evaluated in a randomized, double-blind, active-controlled, interventional, parallel-group, multicenter, non-inferiority study designed to evaluate time to relapse in adults with a DSM-5 diagnosis of schizophrenia.

{ "type": "p", "children": [], "text": "The efficacy of INVEGA HAFYERA for the treatment of schizophrenia in patients who had previously been stably treated with either PP1M for at least 4 months or PP3M for at least one 3-month injection cycle was evaluated in a randomized, double-blind, active-controlled, interventional, parallel-group, multicenter, non-inferiority study designed to evaluate time to relapse in adults with a DSM-5 diagnosis of schizophrenia." }

Patients could enter the study if previously treated with PP1M at dosages of 156 or 234 mg, PP3M at dosages of 546 or 819 mg, injectable risperidone at dosages of 50 mg, or any oral antipsychotic with a reason to change (e.g., efficacy, safety, tolerability, or a preference for a long-acting injectable medication) and with a PANSS total score of <70 points.

{ "type": "p", "children": [], "text": "Patients could enter the study if previously treated with PP1M at dosages of 156 or 234 mg, PP3M at dosages of 546 or 819 mg, injectable risperidone at dosages of 50 mg, or any oral antipsychotic with a reason to change (e.g., efficacy, safety, tolerability, or a preference for a long-acting injectable medication) and with a PANSS total score of <70 points." }

After establishing tolerability with PP1M (at dosages of 156 or 234 mg) or PP3M (at dosages of 546 or 819 mg) and clinical stability, defined by having a PANSS total score of <70 points for the previous 2 assessments prior to the double-blind phase, patients were randomized in a 2:1 ratio to receive INVEGA HAFYERA (478 patients) or PP3M (224 patients).

{ "type": "p", "children": [], "text": "After establishing tolerability with PP1M (at dosages of 156 or 234 mg) or PP3M (at dosages of 546 or 819 mg) and clinical stability, defined by having a PANSS total score of <70 points for the previous 2 assessments prior to the double-blind phase, patients were randomized in a 2:1 ratio to receive INVEGA HAFYERA (478 patients) or PP3M (224 patients)." }

The primary efficacy variable was time to first relapse in the double-blind phase. The primary efficacy analysis was based on the difference in Kaplan-Meier 12-month estimates of percentage of subjects remaining relapse-free between INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. Relapse was pre-defined as emergence of one or more of the following: psychiatric hospitalization, ≥25% increase (if the baseline score was >40) or a 10-point increase (if the baseline score was ≤40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation: a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items.

{ "type": "p", "children": [], "text": "The primary efficacy variable was time to first relapse in the double-blind phase. The primary efficacy analysis was based on the difference in Kaplan-Meier 12-month estimates of percentage of subjects remaining relapse-free between INVEGA HAFYERA and 3-month paliperidone palmitate extended-release injectable suspension. Relapse was pre-defined as emergence of one or more of the following: psychiatric hospitalization, ≥25% increase (if the baseline score was >40) or a 10-point increase (if the baseline score was ≤40) in total PANSS score on two consecutive assessments, deliberate self-injury, violent behavior, suicidal/homicidal ideation: a score of ≥5 (if the maximum baseline score was ≤3) or ≥6 (if the maximum baseline score was 4) on two consecutive assessments of the specific PANSS items." }

A relapse event was experienced by 7.5% and 4.9% of patients in the INVEGA HAFYERA and PP3M treatment groups, respectively, with the Kaplan-Meier estimated difference (INVEGA HAFYERA – PP3M) of 2.9% (95% CI: -1.1 to 6.8). The upper bound of the 95% CI (6.8%) was less than 10%, the prespecified non-inferiority margin. The study demonstrated non-inferiority of INVEGA HAFYERA to PP3M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4.

{ "type": "p", "children": [], "text": "A relapse event was experienced by 7.5% and 4.9% of patients in the INVEGA HAFYERA and PP3M treatment groups, respectively, with the Kaplan-Meier estimated difference (INVEGA HAFYERA – PP3M) of 2.9% (95% CI: -1.1 to 6.8). The upper bound of the 95% CI (6.8%) was less than 10%, the prespecified non-inferiority margin. The study demonstrated non-inferiority of INVEGA HAFYERA to PP3M. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 4." }

Figure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse Over Time

{ "type": "p", "children": [], "text": "\nFigure 4: Kaplan-Meier Plot of Cumulative Proportion of Patients with Relapse Over Time\n" }

An evaluation of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race.

{ "type": "p", "children": [], "text": "An evaluation of population subgroups did not reveal any clinically significant differences in responsiveness on the basis of gender, age, or race." }

Storage and Handling

Store at room temperature 20 °C to 25 °C (68 °F to 77 °F); excursions between 15 °C and 30 °C (59 °F and 86 °F) are permitted. Do not mix with any other product or diluent.

Ship and store in a horizontal position. See arrows on product carton for proper orientation.

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal side effect referred to as Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Patients should contact their health care provider or report to the emergency room if they experience the following signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia [see Warnings and Precautions (5.3)] .

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Warnings and Precautions (5.5)] .

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia (high blood sugar) and diabetes mellitus (e.g., polydipsia, polyuria, polyphagia, and weakness), and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)] .

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.7)] .

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia they should have their CBC monitored while taking INVEGA HAFYERA [see Warnings and Precautions (5.9)] .

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA HAFYERA. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males. [See Warnings and Precautions (5.10)].

Interference with Cognitive and Motor Performance

As INVEGA HAFYERA has the potential to impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that INVEGA HAFYERA therapy does not affect them adversely [see Warnings and Precautions (5.11)] .

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.14)] .

Heat Exposure and Dehydration

Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.15)] .

Concomitant Medication

Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)] .

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA HAFYERA. Advise patients that INVEGA HAFYERA may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA HAFYERA during pregnancy [see Use in Specific Populations (8.1)] .

Lactation

Advise breastfeeding women using INVEGA HAFYERA to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)] .

Infertility

Advise females of reproductive potential that INVEGA HAFYERA may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)] .

INVEGA HAFYERA (paliperidone palmitate) Extended-Release Injectable Suspension

{ "type": "p", "children": [], "text": "INVEGA HAFYERA (paliperidone palmitate) Extended-Release Injectable Suspension" }

IINVEGA TRINZA, INVEGA SUSTENNA, RISPERDAL, and RISPERDAL CONSTA are trademarks of Janssen Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "IINVEGA TRINZA, INVEGA SUSTENNA, RISPERDAL, and RISPERDAL CONSTA are trademarks of Janssen Pharmaceuticals, Inc." }

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA

{ "type": "p", "children": [], "text": "Manufactured for: \n Janssen Pharmaceuticals, Inc. \n Titusville, NJ 08560, USA\n " }

For patent information: www.janssenpatents.com

{ "type": "p", "children": [], "text": "For patent information: www.janssenpatents.com" }

© Johnson & Johnson and its affiliates 2021

{ "type": "p", "children": [], "text": "© Johnson & Johnson and its affiliates 2021" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="3%"/> <col align="left" valign="top" width="32%"/> <col align="left" valign="top" width="35%"/> <col align="left" valign="top" width="27%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="left" colspan="4" valign="top">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align="left" valign="top">Revised: January 2025</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5"><span class="Bold">PATIENT INFORMATION <br/> INVEGA HAFYERA </span><span class="Sup">®</span><span class="Bold">(in-VAY-guh HAF-ye-RA) <br/> (paliperidone palmitate) <br/> extended-release injectable suspension </span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is the most important information I should know about INVEGA HAFYERA? <br/> INVEGA HAFYERA may cause serious side effects, including: </span> <ul> <li> <span class="Bold">Increased risk of death in elderly people with dementia-related psychosis. </span>INVEGA HAFYERA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). INVEGA HAFYERA is not for the treatment of people with dementia-related psychosis. </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is INVEGA HAFYERA?</span> <br/> INVEGA HAFYERA is a prescription medicine given by injection by a healthcare provider 1 time every 6 months and used for the treatment of schizophrenia in adults who have been adequately treated with either: <ul> <li>A 1 time each month paliperidone palmitate extended-release injectable suspension for at least 4 months.</li> <li>A 1 time every 3 months paliperidone palmitate extended-release injectable suspension for at least 3 months.</li> </ul> It is not known if INVEGA HAFYERA is safe and effective in children under 18 years of age. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Do not receive INVEGA HAFYERA if you </span>are allergic to paliperidone palmitate, risperidone, or any of the ingredients in INVEGA HAFYERA. See the end of this Patient Information leaflet for a complete list of ingredients in INVEGA HAFYERA. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before receiving INVEGA HAFYERA, tell your healthcare provider about all your medical conditions, including if you:</span> <ul> <li>have had Neuroleptic Malignant Syndrome (NMS)</li> <li>have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome</li> <li>have or have had low levels of potassium or magnesium in your blood</li> <li>have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)</li> <li>have or have had kidney or liver problems</li> <li>have diabetes or have a family history of diabetes</li> <li>have Parkinson's disease or a type of dementia called Lewy Body Dementia</li> <li>have had a low white blood cell count</li> <li>have had problems with dizziness or fainting or are being treated for high blood pressure</li> <li>have or have had seizures or epilepsy</li> <li>are pregnant or plan to become pregnant. It is not known if INVEGA HAFYERA will harm your unborn baby. <ul class="Circle"> <li>Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INVEGA HAFYERA.</li> <li>If you become pregnant while receiving INVEGA HAFYERA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li> <li>Babies born to mothers who receive INVEGA HAFYERA during their third trimester of pregnancy may develop agitation, low muscle tone (floppy baby syndrome) tremors, excessive sleepiness, breathing problems, and feeding problems. Tell your healthcare provider right away if your baby develops any of these symptoms.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. INVEGA HAFYERA can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with INVEGA HAFYERA.</li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. <br/> INVEGA HAFYERA and other medicines may affect each other causing possible serious side effects. INVEGA HAFYERA may affect the way other medicines work, and other medicines may affect how INVEGA HAFYERA works. <br/> Your healthcare provider can tell you if it is safe to receive INVEGA HAFYERA with your other medicines. Do not start or stop any medicines during treatment with INVEGA HAFYERA without talking to your healthcare provider first. <br/> Know the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How will I receive INVEGA HAFYERA?</span> <ul> <li>Follow your INVEGA HAFYERA treatment schedule exactly as your healthcare provider tells you to.</li> <li>Your healthcare provider will tell you how much INVEGA HAFYERA you will receive and when you will receive it.</li> <li>INVEGA HAFYERA is given as an injection by your healthcare provider into the muscle (intramuscularly) of your buttocks, 1 time every 6 months.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What should I avoid while receiving INVEGA HAFYERA?</span> <ul> <li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you. INVEGA HAFYERA may affect your judgment, thinking, or motor skills.</li> <li>Avoid getting too hot or dehydrated. <ul class="Disc"> <li>Do not exercise too much.</li> <li>In hot weather, stay inside in a cool place if possible.</li> <li>Stay out of the sun.</li> <li>Do not wear too much clothing or heavy clothing.</li> <li>Drink plenty of water.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the possible side effects of INVEGA HAFYERA? <br/> INVEGA HAFYERA may cause serious side effects, including: </span> <ul> <li>See <span class="Bold">" <a href="#whatis">What is the most important information I should know about INVEGA HAFYERA?</a>" </span> </li> <li> <span class="Bold">Cerebrovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.</span> </li> <li> <span class="Bold">Neuroleptic Malignant Syndrome (NMS), a serious condition that can lead to death. </span>Call your healthcare provider or go to your nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS: </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="3"> <ul class="Circle"> <li>high fever</li> <li>confusion</li> <li>changes in your breathing, pulse, heart rate, and blood pressure</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>stiff muscles</li> <li>sweating</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul> <li> <span class="Bold">Problems with your heartbeat.</span>These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms: <ul class="Circle"> <li>passing out or feeling like you will pass out</li> <li>dizziness</li> <li>feeling as if your heart is pounding or missing beats</li> </ul> </li> <li> <span class="Bold">Uncontrolled body movements (tardive dyskinesia). </span>INVEGA HAFYERA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving INVEGA HAFYERA. Tardive dyskinesia may also start after you stop receiving INVEGA HAFYERA. </li> <li> <span class="Bold">Problems with your metabolism such as:</span> <ul class="Circle"> <li> <span class="Bold">high blood sugar (hyperglycemia) and diabetes</span>. Increases in blood sugar can happen in some people who receive INVEGA HAFYERA. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start and regularly during treatment with INVEGA HAFYERA. <br/> <span class="Bold">Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with INVEGA HAFYERA:</span> </li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"></td><td align="left"> <ul class="Square"> <li>feel very thirsty</li> <li>feel very hungry</li> <li>feel sick to your stomach</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Square"> <li>need to urinate more than usual</li> <li>feel weak or tired</li> <li>feel confused, or your breath smells fruity</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="4"> <ul class="Circle"> <li> <span class="Bold">increased fat levels (cholesterol and triglycerides) in your blood. </span>Your healthcare provider should check the fat levels in your blood before you start and regularly during treatment with INVEGA HAFYERA. </li> <li> <span class="Bold">weight gain. </span>You and your healthcare provider should check your weight before you start and often during treatment with INVEGA HAFYERA. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul> <li> <span class="Bold">Decreased blood pressure (orthostatic hypotension) and fainting.</span>You may feel lightheaded or faint when you rise too quickly from a sitting or lying position, especially early in treatment or when the dose is changed. </li> <li> <span class="Bold">Falls. </span>INVEGA HAFYERA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries. </li> <li> <span class="Bold">Low white blood cell count. </span>Your healthcare provider may do blood tests during the first few months of treatment with INVEGA HAFYERA. </li> <li> <span class="Bold">Increased prolactin levels in your blood (hyperprolactinemia). </span>INVEGA HAFYERA may cause a rise in the blood levels of a hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, a reversible reduction in fertility in females who are able to become pregnant, leakage of milk from the breasts, development of breasts in men, or problems with erection. </li> <li> <span class="Bold">INVEGA HAFYERA can make you sleepy or dizzy, and can slow your thinking and motor skills. </span>Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you. </li> <li> <span class="Bold">Seizures (convulsions).</span> </li> <li> <span class="Bold">Difficulty swallowing </span>that can cause food or liquid to get into your lungs. </li> <li> <span class="Bold">Prolonged or painful erection lasting more than 4 hours (priapism). </span>Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours. </li> <li> <span class="Bold">Problems controlling your body temperature so that you feel too warm. </span>See, " <a href="#whatshould">What should I avoid while receiving INVEGA HAFYERA?</a>" </li> </ul> <span class="Bold">The most common side effects of INVEGA HAFYERA include:</span></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul> <li>upper respiratory tract infections</li> <li>weight gain</li> <li>feeling restlessness or difficulty sitting still</li> <li>tremors</li> <li>shuffling walk</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul> <li>injection site reactions</li> <li>headache</li> <li>slow movements</li> <li>stiffness</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">These are not all the possible side effects of INVEGA HAFYERA. <br/> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about INVEGA HAFYERA.</span> <br/> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about INVEGA HAFYERA that is written for health professionals. </td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in INVEGA HAFYERA?</span> <br/> <span class="Bold">Active ingredient</span>: paliperidone palmitate <br/> <span class="Bold">Inactive ingredients: </span>polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection <br/> Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA <br/> For patent information: www.janssenpatents.com <br/> © Johnson &amp; Johnson and its affiliates 2021 <br/> For more information, go to www.invegahafyerahcp.com or call 1-800-526-7736. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"3%\"/>\n<col align=\"left\" valign=\"top\" width=\"32%\"/>\n<col align=\"left\" valign=\"top\" width=\"35%\"/>\n<col align=\"left\" valign=\"top\" width=\"27%\"/>\n</colgroup>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"4\" valign=\"top\">This Patient Information has been approved by the U.S. Food and Drug Administration.</td><td align=\"left\" valign=\"top\">Revised: January 2025</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"center\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">PATIENT INFORMATION\n <br/>\n\t\t\tINVEGA HAFYERA\n </span><span class=\"Sup\">®</span><span class=\"Bold\">(in-VAY-guh HAF-ye-RA)\n <br/>\n\t\t\t(paliperidone palmitate)\n <br/>\n\t\t\textended-release injectable suspension\n </span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is the most important information I should know about INVEGA HAFYERA?\n <br/>\n\t\t\tINVEGA HAFYERA may cause serious side effects, including:\n </span>\n<ul>\n<li>\n<span class=\"Bold\">Increased risk of death in elderly people with dementia-related psychosis. </span>INVEGA HAFYERA increases the risk of death in elderly people who have lost touch with reality (psychosis) due to confusion and memory loss (dementia). INVEGA HAFYERA is not for the treatment of people with dementia-related psychosis.\n </li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is INVEGA HAFYERA?</span>\n<br/>\n\t\t\tINVEGA HAFYERA is a prescription medicine given by injection by a healthcare provider 1 time every 6 months and used for the treatment of schizophrenia in adults who have been adequately treated with either:\n\t\t\t\n <ul>\n<li>A 1 time each month paliperidone palmitate extended-release injectable suspension for at least 4 months.</li>\n<li>A 1 time every 3 months paliperidone palmitate extended-release injectable suspension for at least 3 months.</li>\n</ul>\n\t\t\tIt is not known if INVEGA HAFYERA is safe and effective in children under 18 years of age.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Do not receive INVEGA HAFYERA if you </span>are allergic to paliperidone palmitate, risperidone, or any of the ingredients in INVEGA HAFYERA. See the end of this Patient Information leaflet for a complete list of ingredients in INVEGA HAFYERA.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before receiving INVEGA HAFYERA, tell your healthcare provider about all your medical conditions, including if you:</span>\n<ul>\n<li>have had Neuroleptic Malignant Syndrome (NMS)</li>\n<li>have or have had heart problems, including a heart attack, heart failure, abnormal heart rhythm, or long QT syndrome</li>\n<li>have or have had low levels of potassium or magnesium in your blood</li>\n<li>have or have had uncontrolled movements of your tongue, face, mouth, or jaw (tardive dyskinesia)</li>\n<li>have or have had kidney or liver problems</li>\n<li>have diabetes or have a family history of diabetes</li>\n<li>have Parkinson's disease or a type of dementia called Lewy Body Dementia</li>\n<li>have had a low white blood cell count</li>\n<li>have had problems with dizziness or fainting or are being treated for high blood pressure</li>\n<li>have or have had seizures or epilepsy</li>\n<li>are pregnant or plan to become pregnant. It is not known if INVEGA HAFYERA will harm your unborn baby.\n\t\t\t\t\n <ul class=\"Circle\">\n<li>Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INVEGA HAFYERA.</li>\n<li>If you become pregnant while receiving INVEGA HAFYERA, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics. You can register by calling 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.</li>\n<li>Babies born to mothers who receive INVEGA HAFYERA during their third trimester of pregnancy may develop agitation, low muscle tone (floppy baby syndrome) tremors, excessive sleepiness, breathing problems, and feeding problems. Tell your healthcare provider right away if your baby develops any of these symptoms.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. INVEGA HAFYERA can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with INVEGA HAFYERA.</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.\n <br/>\n\t\t\tINVEGA HAFYERA and other medicines may affect each other causing possible serious side effects. INVEGA HAFYERA may affect the way other medicines work, and other medicines may affect how INVEGA HAFYERA works.\n <br/>\n\t\t\tYour healthcare provider can tell you if it is safe to receive INVEGA HAFYERA with your other medicines. Do not start or stop any medicines during treatment with INVEGA HAFYERA without talking to your healthcare provider first.\n <br/>\n\t\t\tKnow the medicines you take. Keep a list of them to show to your healthcare provider or pharmacist when you get a new medicine.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How will I receive INVEGA HAFYERA?</span>\n<ul>\n<li>Follow your INVEGA HAFYERA treatment schedule exactly as your healthcare provider tells you to.</li>\n<li>Your healthcare provider will tell you how much INVEGA HAFYERA you will receive and when you will receive it.</li>\n<li>INVEGA HAFYERA is given as an injection by your healthcare provider into the muscle (intramuscularly) of your buttocks, 1 time every 6 months.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What should I avoid while receiving INVEGA HAFYERA?</span>\n<ul>\n<li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you. INVEGA HAFYERA may affect your judgment, thinking, or motor skills.</li>\n<li>Avoid getting too hot or dehydrated.\n\t\t\t\t\n <ul class=\"Disc\">\n<li>Do not exercise too much.</li>\n<li>In hot weather, stay inside in a cool place if possible.</li>\n<li>Stay out of the sun.</li>\n<li>Do not wear too much clothing or heavy clothing.</li>\n<li>Drink plenty of water.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the possible side effects of INVEGA HAFYERA?\n <br/>\n\t\t\tINVEGA HAFYERA may cause serious side effects, including:\n </span>\n<ul>\n<li>See \n <span class=\"Bold\">\" \n <a href=\"#whatis\">What is the most important information I should know about INVEGA HAFYERA?</a>\" \n </span>\n</li>\n<li>\n<span class=\"Bold\">Cerebrovascular problems (including stroke) in elderly people with dementia-related psychosis that can lead to death.</span>\n</li>\n<li>\n<span class=\"Bold\">Neuroleptic Malignant Syndrome (NMS), a serious condition that can lead to death. </span>Call your healthcare provider or go to your nearest hospital emergency room right away if you have some or all of the following signs and symptoms of NMS:\n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"3\">\n<ul class=\"Circle\">\n<li>high fever</li>\n<li>confusion</li>\n<li>changes in your breathing, pulse, heart rate, and blood pressure</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>stiff muscles</li>\n<li>sweating</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul>\n<li>\n<span class=\"Bold\">Problems with your heartbeat.</span>These heart problems can cause death. Call your healthcare provider right away if you have any of these symptoms:\n\t\t\t\t\n <ul class=\"Circle\">\n<li>passing out or feeling like you will pass out</li>\n<li>dizziness</li>\n<li>feeling as if your heart is pounding or missing beats</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Uncontrolled body movements (tardive dyskinesia). </span>INVEGA HAFYERA may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop receiving INVEGA HAFYERA. Tardive dyskinesia may also start after you stop receiving INVEGA HAFYERA.\n </li>\n<li>\n<span class=\"Bold\">Problems with your metabolism such as:</span>\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">high blood sugar (hyperglycemia) and diabetes</span>. Increases in blood sugar can happen in some people who receive INVEGA HAFYERA. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before you start and regularly during treatment with INVEGA HAFYERA.\n <br/>\n<span class=\"Bold\">Call your healthcare provider if you have any of these symptoms of high blood sugar during treatment with INVEGA HAFYERA:</span>\n</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\"></td><td align=\"left\">\n<ul class=\"Square\">\n<li>feel very thirsty</li>\n<li>feel very hungry</li>\n<li>feel sick to your stomach</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Square\">\n<li>need to urinate more than usual</li>\n<li>feel weak or tired</li>\n<li>feel confused, or your breath smells fruity</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"4\">\n<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">increased fat levels (cholesterol and triglycerides) in your blood. </span>Your healthcare provider should check the fat levels in your blood before you start and regularly during treatment with INVEGA HAFYERA.\n </li>\n<li>\n<span class=\"Bold\">weight gain. </span>You and your healthcare provider should check your weight before you start and often during treatment with INVEGA HAFYERA.\n </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul>\n<li>\n<span class=\"Bold\">Decreased blood pressure (orthostatic hypotension) and fainting.</span>You may feel lightheaded or faint when you rise too quickly from a sitting or lying position, especially early in treatment or when the dose is changed.\n </li>\n<li>\n<span class=\"Bold\">Falls. </span>INVEGA HAFYERA may make you sleepy or dizzy, may cause a decrease in your blood pressure when changing position (orthostatic hypotension), and can slow your thinking and motor skills which may lead to falls that can cause fractures or other injuries.\n </li>\n<li>\n<span class=\"Bold\">Low white blood cell count. </span>Your healthcare provider may do blood tests during the first few months of treatment with INVEGA HAFYERA.\n </li>\n<li>\n<span class=\"Bold\">Increased prolactin levels in your blood (hyperprolactinemia). </span>INVEGA HAFYERA may cause a rise in the blood levels of a hormone called prolactin (hyperprolactinemia) that may cause side effects including missed menstrual periods, a reversible reduction in fertility in females who are able to become pregnant, leakage of milk from the breasts, development of breasts in men, or problems with erection.\n </li>\n<li>\n<span class=\"Bold\">INVEGA HAFYERA can make you sleepy or dizzy, and can slow your thinking and motor skills. </span>Do not drive, operate heavy machinery, or do other dangerous activities until you know how INVEGA HAFYERA affects you.\n </li>\n<li>\n<span class=\"Bold\">Seizures (convulsions).</span>\n</li>\n<li>\n<span class=\"Bold\">Difficulty swallowing </span>that can cause food or liquid to get into your lungs.\n </li>\n<li>\n<span class=\"Bold\">Prolonged or painful erection lasting more than 4 hours (priapism). </span>Call your healthcare provider or go to your nearest emergency room right away if you have an erection that lasts more than 4 hours.\n </li>\n<li>\n<span class=\"Bold\">Problems controlling your body temperature so that you feel too warm. </span>See, \" \n <a href=\"#whatshould\">What should I avoid while receiving INVEGA HAFYERA?</a>\"\n </li>\n</ul>\n<span class=\"Bold\">The most common side effects of INVEGA HAFYERA include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul>\n<li>upper respiratory tract infections</li>\n<li>weight gain</li>\n<li>feeling restlessness or difficulty sitting still</li>\n<li>tremors</li>\n<li>shuffling walk</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul>\n<li>injection site reactions</li>\n<li>headache</li>\n<li>slow movements</li>\n<li>stiffness</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">These are not all the possible side effects of INVEGA HAFYERA.\n <br/>\n\t\t\tCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\n </td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about INVEGA HAFYERA.</span>\n<br/>\n\t\t\tMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about INVEGA HAFYERA that is written for health professionals.\n </td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in INVEGA HAFYERA?</span>\n<br/>\n<span class=\"Bold\">Active ingredient</span>: paliperidone palmitate\n <br/>\n<span class=\"Bold\">Inactive ingredients: </span>polysorbate 20, polyethylene glycol 4000, citric acid monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide, and water for injection\n <br/>\n\t\t\tManufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560, USA\n <br/>\n\t\t\tFor patent information: www.janssenpatents.com\n <br/>\n\t\t\t© Johnson &amp; Johnson and its affiliates 2021\n <br/>\n\t\t\tFor more information, go to www.invegahafyerahcp.com or call 1-800-526-7736.\n </td>\n</tr>\n</tbody>\n</table></div>" }

INVEGA HAFYERA ® in-VAY-guh HAF-ye-RA (paliperidone palmitate) extended-release injectable suspension For Gluteal Intramuscular Injection Only

{ "type": "p", "children": [], "text": "\nINVEGA HAFYERA\n ®\n\nin-VAY-guh HAF-ye-RA\n \n(paliperidone palmitate)\n \nextended-release injectable suspension\n \nFor Gluteal Intramuscular\n \nInjection Only\n " }

Administer every 6 months

{ "type": "p", "children": [], "text": "\nAdminister every 6 months\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="15%"/> <col align="left" valign="top" width="85%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-29.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"15%\"/>\n<col align=\"left\" valign=\"top\" width=\"85%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-29.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds</span></td>\n</tr>\n</tbody>\n</table></div>" }

Important

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="7%"/> <col align="left" valign="top" width="93%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-30.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Shipping and storing the carton in a horizontal orientation improves the ability to resuspend this highly concentrated product.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"7%\"/>\n<col align=\"left\" valign=\"top\" width=\"93%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-30.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Shipping and storing the carton in a horizontal orientation improves the ability to resuspend this highly concentrated product.</span></td>\n</tr>\n</tbody>\n</table></div>" }

INVEGA HAFYERA must be administered by a healthcare professional as a single injection. Do not divide dose into multiple injections. INVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.

{ "type": "p", "children": [], "text": "INVEGA HAFYERA must be administered by a healthcare professional as a single injection.\n \nDo not divide dose into multiple injections.\n \nINVEGA HAFYERA is intended for gluteal intramuscular use only. Inject slowly, deep into the muscle taking care to avoid injection into a blood vessel.\n " }

Dosing

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

Administer INVEGA HAFYERA once every 6 months.

{ "type": "p", "children": [], "text": "Administer INVEGA HAFYERA \n once every 6 months.\n" }

Thin Wall Safety Needle

{ "type": "p", "children": [], "text": "\nThin Wall Safety Needle\n" }

Thin wall safety needle is designed to be used with INVEGA HAFYERA. Therefore, it is important to only use the needle provided in the INVEGA HAFYERA suspension kit.

{ "type": "p", "children": [], "text": "Thin wall safety needle is designed to be used with INVEGA HAFYERA. Therefore, it is important to \n only use the needle provided in the INVEGA HAFYERA suspension kit.\n" }

Dose pack contents

{ "type": "p", "children": [], "text": "\nDose pack contents\n" }

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

Hold syringe with the tip cap pointing up

{ "type": "p", "children": [], "text": "\nHold syringe with the tip cap pointing up\n" }

Shake syringe VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds To ensure complete resuspension shake syringe with:

{ "type": "p", "children": [], "text": "\nShake syringe VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds\n\nTo ensure complete resuspension shake syringe with:\n " }

{ "type": "ul", "children": [ "\nShort, VERY FAST up and down motion\n", "\nLoose wrist\n" ], "text": "" }

Proceed to the next step immediately after shaking.

{ "type": "p", "children": [], "text": "Proceed to the next step immediately after shaking." }

Check suspension for solid product

{ "type": "p", "children": [], "text": "\nCheck suspension for solid product\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="9%"/> <col align="left" valign="top" width="48%"/> <col align="left" valign="top" width="43%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"></td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-38.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><ul class="Disc"> <li>Uniform, thick and milky white</li> <li>It is normal to see air bubbles</li> </ul> </td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-39.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><ul class="Disc"> <li>Solid product on sides and top of syringe</li> <li>Uneven mix</li> <li>Thin liquid</li> </ul> </td> </tr> <tr> <td align="left"></td><td align="left"></td><td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-40.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/><br/> <span class="Bold">Product may clog. </span>Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"9%\"/>\n<col align=\"left\" valign=\"top\" width=\"48%\"/>\n<col align=\"left\" valign=\"top\" width=\"43%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"></td><td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-38.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/><ul class=\"Disc\">\n<li>Uniform, thick and milky white</li>\n<li>It is normal to see air bubbles</li>\n</ul>\n</td><td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-39.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/><ul class=\"Disc\">\n<li>Solid product on sides and top of syringe</li>\n<li>Uneven mix</li>\n<li>Thin liquid</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-40.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/><br/>\n<span class=\"Bold\">Product may clog. </span>Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest, then shake again for 15 seconds.\n </td>\n</tr>\n</tbody>\n</table></div>" }

Open needle pouch Peel off the pouch cover. Place pouch with the needle inside on a clean surface.

{ "type": "p", "children": [], "text": "\nOpen needle pouch\n\nPeel off the pouch cover.\n \nPlace pouch with the needle inside on a clean surface.\n " }

Remove syringe tip cap and attach needle Hold the syringe with the tip cap pointing up. Twist and pull off the cap. Attach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.

{ "type": "p", "children": [], "text": "\nRemove syringe tip cap and attach needle\n\nHold the syringe with the tip cap pointing up.\n \nTwist and pull off the cap.\n \nAttach the safety needle to the syringe using a gentle twisting motion to avoid needle hub cracks or damage. Always check for signs of damage or leakage prior to administration.\n " }

Pull back plunger Hold the syringe upright. Gently pull back the plunger to clear the syringe tip of any solid product. This will make pressing the plunger easier during the injection. Remove air bubbles Press the plunger carefully until a drop of liquid comes out of the needle tip.

{ "type": "p", "children": [], "text": "\n\n\nPull back plunger\n\nHold the syringe upright.\n \nGently pull back the plunger to clear the syringe tip of any solid product. This will make pressing the plunger easier during the injection.\n \n\nRemove air bubbles\n\nPress the plunger carefully until a drop of liquid comes out of the needle tip.\n " }

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="45%"/> <col align="left" valign="top" width="55%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-46.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Select and clean a gluteal injection site</span> <br/> Wipe the gluteal site with an alcohol swab and allow it to dry. <br/> <span class="Bold">Do not touch, </span>fan or blow on the injection site after you have cleaned it. </td> </tr> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-47.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Remove needle sheath</span> <br/> Pull the needle sheath away from the needle in a straight motion. <br/> <span class="Bold">Do not </span>twist the sheath, as this may loosen the needle from the syringe. </td> </tr> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-48.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Slowly inject and confirm</span> <br/> Use slow, firm, consistent pressure to press the plunger <span class="Bold">completely</span>. This should take approximately <span class="Bold">30 seconds</span>. <br/> <span class="Bold">Continue to press the plunger if you feel resistance. This is normal. <br/> While the needle is in the gluteal muscle, confirm that the entire content of the syringe has been injected. </span> <br/> Remove needle from the muscle. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"45%\"/>\n<col align=\"left\" valign=\"top\" width=\"55%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-46.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Select and clean a gluteal injection site</span>\n<br/>\n\t\t\tWipe the gluteal site with an alcohol swab and allow it to dry.\n <br/>\n<span class=\"Bold\">Do not touch, </span>fan or blow on the injection site after you have cleaned it.\n </td>\n</tr>\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-47.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Remove needle sheath</span>\n<br/>\n\t\t\tPull the needle sheath away from the needle in a straight motion.\n <br/>\n<span class=\"Bold\">Do not </span>twist the sheath, as this may loosen the needle from the syringe.\n </td>\n</tr>\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-48.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Slowly inject and confirm</span>\n<br/>\n\t\t\tUse slow, firm, consistent pressure to press the plunger \n <span class=\"Bold\">completely</span>. This should take approximately \n <span class=\"Bold\">30 seconds</span>.\n <br/>\n<span class=\"Bold\">Continue to press the plunger if you feel resistance. This is normal.\n <br/>\n\t\t\tWhile the needle is in the gluteal muscle, confirm that the entire content of the syringe has been injected.\n </span>\n<br/>\n\t\t\tRemove needle from the muscle.\n </td>\n</tr>\n</tbody>\n</table></div>" }

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

<div class="scrollingtable"><table class="Noautorules" width="100%"> <colgroup> <col align="left" valign="top" width="45%"/> <col align="left" valign="top" width="55%"/> </colgroup> <tbody class="Headless"> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-49.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Secure needle</span> <br/> After the injection is complete, use your thumb or a flat surface to secure the needle in the safety device. <br/> The needle is secure when you hear a "click" sound. </td> </tr> <tr> <td align="left"><img alt="Image" src="/dailymed/image.cfm?name=invega-50.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b"/></td><td align="left"><span class="Bold">Dispose of properly and check injection site</span> <br/> Dispose of the syringe in an approved sharps container. <br/> There may be a small amount of blood or liquid at the injection site. Hold pressure over the skin with a cotton ball or gauze pad until any bleeding stops. <br/> <span class="Bold">Do not </span>rub the injection site. <br/> If needed, cover injection site with a bandage. </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<colgroup>\n<col align=\"left\" valign=\"top\" width=\"45%\"/>\n<col align=\"left\" valign=\"top\" width=\"55%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-49.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Secure needle</span>\n<br/>\n\t\t\tAfter the injection is complete, use your thumb or a flat surface to secure the needle in the safety device.\n <br/>\n\t\t\tThe needle is secure when you hear a \"click\" sound.\n </td>\n</tr>\n<tr>\n<td align=\"left\"><img alt=\"Image\" src=\"/dailymed/image.cfm?name=invega-50.jpg&amp;setid=6cd61892-d2cb-434d-83ed-5c1b2c4e7a0b\"/></td><td align=\"left\"><span class=\"Bold\">Dispose of properly and check injection site</span>\n<br/>\n\t\t\tDispose of the syringe in an approved sharps container.\n <br/>\n\t\t\tThere may be a small amount of blood or liquid at the injection site. Hold pressure over the skin with a cotton ball or gauze pad until any bleeding stops.\n <br/>\n<span class=\"Bold\">Do not </span>rub the injection site.\n <br/>\n\t\t\tIf needed, cover injection site with a bandage.\n </td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA

{ "type": "p", "children": [], "text": "Janssen Pharmaceuticals, Inc.\n \nTitusville, NJ 08560, USA\n " }

For patent information: www.janssenpatents.com

{ "type": "p", "children": [], "text": "For patent information: www.janssenpatents.com" }

© Johnson & Johnson and its affiliates 2021

{ "type": "p", "children": [], "text": "© Johnson & Johnson and its affiliates 2021 " }

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/2025

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 2/2025" }

NDC 50458-611-01

{ "type": "p", "children": [], "text": "NDC 50458-611-01" }

Single-dose prefilled syringe. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "Single-dose prefilled syringe. Use entire contents of syringe." }

INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "INVEGA HAFYERA™ \n (paliperidone palmitate) \n extended-release injectable suspension\n " }

FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY

{ "type": "p", "children": [], "text": "FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY" }

Each injection must be administered only by a healthcare professional.

{ "type": "p", "children": [], "text": "Each injection must be administered only by \n a healthcare professional.\n " }

Shake before using.

{ "type": "p", "children": [], "text": "Shake before using." }

CONTENTS: 1 single-dose prefilled syringe and 1 needle (a 20G,1.5-inch thin wall safety needle).

{ "type": "p", "children": [], "text": "CONTENTS: 1 single-dose prefilled syringe and \n 1 needle (a 20G,1.5-inch thin wall safety needle).\n " }

Recommended Dosage: See Prescribing Information.

{ "type": "p", "children": [], "text": "Recommended Dosage: See Prescribing Information." }

Rx only

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

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted.

{ "type": "p", "children": [], "text": "Store at room temperature 20°C to 25°C \n (68°F to 77°F); excursions between \n 15°C and 30°C (59°F and 86°F) are permitted.\n " }

SHIP AND STORE THIS SIDE UP LAY FLAT

{ "type": "p", "children": [], "text": "SHIP AND STORE \n THIS SIDE UP \n LAY \n FLAT\n " }

1,092 mg/3.5 mL

{ "type": "p", "children": [], "text": "1,092 mg/3.5 mL" }

Each single-dose prefilled syringe contains 1,092 mg paliperidone palmitate.

{ "type": "p", "children": [], "text": "Each single-dose prefilled syringe contains \n 1,092 mg paliperidone palmitate.\n " }

6 MONTHS

{ "type": "p", "children": [], "text": "6 \n MONTHS\n " }

Administer every 6 months

{ "type": "p", "children": [], "text": "Administer \n every 6 months\n " }

Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds

{ "type": "p", "children": [], "text": "Shake syringe \n with the syringe \n tip cap pointing \n up VERY FAST \n for at least \n 15 seconds, rest \n briefly, then \n shake again for \n 15 seconds\n " }

NDC 50458-612-01

{ "type": "p", "children": [], "text": "NDC 50458-612-01" }

Single-dose prefilled syringe. Use entire contents of syringe.

{ "type": "p", "children": [], "text": "Single-dose prefilled syringe. Use entire contents of syringe." }

INVEGA HAFYERA™ (paliperidone palmitate) extended-release injectable suspension

{ "type": "p", "children": [], "text": "INVEGA HAFYERA™ \n (paliperidone palmitate) \n extended-release injectable suspension\n " }

FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY

{ "type": "p", "children": [], "text": "FOR GLUTEAL INTRAMUSCULAR INJECTION ONLY" }

Each injection must be administered only by a healthcare professional.

{ "type": "p", "children": [], "text": "Each injection must be administered only by \n a healthcare professional.\n " }

Shake before using.

{ "type": "p", "children": [], "text": "Shake before using." }

CONTENTS: 1 single-dose prefilled syringe and 1 needle (a 20G,1.5-inch thin wall safety needle).

{ "type": "p", "children": [], "text": "CONTENTS: 1 single-dose prefilled syringe and \n 1 needle (a 20G,1.5-inch thin wall safety needle).\n " }

Recommended Dosage: See Prescribing Information.

{ "type": "p", "children": [], "text": "Recommended Dosage: See Prescribing Information." }

Rx only

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

Store at room temperature 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted.

{ "type": "p", "children": [], "text": "Store at room temperature 20°C to 25°C \n (68°F to 77°F); excursions between \n 15°C and 30°C (59°F and 86°F) are permitted.\n " }

SHIP AND STORE THIS SIDE UP LAY FLAT

{ "type": "p", "children": [], "text": "SHIP AND STORE \n THIS SIDE UP \n LAY \n FLAT\n " }

1,560 mg/5 mL

{ "type": "p", "children": [], "text": "1,560 mg/5 mL" }

Each single-dose prefilled syringe contains 1,560 mg paliperidone palmitate.

{ "type": "p", "children": [], "text": "Each single-dose prefilled syringe contains \n 1,560 mg paliperidone palmitate.\n " }

6 MONTHS

{ "type": "p", "children": [], "text": "6 \n MONTHS\n " }

Administer every 6 months

{ "type": "p", "children": [], "text": "Administer \n every 6 months\n " }

Shake syringe with the syringe tip cap pointing up VERY FAST for at least 15 seconds, rest briefly, then shake again for 15 seconds

{ "type": "p", "children": [], "text": "Shake syringe \n with the syringe \n tip cap pointing \n up VERY FAST \n for at least \n 15 seconds, rest \n briefly, then \n shake again for \n 15 seconds\n " }

Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)].

The efficacy of paliperidone extended-release tablets in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults.

Paliperidone extended-release tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)].

The efficacy of paliperidone extended-release tablets in schizoaffective disorder was established in two 6-week trials in adults.

Adults

The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. Initial dose titration is not required.

Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.

In a longer-term study, paliperidone extended-release tablets has been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release tablets for 6 weeks [see Clinical Studies (14)]. Paliperidone extended-release tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients.

Adolescents (12 to 17 years of age)

The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 to 17 years of age is 3 mg administered once daily. Initial dose titration is not required. Dose increases, if considered necessary, should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related.

The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses.

This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.

Paliperidone extended-release tablets can be taken with or without food.

Paliperidone extended-release tablets must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed.

Concomitant use of paliperidone extended-release tablets with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with paliperidone extended-release tablets.

Renal Impairment

Dosing must be individualized according to the patient’s renal function status. For patients with mild renal impairment (creatinine clearance ≥50 mL/min to <80 mL/min), the recommended initial dose of paliperidone extended-release tablet is 3 mg once daily. The dose may then be increased to a maximum of 6 mg once daily based on clinical response and tolerability. For patients with moderate to severe renal impairment (creatinine clearance ≥10 mL/min to <50 mL/min), the recommended initial dose of paliperidone extended-release tablet is 3 mg every other day, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone extended-release tablet has not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients [see Clinical Pharmacology (12.3)].

Hepatic Impairment

For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended [see Clinical Pharmacology (12.3)]. Paliperidone extended-release tablet has not been studied in patients with severe hepatic impairment.

Elderly

Because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status. In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. For patients with moderate to severe renal impairment (creatinine clearance 10 mL/min to < 50 mL/min), the maximum recommended dose of paliperidone extended-release tablet is 3 mg once daily [see Renal Impairment above].

Paliperidone extended-release tablets are available in the following strengths and colors: 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped, biconvex, coated tablet and are imprinted with either “T1”, “T2”, “T3”, or “T4”.

{ "type": "p", "children": [], "text": "Paliperidone extended-release tablets are available in the following strengths and colors: 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped, biconvex, coated tablet and are imprinted with either “T1”, “T2”, “T3”, or “T4”." }

Paliperidone extended-release tablets are contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone extended-release tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

{ "type": "p", "children": [], "text": "Paliperidone extended-release tablets are contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone extended-release tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone." }

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Paliperidone extended-release tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning].

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone extended-release tablets were not marketed at the time these studies were performed. Paliperidone extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.

If NMS is suspected, immediately discontinue paliperidone extended-release tablets  and provide symptomatic treatment and monitoring.

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of paliperidone extended-release tablets (Cmax  ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax  ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the paliperidone extended-release tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec at any time in any of these three studies.

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, paliperidone extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on paliperidone extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with paliperidone extended-release tablets despite the presence of the syndrome.

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone extended-release tablets. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because paliperidone extended-release tablets were not marketed at the time these studies were performed, it is not known if paliperidone extended-release tablets are associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table 1a: Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="34.28%"/> <col width="11.68%"/> <col width="12.36%"/> <col width="13.26%"/> <col width="13.74%"/> <col width="14.68%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="4" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">9 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">n=322</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=122</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=212</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=234</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=218</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Serum Glucose Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 0.8<br/> </td><td align="center" class="Rrule" valign="bottom"> -0.7<br/> </td><td align="center" class="Rrule" valign="bottom"> 0.4<br/> </td><td align="center" class="Rrule" valign="bottom"> 2.3<br/> </td><td align="center" class="Rrule" valign="bottom"> 4.3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Proportion of Patients with Shifts</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="bottom"> <span class="Bold">Serum Glucose Normal to High </span>(&lt;100 mg/dL to ≥126 mg/dL)<br/> </td><td align="center" class="Rrule" valign="bottom"> 5.1%<br/> (12/236)<br/> </td><td align="center" class="Rrule" valign="bottom"> 3.2%<br/> (3/93)<br/> </td><td align="center" class="Rrule" valign="bottom"> 4.5%<br/> (7/156)<br/> </td><td align="center" class="Rrule" valign="bottom"> 4.8%<br/> (9/187)<br/> </td><td align="center" class="Rrule" valign="bottom"> 3.8%<br/> (6/157)<br/> </td> </tr> </tbody> </table></div>

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52 (n=314).

Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 1b.

Table 1b: Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="34.16%"/> <col width="11.82%"/> <col width="14.58%"/> <col width="12.88%"/> <col width="12.74%"/> <col width="13.82%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="4" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold"><span class="Bold">Paliperidone Extended-Release Tablets</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">1.5 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">n=41</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=44</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=11</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=28</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=32</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Serum Glucose</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 0.8<br/> </td><td align="center" class="Rrule" valign="bottom"> -1.4<br/> </td><td align="center" class="Rrule" valign="bottom"> -1.8<br/> </td><td align="center" class="Rrule" valign="bottom"> -0.1<br/> </td><td align="center" class="Rrule" valign="bottom"> 5.2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Proportion of Patients with Shifts</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Serum Glucose </span> <br/> <span class="Bold">Normal to High</span> <br/> (&lt;100 mg/dL to ≥126 mg/dL)<br/> </td><td align="center" class="Rrule" valign="bottom"> 3%<br/> (1/32)<br/> </td><td align="center" class="Rrule" valign="bottom"> 0%<br/> (0/34)<br/> </td><td align="center" class="Rrule" valign="bottom"> 0%<br/> (0/9)<br/> </td><td align="center" class="Rrule" valign="bottom"> 0%<br/> (0/20)<br/> </td><td align="center" class="Rrule" valign="bottom"> 11%<br/> (3/27)<br/> </td> </tr> </tbody> </table></div>

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.

Table 2a: Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="28.72%"/> <col width="14.28%"/> <col width="13.82%"/> <col width="14.28%"/> <col width="13.82%"/> <col width="15.08%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="3">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold"><span class="Bold">Paliperidone Extended-Release Tablets</span></span> <br/> </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">3 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">6 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">9 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">12 mg/day</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cholesterol</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=331</span> <br/> -6.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=120</span> <br/> -4.4<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=216</span> <br/> -2.4<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=236</span> <br/> -5.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=231</span> <br/> -4<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">LDL</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=322</span> <br/> -3.2<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=116</span> <br/> 0.5<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=210</span> <br/> -0.8<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=231</span> <br/> -3.9<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=225</span> <br/> -2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">HDL</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=331</span> <br/> 0.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=119</span> <br/> -0.4<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=216</span> <br/> 0.5<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=234</span> <br/> 0.8<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=230</span> <br/> 1.2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Triglycerides</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=331</span> <br/> -22.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=120</span> <br/> -18.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=216</span> <br/> -12.6<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=236</span> <br/> -10.6<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=231</span> <br/> -15.4<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Proportion of Patients with Shifts</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cholesterol </span> <br/> <span class="Bold">Normal to High</span> <br/> <span class="Bold">(&lt;200 mg/dL to ≥240 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> 2.6%<br/> (5/194)<br/> </td><td align="center" class="Rrule" valign="middle"> 2.8%<br/> (2/71)<br/> </td><td align="center" class="Rrule" valign="middle"> 5.6%<br/> (7/125)<br/> </td><td align="center" class="Rrule" valign="middle"> 4.1%<br/> (6/147)<br/> </td><td align="center" class="Rrule" valign="middle"> 3.1%<br/> (4/130)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">LDL</span> <br/> <span class="Bold">Normal to High</span> <br/> <span class="Bold">(&lt;100 mg/dL to ≥160 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> 1.9%<br/> (2/105)<br/> </td><td align="center" class="Rrule" valign="middle"> 0%<br/> (0/44)<br/> </td><td align="center" class="Rrule" valign="middle"> 5%<br/> (3/60)<br/> </td><td align="center" class="Rrule" valign="middle"> 3.7%<br/> (3/81)<br/> </td><td align="center" class="Rrule" valign="middle"> 0%<br/> (0/69)<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">HDL</span> <br/> <span class="Bold">Normal to Low</span> <br/> <span class="Bold">(≥40 mg/dL to &lt;40 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> 22%<br/> (44/200)<br/> </td><td align="center" class="Rrule" valign="middle"> 16.3%<br/> (13/80)<br/> </td><td align="center" class="Rrule" valign="middle"> 29.1%<br/> (39/134)<br/> </td><td align="center" class="Rrule" valign="middle"> 23.4%<br/> (32/137)<br/> </td><td align="center" class="Rrule" valign="middle"> 20%<br/> (27/135)<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Triglycerides</span> <br/> <span class="Bold">Normal to High</span> <br/> <span class="Bold">(&lt;150 mg/dL to ≥200 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="middle"> 5.3%<br/> (11/208)<br/> </td><td align="center" class="Rrule" valign="middle"> 11%<br/> (9/82)<br/> </td><td align="center" class="Rrule" valign="middle"> 8.8%<br/> (12/136)<br/> </td><td align="center" class="Rrule" valign="middle"> 8.7%<br/> (13/150)<br/> </td><td align="center" class="Rrule" valign="middle"> 4.3%<br/> (6/139)<br/> </td> </tr> </tbody> </table></div>

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week 52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52 (n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and (d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302).

Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 2b.

Table 2b: Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="32.92%"/> <col width="13.66%"/> <col width="14.6%"/> <col width="12.88%"/> <col width="12.74%"/> <col width="13.2%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="3">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold"><span class="Bold">Paliperidone Extended-Release Tablets</span></span> <br/> </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">1.5 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">3 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">6 mg/day</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">12 mg/day</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Mean change from baseline (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cholesterol </span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=39</span> <br/> -7.8<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=45</span> <br/> -3.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=11</span> <br/> 12.7<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=28</span> <br/> 3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=32</span> <br/> -1.5<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">LDL</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=37</span> <br/> -4.1<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=40</span> <br/> -3.1<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=9</span> <br/> 7.2<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=27</span> <br/> 2.4<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=31</span> <br/> 0.6<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">HDL</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=37</span> <br/> -1.9<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=41</span> <br/> 0<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=9</span> <br/> 1.3<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=27</span> <br/> 1.4<br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=31</span> <br/> 0<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Triglycerides</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=39</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=44</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=11</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=28</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=32</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="top"> -8.9<br/> </td><td align="center" class="Rrule" valign="top"> 3.2<br/> </td><td align="center" class="Rrule" valign="top"> 17.6<br/> </td><td align="center" class="Rrule" valign="top"> -5.4<br/> </td><td align="center" class="Rrule" valign="top"> 3.9<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Proportion of Patients with Shifts</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Cholesterol Normal to High</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 7%<br/> </td><td align="center" class="Rrule" valign="bottom"> 4%<br/> </td><td align="center" class="Rrule" valign="bottom"> 0%<br/> </td><td align="center" class="Rrule" valign="bottom"> 6%<br/> </td><td align="center" class="Rrule" valign="bottom"> 11%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">(&lt;170 mg/dL to ≥200 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="top"> (2/27)<br/> </td><td align="center" class="Rrule" valign="top"> (1/26)<br/> </td><td align="center" class="Rrule" valign="top"> (0/6)<br/> </td><td align="center" class="Rrule" valign="top"> (1/18)<br/> </td><td align="center" class="Rrule" valign="top"> (2/19)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">LDL Normal to High</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 3%<br/> </td><td align="center" class="Rrule" valign="bottom"> 4%<br/> </td><td align="center" class="Rrule" valign="bottom"> 14%<br/> </td><td align="center" class="Rrule" valign="bottom"> 0%<br/> </td><td align="center" class="Rrule" valign="bottom"> 9%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">(&lt;110 mg/dL to ≥130 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="top"> (1/32)<br/> </td><td align="center" class="Rrule" valign="top"> (1/25)<br/> </td><td align="center" class="Rrule" valign="top"> (1/7)<br/> </td><td align="center" class="Rrule" valign="top"> (0/22)<br/> </td><td align="center" class="Rrule" valign="top"> (2/22)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">HDL Normal to Low</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 14%<br/> </td><td align="center" class="Rrule" valign="bottom"> 7%<br/> </td><td align="center" class="Rrule" valign="bottom"> 29%<br/> </td><td align="center" class="Rrule" valign="bottom"> 13%<br/> </td><td align="center" class="Rrule" valign="bottom"> 23%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">(</span><span class="Bold">≥4</span><span class="Bold">0 mg/dL to &lt;40 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="top"> (4/28)<br/> </td><td align="center" class="Rrule" valign="top"> (2/30)<br/> </td><td align="center" class="Rrule" valign="top"> (2/7)<br/> </td><td align="center" class="Rrule" valign="top"> (3/23)<br/> </td><td align="center" class="Rrule" valign="top"> (5/22)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Triglycerides Normal to High</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 3%<br/> </td><td align="center" class="Rrule" valign="bottom"> 5%<br/> </td><td align="center" class="Rrule" valign="bottom"> 13%<br/> </td><td align="center" class="Rrule" valign="bottom"> 8%<br/> </td><td align="center" class="Rrule" valign="bottom"> 7%<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> <span class="Bold">(&lt;150 mg/dL to ≥200 mg/dL)</span> <br/> </td><td align="center" class="Rrule" valign="top"> (1/34)<br/> </td><td align="center" class="Rrule" valign="top"> (2/38)<br/> </td><td align="center" class="Rrule" valign="top"> (1/8)<br/> </td><td align="center" class="Rrule" valign="top"> (2/26)<br/> </td><td align="center" class="Rrule" valign="top"> (2/28)<br/> </td> </tr> </tbody> </table></div>

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia Trials

Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.

Table 3a: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="34.98%"/> <col width="11.34%"/> <col width="12.86%"/> <col width="13.02%"/> <col width="13.66%"/> <col width="14.14%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold"><span class="Bold">Paliperidone Extended-Release Tablets</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">9 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">n=323</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=112</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=215</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=235</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=218</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Weight (kg)</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom">  <br/> -0.4<br/> </td><td align="center" class="Rrule" valign="bottom">  <br/> 0.6<br/> </td><td align="center" class="Rrule" valign="bottom">  <br/> 0.6<br/> </td><td align="center" class="Rrule" valign="bottom">  <br/> 1<br/> </td><td align="center" class="Rrule" valign="bottom">  <br/> 1.1<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Weight Gain</span> <br/> <span class="Bold">≥ 7% increase from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 5%<br/> </td><td align="center" class="Rrule" valign="bottom"> 7%<br/> </td><td align="center" class="Rrule" valign="bottom"> 6%<br/> </td><td align="center" class="Rrule" valign="bottom"> 9%<br/> </td><td align="center" class="Rrule" valign="bottom"> 9%<br/> </td> </tr> </tbody> </table></div>

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302).

Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebo-controlled study and an open-label extension with a median duration of exposure to paliperidone extended-release tablets of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) are presented in Table 3b.

Table 3b: Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="98%"> <colgroup> <col width="26.5%"/> <col width="12.38%"/> <col width="15.5%"/> <col width="17.06%"/> <col width="13.96%"/> <col width="14.6%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top">  <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Paliperidone Extended-Release Tablets </span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">1.5 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg/day</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">n=51</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=54</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=16</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=45</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">n=34</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Weight (kg)</span> <br/> <span class="Bold">Change from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 0<br/> </td><td align="center" class="Rrule" valign="bottom"> 0.3<br/> </td><td align="center" class="Rrule" valign="bottom"> 0.8<br/> </td><td align="center" class="Rrule" valign="bottom"> 1.2<br/> </td><td align="center" class="Rrule" valign="bottom"> 1.5<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Weight Gain</span> <br/> <span class="Bold">≥ 7% increase from baseline</span> <br/> </td><td align="center" class="Rrule" valign="bottom"> 2%<br/> </td><td align="center" class="Rrule" valign="bottom"> 6%<br/> </td><td align="center" class="Rrule" valign="bottom"> 19%<br/> </td><td align="center" class="Rrule" valign="bottom"> 7%<br/> </td><td align="center" class="Rrule" valign="bottom"> 18%<br/> </td> </tr> </tbody> </table></div>

In the open-label long-term study the proportion of total subjects treated with paliperidone extended-release tablets  with an increase in body weight of ≥7% from baseline was 33%. When treating adolescent patients with paliperidone extended-release tablets, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone extended-release tablets in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of paliperidone extended-release tablets-treated subjects (5%) had an increase in body weight of ≥7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

Like other drugs that antagonize dopamine D2 receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Published epidemiologic studies have shown inconsistent results when exploring the potential association between hyperprolactinemia and breast cancer.

Because the paliperidone extended-release tablets are non-deformable and does not appreciably change in shape in the gastrointestinal tract, paliperidone extended-release tablets should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example:  esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel’s diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Because of the controlled-release design of the tablet, paliperidone extended-release tablets should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3) and Patient Counseling Information (17)].

A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract.

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with paliperidone extended-release tablets (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo.

Paliperidone extended-release tablets should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including paliperidone extended-release tablets, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including paliperidone extended-release tablets. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of paliperidone extended-release tablets at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue paliperidone extended-release tablets in patients with severe neutropenia (absolute neutrophil count < 1000/mm3) and follow their WBC until recovery.

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with paliperidone extended-release tablets [see Adverse Reactions (6.2)]. Antipsychotics, including paliperidone extended-release tablets, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with paliperidone extended-release tablets (3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, paliperidone extended-release tablets should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Paliperidone extended-release tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with paliperidone extended-release tablets during postmarketing surveillance. Severe priapism may require surgical intervention.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing paliperidone extended-release tablets to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone extended-release tablets and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with paliperidone extended-release tablets and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of paliperidone extended-release tablets-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of paliperidone extended-release tablets-treated subjects. [See Adverse Reactions (6)].

The safety of paliperidone extended-release tablets were evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone extended-release tablets  at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received paliperidone extended-release tablets at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

The safety of paliperidone extended-release tablets were evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of paliperidone extended-release tablet was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of paliperidone extended-release tablets: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of paliperidone extended-release tablets (3 to 12 mg once daily). Both studies included subjects who received paliperidone extended-release tablets either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone extended-release tablets (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone extended-release tablets often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia in Adults and Adolescents

Adult Patients with Schizophrenia

Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4: Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="36.12%"/> <col width="15.42%"/> <col width="11.68%"/> <col width="11.68%"/> <col width="11.72%"/> <col width="13.38%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="3">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Percentage of Patients</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">3 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">6 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">9 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">12 mg once daily</span> <br/> </th> </tr> <tr class="Last"> <th align="justify" class="Lrule Rrule Toprule"> <span class="Bold">Body System or Organ Class</span> <br/> Dictionary-Derived Term<br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=355)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=127)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=235)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=246)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=242)</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Total percentage of subjects with adverse reactions</span> <br/> </td><td align="center" class="Rrule" valign="top"> 37<br/> </td><td align="center" class="Rrule" valign="top"> 48<br/> </td><td align="center" class="Rrule" valign="top"> 47<br/> </td><td align="center" class="Rrule" valign="top"> 53<br/> </td><td align="center" class="Rrule" valign="top"> 59<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cardiac disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Atrioventricular block first degree<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Bundle branch block<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Sinus arrhythmia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Tachycardia<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Gastrointestinal disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Abdominal pain upper<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dry mouth<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Salivary hypersecretion<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">General disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Asthenia<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Fatigue<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Nervous system disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Akathisia<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dizziness<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Extrapyramidal symptoms<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 20<br/> </td><td align="center" class="Rrule" valign="top"> 18<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Vascular disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Orthostatic hypotension<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td> </tr> </tbody> </table></div>

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily paliperidone extended-release tablets doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg [see Clinical Studies (14)]. Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the paliperidone extended-release tablets incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting.

Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12 to 17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5: Adverse Reactions Reported by ≥2% of Paliperidone Extended-Release Tablets-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial *

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="36.12%"/> <col width="15.42%"/> <col width="11.68%"/> <col width="11.68%"/> <col width="11.72%"/> <col width="13.38%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="3">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Percentage of Patients</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">1.5 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">3 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">6 mg once daily</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">12 mg once daily</span> <br/> </th> </tr> <tr class="Last"> <th align="justify" class="Lrule Rrule Toprule"> <span class="Bold">Body System or Organ Class</span> <br/> Dictionary-Derived Term<br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=51)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=54)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=16)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=45)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=35)</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Total percentage of subjects with adverse reactions</span> <br/> </td><td align="center" class="Rrule" valign="top"> 43<br/> </td><td align="center" class="Rrule" valign="top"> 37<br/> </td><td align="center" class="Rrule" valign="top"> 50<br/> </td><td align="center" class="Rrule" valign="top"> 58<br/> </td><td align="center" class="Rrule" valign="top"> 74<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cardiac disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Tachycardia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Eye disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Vision blurred<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Gastrointestinal disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dry mouth<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Salivary hypersecretion<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Swollen tongue<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Vomiting<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">General disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Asthenia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Fatigue<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Infections and infestations</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Nasopharyngitis<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Investigations</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Weight increased<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Nervous system disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Akathisia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 17<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dizziness<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Extrapyramidal symptoms<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 19<br/> </td><td align="center" class="Rrule" valign="top"> 18<br/> </td><td align="center" class="Rrule" valign="top"> 23<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Headache<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Lethargy<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 13<br/> </td><td align="center" class="Rrule" valign="top"> 20<br/> </td><td align="center" class="Rrule" valign="top"> 26<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Tongue paralysis<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Psychiatric disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Anxiety<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Reproductive system and breast disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Amenorrhea<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Galactorrhea<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Gynecomastia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="6" valign="top"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> <br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Epistaxis<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> </tbody> </table></div>

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults

Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets and for which the incidence in paliperidone extended-release tablets-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6: Adverse Drug Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablets-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials *

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="36.4%"/> <col width="12.1%"/> <col width="17.4%"/> <col width="16.98%"/> <col width="17.12%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="2">  <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="4"> <span class="Bold">Percentage of Patients</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> <span class="Bold"> 3 to 6 mg</span> <br/> <span class="Bold">once-daily</span> <br/> <span class="Bold">fixed-dose range</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> <span class="Bold">9 to 12 mg</span> <br/> <span class="Bold">once-daily</span> <br/> <span class="Bold">fixed-dose range</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> <span class="Bold"> 3 to 12 mg</span> <br/> <span class="Bold">once-daily</span> <br/> <span class="Bold">flexible dose</span> <br/> </th> </tr> <tr class="Last"> <th align="justify" class="Lrule Rrule Toprule"> <span class="Bold">Body System or Organ Class</span> <br/> Dictionary-Derived Term<br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=202)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=108)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=98)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">(N=214)</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Total percentage of subjects with adverse reactions</span> <br/> </td><td align="center" class="Rrule" valign="top"> 32<br/> </td><td align="center" class="Rrule" valign="top"> 48<br/> </td><td align="center" class="Rrule" valign="top"> 50<br/> </td><td align="center" class="Rrule" valign="top"> 43<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Cardiac disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Tachycardia<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Gastrointestinal disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Abdominal discomfort/Abdominal pain upper<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Constipation<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dyspepsia<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Nausea<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Stomach discomfort<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">General disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Asthenia<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Infections and Infestations</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Nasopharyngitis<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Rhinitis<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Upper respiratory tract infection<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Investigations</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Weight increased<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Metabolism and nutrition disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Decreased appetite<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Increased appetite<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Musculoskeletal and connective tissue disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Back pain<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Myalgia<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Nervous system disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Akathisia<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dysarthria<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Extrapyramidal symptoms<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 20<br/> </td><td align="center" class="Rrule" valign="top"> 17<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Somnolence<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> <span class="Bold">Psychiatric disorders</span> <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td><td align="center" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Sleep disorder<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <span class="Bold">Respiratory, thoracic and mediastinal disorders</span> <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td><td align="justify" class="Rrule" valign="top">  <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Cough<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Pharyngolaryngeal pain<br/> </td><td align="center" class="Rrule" valign="top"> &lt;1<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> </tbody> </table></div>

* Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily paliperidone extended-release tablets doses of 6 mg (with the option to reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 to 12 mg. Among the 420 subjects treated with paliperidone extended-release tablets, 230 (55%) received paliperidone extended-release tablets as monotherapy and 190 (45%) received paliperidone extended-release tablets as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased.

Monotherapy versus Adjunctive Therapy

The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received paliperidone extended-release tablets as monotherapy and 190 (45%) subjects received paliperidone extended-release tablets as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving paliperidone extended-release tablets as monotherapy.

Discontinuations Due to Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in paliperidone extended-release tablets-and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone extended-release tablets-and placebo-treated subjects, respectively).

Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of paliperidone extended-release tablets-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in paliperidone extended-release tablets-and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone extended-release tablets-and placebo-treated subjects, respectively).

Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with paliperidone extended-release tablets, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.

In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with paliperidone extended-release tablets, the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of paliperidone extended-release tablets compared with subjects who received lower doses.

Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific Populations (8.5)].

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 7), and (4) incidence of spontaneous reports of EPS (Table 8). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and paliperidone extended-release tablets 3 mg and 6 mg doses for any of these EPS measures.

Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="29.78%"/> <col width="14.04%"/> <col width="14.04%"/> <col width="14.06%"/> <col width="14.04%"/> <col width="14.06%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="bottom">  <br/>  <br/>  <br/>  <br/> <span class="Bold">EPS Group</span> <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Percentage of Patients</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/>  <br/> <span class="Bold">(N=355)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg once daily</span> <br/> <span class="Bold">(N=127)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg once daily</span> <br/> <span class="Bold">(N=235)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">9 mg once daily</span> <br/> <span class="Bold">(N=246)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg once daily</span> <br/> <span class="Bold">(N=242)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Parkinsonism<span class="Sup">a</span> <br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 15<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Akathisia<span class="Sup">b</span> <br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> Use of anticholinergic medications<span class="Sup">c</span> <br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td><td align="center" class="Rrule" valign="top"> 22<br/> </td><td align="center" class="Rrule" valign="top"> 22<br/> </td> </tr> </tbody> </table></div>

a For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items)

b For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2

c Percent of patients who received anticholinergic medications to treat emergent EPS

Table 8: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adults

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="26.74%"/> <col width="13.38%"/> <col width="14.96%"/> <col width="14.98%"/> <col width="14.96%"/> <col width="14.98%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="bottom"> <span class="Bold">EPS Group</span> <br/> </td><td align="center" class="Rrule" colspan="5" valign="top"> <span class="Bold">Percentage of Patients</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="top"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/>  <br/> <span class="Bold">(N=355)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 mg once daily</span> <br/> <span class="Bold">(N=127)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">6 mg once daily</span> <br/> <span class="Bold">(N=235)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">9 mg once daily</span> <br/> <span class="Bold">(N=246)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">12 mg once daily</span> <br/> <span class="Bold">(N=242)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Overall percentage of patients with EPS-related AE<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 13<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td><td align="center" class="Rrule" valign="top"> 25<br/> </td><td align="center" class="Rrule" valign="top"> 26<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Dyskinesia<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Dystonia<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Hyperkinesia<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Parkinsonism<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top"> Tremor<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td> </tr> </tbody> </table></div>

Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia

Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus

Hyperkinesia group includes: Akathisia, hyperkinesia

Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism

Tremor group includes: Tremor

Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications.

Table 9 shows the EPS data from the pooled schizoaffective disorder trials.

Table 9: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies in Adults

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="35.3%"/> <col width="14.72%"/> <col width="16.86%"/> <col width="16.4%"/> <col width="16.72%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="bottom"> <span class="Bold">EPS Group</span> <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"> <span class="Bold">Percentage of Patients</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="4" valign="top"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <span class="Bold">Placebo</span> <br/>  <br/>  <br/> <span class="Bold">(N=202)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 to 6 mg once-daily fixed-dose range</span> <br/> <span class="Bold">(N=108)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">9 to 12 mg once-daily fixed-dose range</span> <br/> <span class="Bold">(N=98)</span> <br/> </td><td align="center" class="Rrule" valign="top"> <span class="Bold">3 to 12 mg once-daily flexible dose</span> <br/>  <br/> <span class="Bold">(N=214)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Overall percentage of patients with EPS-related AE<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 23<br/> </td><td align="center" class="Rrule" valign="top"> 22<br/> </td><td align="center" class="Rrule" valign="top"> 17<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dyskinesia<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dystonia<br/> </td><td align="center" class="Rrule" valign="top"> 1<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Hyperkinesia<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td><td align="center" class="Rrule" valign="top"> 8<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Parkinsonism<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Tremor<br/> </td><td align="center" class="Rrule" valign="top"> 3<br/> </td><td align="center" class="Rrule" valign="top"> 12<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 5<br/> </td> </tr> </tbody> </table></div>

Dyskinesia group includes: Dyskinesia, muscle twitching

Dystonia group includes: Dystonia, muscle spasms, oculogyration

Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness

Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism

Tremor group includes: Tremor

The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10).

Table 10: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="97%"> <colgroup> <col width="28.44%"/> <col width="14.32%"/> <col width="14.32%"/> <col width="14.32%"/> <col width="14.32%"/> <col width="14.28%"/> </colgroup> <thead> <tr class="First"> <th align="justify" class="Lrule Rrule Toprule" rowspan="3"> <span class="Bold">EPS Group</span> <br/> </th><th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Percentage of Patients</span> <br/> </th> </tr> <tr> <th align="center" class="Lrule Rrule Toprule" colspan="5"> <span class="Bold">Paliperidone Extended-Release Tablets</span> <br/> </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule"> <span class="Bold">Placebo</span> <br/>  <br/> <span class="Bold">(N=51)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">1.5 mg once-daily </span> <br/> <span class="Bold">(N=54)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">3 mg once-daily </span> <br/> <span class="Bold">(N=16)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">6 mg once-daily </span> <br/> <span class="Bold">(N=45)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"> <span class="Bold">12 mg once-daily </span> <br/> <span class="Bold">(N=35)</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> Overall percentage of patients with EPS-related AE<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 25<br/> </td><td align="center" class="Rrule" valign="top"> 22<br/> </td><td align="center" class="Rrule" valign="top"> 40<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> Hyperkinesia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 4<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 17<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Dystonia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Tremor<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 7<br/> </td><td align="center" class="Rrule" valign="top"> 11<br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top"> Parkinsonism<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 14<br/> </td> </tr> <tr class="Last"> <td align="justify" class="Lrule Rrule" valign="top"> Dyskinesia<br/> </td><td align="center" class="Rrule" valign="top"> 0<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td><td align="center" class="Rrule" valign="top"> 2<br/> </td><td align="center" class="Rrule" valign="top"> 6<br/> </td> </tr> </tbody> </table></div>

Hyperkinesia group includes: Akathisia

Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis

Tremor group includes: Tremor

Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity

Dyskinesia group includes: Dyskinesia, muscle contractions involuntary

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between paliperidone extended-release tablets and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between paliperidone extended-release tablets and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, paliperidone extended-release tablets were associated with increases in serum prolactin [see Warnings and Precautions (5.7)].

Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone Extended-Release Tablets

The following additional adverse reactions occurred in < 2% of paliperidone extended-release tablets-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by paliperidone extended-release tablets-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare

Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

The safety of paliperidone extended-release tablet was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone extended-release tablets in adults with schizophrenia [see Clinical Studies (14)]. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

The following adverse reactions have been identified during postapproval use of paliperidone extended-release tablets; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, catatonia, ileus, priapism, somnambulism, swollen tongue, tardive dyskinesia, thrombotic thrombocytopenic purpura, urinary incontinence, urinary retention.

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], paliperidone extended-release tablets should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when paliperidone extended-release tablet is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9)].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Pharmacokinetic interaction between lithium and paliperidone extended-release tablet is unlikely.

In a drug interaction study, co-administration of paliperidone extended-release tablets (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when paliperidone extended-release tablets 3 to 15 mg/day was added to their existing valproate treatment.

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.

Co-administration of paliperidone extended-release tablets 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of paliperidone extended-release tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone extended-release tablets should be reevaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of paliperidone extended-release tablet was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for paliperidone extended-release tablets should be considered when paliperidone extended-release tablet is co-administered with valproate after clinical assessment.

 Pharmacokinetic interaction between lithium and paliperidone extended-release tablet is unlikely.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical  Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including paliperidone extended-release tablets, during pregnancy (see Clinical Considerations).

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

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m2 body surface area. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Animal data).

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.

Fetal/Neonatal Adverse Reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone extended-release tablets, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1.26, 95% CI 1.02 to 1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88 to 1.81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data 

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m2 body surface area.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m2 body surface area; maternal toxicity occurred at 4 times the MHRD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m2 body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.

In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m2 body surface area; it is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams (see RISPERDAL® package insert).

Risk Summary

Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone’s parent compound, risperidone (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for paliperidone extended-release tablets and any potential adverse effects on the breastfed child from paliperidone extended-release tablets or from the mother’s underlying condition.

Clinical Considerations

Infants exposed to paliperidone extended-release tablets through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).

Infertility

Females

Based on the pharmacologic action of paliperidone (D2 receptor antagonism), treatment with paliperidone extended-release tablets may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions (5.7)].

Safety and effectiveness of paliperidone extended-release tablets in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12 to 17 years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of paliperidone extended-release tablets for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone extended-release tablets for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.

Juvenile Animal Studies

In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents at MRHD of 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which produced plasma levels of paliperidone 2 to 3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period.

The long-term effects of paliperidone extended-release tablets on growth and sexual maturation have not been fully evaluated in children and adolescents.

The safety, tolerability, and efficacy of paliperidone extended-release tablets were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of paliperidone extended-release tablets (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of paliperidone extended-release tablets (3 mg to 15 mg once daily) [see Clinical Studies (14)]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone extended-release tablets (n=1796), including those who received paliperidone extended-release tablets or placebo, 125 (7%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)].

Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration (2.5)].

No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone extended-release tablets has not been studied in patients with severe hepatic impairment.

Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to paliperidone extended-release tablets. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Paliperidone extended-release tablet is not a controlled substance.

Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of paliperidone extended-release tablets misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone extended-release tablet was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone’s known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

  Paliperidone extended-release tablet contains paliperidone, USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contain a racemic mixture of (+)- and (-)- paliperidone, USP. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido [l,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O3 and its molecular weight is 426.49. The structural formula is:

{ "type": "p", "children": [], "text": "  Paliperidone extended-release tablet contains paliperidone, USP, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contain a racemic mixture of (+)- and (-)- paliperidone, USP. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido [l,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O3 and its molecular weight is 426.49. The structural formula is:" }

Paliperidone, USP is sparingly soluble in 0.1N hydrochloride and methylene chloride; practically insoluble in water, 0.1N sodium hydroxide, and hexane; and slightly soluble in N,N-dimethyl formamide and tetrahydrofuran.  Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use. Inactive ingredients are dibutyl sebacate, ethylcellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol and titanium dioxide.  The 1.5 mg tablets also contain D&C Yellow #10 Aluminum Lake, FD&C Blue #2 Aluminum Lake and FD&C Yellow #6 Aluminum Lake. The 6 mg tablets also contain iron oxide black, iron oxide red and iron oxide yellow. The 9 mg tablets also contain iron oxide red. The tablets are imprinted with edible black ink. The edible ink contains iron oxide black and propylene glycol, shellac.    Delivery System Components and Performance Paliperidone extended-release tablet uses a pH-independent hydrophilic matrix and pH dependent enteric coating to deliver paliperidone, USP at a controlled rate. The paliperidone extended-release tablet comprises of an inner core made of the drug, rate controlling pH independent hydrophilic polymers and other excipients. The core is surrounded by barrier layer of pH independent polymer followed by enteric coating. When tablet expose to an acidic environment such as the stomach, the drug release will be minimal due to outer enteric coating of the pH dependent polymer. The outer enteric coating upon reaching an environment of pH 5.5 and above it starts to dissolve and the polymer in the inner core tablet will hydrate to form a gel layer. The drug releases via diffusion from a gel layer and subsequently through gel erosion.

{ "type": "p", "children": [], "text": "Paliperidone, USP is sparingly soluble in 0.1N hydrochloride and methylene chloride; practically insoluble in water, 0.1N sodium hydroxide, and hexane; and slightly soluble in N,N-dimethyl formamide and tetrahydrofuran. \n Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (orange-brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use.\n Inactive ingredients are dibutyl sebacate, ethylcellulose, hydroxypropyl cellulose, hypromellose, hypromellose phthalate, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol and titanium dioxide. \n The 1.5 mg tablets also contain D&C Yellow #10 Aluminum Lake, FD&C Blue #2 Aluminum Lake and FD&C Yellow #6 Aluminum Lake. The 6 mg tablets also contain iron oxide black, iron oxide red and iron oxide yellow. The 9 mg tablets also contain iron oxide red.\n The tablets are imprinted with edible black ink. The edible ink contains iron oxide black and propylene glycol, shellac.   \n Delivery System Components and Performance Paliperidone extended-release tablet uses a pH-independent hydrophilic matrix and pH dependent enteric coating to deliver paliperidone, USP at a controlled rate. The paliperidone extended-release tablet comprises of an inner core made of the drug, rate controlling pH independent hydrophilic polymers and other excipients. The core is surrounded by barrier layer of pH independent polymer followed by enteric coating. When tablet expose to an acidic environment such as the stomach, the drug release will be minimal due to outer enteric coating of the pH dependent polymer. The outer enteric coating upon reaching an environment of pH 5.5 and above it starts to dissolve and the polymer in the inner core tablet will hydrate to form a gel layer. The drug releases via diffusion from a gel layer and subsequently through gel erosion." }

  Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug’s therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptor antagonism. 

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D2) and serotonin Type 2 (5HT2A) receptors, with binding affinities (Ki values) of 1.6 to 2.8 nM for D2 and 0.8 to 1.2 nM for 5HT2A receptors. Paliperidone is also active as an antagonist at the α1 and α2 adrenergic receptors and H1 histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following paliperidone extended-release tablets administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours.

Steady-state concentrations of paliperidone are attained within 4 to 5 days of dosing with paliperidone extended-release tablets in most subjects. The mean steady-state peak:trough ratio for an paliperidone extended-release tablets dose of 9 mg was 1.7 with a range of 1.2 to 3.1.

Following administration of paliperidone extended-release tablets, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

Absorption and Distribution

The absolute oral bioavailability of paliperidone extended-release tablets following paliperidone administration is 28%.

Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean Cmax and AUC values of paliperidone that were increased by 60% and 54%, respectively, compared with administration under fasting conditions. Clinical trials establishing the safety and efficacy of paliperidone extended-release tablets were carried out in subjects without regard to the timing of meals. While paliperidone extended-release tablets can be taken without regard to food, the presence of food at the time of paliperidone extended-release tablets administration may increase exposure to paliperidone [see Dosage and Administration (2.3)].

Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%.

Metabolism and Elimination

Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, in vivo results indicate that these isozymes play a limited role in the overall elimination of paliperidone [see Drug Interactions (7)].

One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone to 5 healthy volunteers, 59% (range 51% to 67%) of the dose was excreted unchanged into urine, 32% (26% to 41%) of the dose was recovered as metabolites, and 6% to 12% of the dose was not recovered. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the feces. Four primary metabolic pathways have been identified in vivo, none of which could be shown to account for more than 10% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole scission.

Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

Special Populations

Renal Impairment

The dose of paliperidone extended-release tablets should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2.5)]. The disposition of a single dose paliperidone 3 mg extended-release tablet was studied in adult subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% on average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to < 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment, corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold, respectively, compared to healthy subjects. The mean terminal elimination half-life of paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).

Hepatic Impairment

In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone extended-release tablet has not been studied in patients with severe hepatic impairment.

Adolescents (12 to 17 years of age)

Paliperidone systemic exposure in adolescents weighing ≥ 51 kg (≥ 112 lbs) was similar to that in adults. In adolescents weighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this is considered not to be clinically significant. Age did not influence the paliperidone exposure.

Elderly

No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and Dosage and Administration (2.1, 2.5)].

Race

No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians.

Gender

No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women.

Smoking

No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Carcinogenesis

Carcinogenicity studies with paliperidone administered orally have not been performed.

Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on mg/m2 body surface area (see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The relevance of these tumor findings in rodents to human risk is unclear [see Warnings and Precautions (5.7)].

Mutagenesis

No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo rat micronucleus test.

Impairment of Fertility

In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the MRHD based on mg/m2 body surface area. However, pre- and post-implantation loss was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg, which is half of the MRHD based on mg/m2 body surface area.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m2 body surface area, although sperm count and sperm viability studies were not conducted with paliperidone. In a subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone in dogs and humans, all doses tested (0.31 mg/kg to 5 mg/kg) resulted in decreases in serum testosterone and in sperm motility and concentration (0.6 to 10 times the MRHD of 16 mg/day for risperidone, based on mg/m2 body surface area). Serum testosterone and sperm parameters partially recovered, but remained decreased after the last observation (two months after treatment was discontinued).

Adults

The acute efficacy of paliperidone extended-release tablets (3 mg to 15 mg once daily) was established in three placebo controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without regard to meals.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in the domains of socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors.

In all 3 studies (n=1665), paliperidone extended-release tablets were superior to placebo on the PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. Paliperidone extended-release tablets were also superior to placebo on the PSP in these trials.

An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age (there were few patients over 65), or geographic region. There were insufficient data to explore differential effects based on race.

In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically responded (defined as PANSS score ≤ 70 or ≤ 4 on pre-defined PANSS subscales, as well as having been on a stable fixed dose of paliperidone extended-release tablets for the last two weeks of an 8-week run-in phase) were entered into a 6-week open-label stabilization phase where they received paliperidone extended-release tablets (doses ranging from 3 mg to 15 mg once daily). After the stabilization phase, patients were randomized in a double-blind manner to either continue on paliperidone extended-release tablets at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly longer time to relapse in patients treated with paliperidone extended-release tablets compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated.

Adolescents

The efficacy of paliperidone extended-release tablets in adolescent subjects with schizophrenia was established in a randomized, double-blind, parallel-group, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1.5 to 12 mg/day. The study was carried out in the US, India, Romania, Russia, and Ukraine, and involved subjects 12 to 17 years of age meeting DSM-IV criteria for schizophrenia, with diagnosis confirmation using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL).

Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or paliperidone extended-release tablets Low, Medium, or High dose groups. Doses were administered based on body weight to minimize the risk of exposing lower-weight adolescents to high doses of paliperidone extended-release tablets. Subjects weighing between 29 kg and less than 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of paliperidone extended-release tablets daily, and subjects weighing at least 51 kg at the baseline visit were randomly assigned to receive placebo or 1.5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High dose) of paliperidone extended-release tablets daily. Dosing was in the morning without regard to meals.

Efficacy was evaluated using PANSS. Overall, this study demonstrated the efficacy of paliperidone extended-release tablets in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses within this broad range were shown to be effective, however, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater. Although paliperidone was adequately tolerated within the dose range of 3 to 12 mg/day, adverse events were dose related.

Adults

The acute efficacy of paliperidone extended-release tablets (3 mg to 12 mg once daily) in the treatment of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of paliperidone extended-release tablets (3 to 12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of paliperidone extended-release tablets: 6 mg with the option to reduce to 3 mg (n=105) or 12 mg with the option to reduce to 9 mg (n=98) once daily. Both studies included subjects who received paliperidone extended-release tablets either as monotherapy [no mood stabilizers and/or antidepressants (55%)] or as an adjunct to mood stabilizers and/or antidepressants (45%). The most commonly used mood stabilizers were valproate and lithium. The most commonly used antidepressants were SSRIs and SNRIs. Paliperidone extended-release tablet was dosed in the morning without regard to meals. Studies were carried out in the United States, Eastern Europe, Russia, and Asia.

Efficacy was evaluated using the PANSS, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania Rating Scale (YMRS).

The paliperidone extended-release tablets group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of 8.6 mg/day) and the higher dose group of paliperidone extended-release tablets in the 2 dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS. Numerical improvements in mood symptoms were also observed, as measured by the HAM-D-21 and YMRS. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), paliperidone extended-release tablets were not significantly different from placebo as measured by the PANSS.

Taking the results of both studies together, paliperidone extended-release tablets improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race.

Paliperidone extended-release tablets are available in the following strengths and packages.

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1.5 mg tablets are orange-brown, capsule-shaped, biconvex coated tablets, imprinted with ‘T1’ on one side and plain on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "1.5 mg tablets are orange-brown, capsule-shaped, biconvex coated tablets, imprinted with ‘T1’ on one side and plain on the other side. They are available as follows:" }

Bottle of 30 tablets with child-resistant closure, NDC 62332-803-30

{ "type": "p", "children": [], "text": "Bottle of 30 tablets with child-resistant closure, NDC 62332-803-30" }

3 mg tablets are white, capsule-shaped, biconvex coated tablets, imprinted with ‘T2’ on one side and plain on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "3 mg tablets are white, capsule-shaped, biconvex coated tablets, imprinted with ‘T2’ on one side and plain on the other side. They are available as follows:" }

Bottle of 30 tablets with child-resistant closure, NDC 62332-804-30

{ "type": "p", "children": [], "text": "Bottle of 30 tablets with child-resistant closure, NDC 62332-804-30" }

6 mg tablets are beige, capsule-shaped, biconvex coated tablets, imprinted with ‘T3’ on one side and plain on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "6 mg tablets are beige, capsule-shaped, biconvex coated tablets, imprinted with ‘T3’ on one side and plain on the other side. They are available as follows:" }

Bottle of 30 tablets with child-resistant closure, NDC 62332-805-30

{ "type": "p", "children": [], "text": "Bottle of 30 tablets with child-resistant closure, NDC 62332-805-30" }

9 mg tablets are pink, capsule-shaped, biconvex coated tablets, imprinted with ‘T4’ on one side and plain on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "9 mg tablets are pink, capsule-shaped, biconvex coated tablets, imprinted with ‘T4’ on one side and plain on the other side. They are available as follows:" }

Bottle of 30 tablets with child-resistant closure, NDC 62332-806-30

{ "type": "p", "children": [], "text": "Bottle of 30 tablets with child-resistant closure, NDC 62332-806-30" }

Storage and Handling

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Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

{ "type": "p", "children": [], "text": "Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture." }

Keep out of reach of children.

{ "type": "p", "children": [], "text": "Keep out of reach of children." }

Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone extended-release tablets.

{ "type": "p", "children": [], "text": "Physicians are advised to discuss the following issues with patients for whom they prescribe paliperidone extended-release tablets." }

Neuroleptic Malignant Syndrome (NMS)

{ "type": "p", "children": [], "text": "\nNeuroleptic Malignant Syndrome (NMS)\n" }

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].\n" }

Tardive Dyskinesia

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

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].\n" }

Metabolic Changes

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

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].\n" }

Orthostatic Hypotension

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

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)]." }

Leukopenia/Neutropenia

{ "type": "p", "children": [], "text": "\nLeukopenia/Neutropenia\n" }

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking paliperidone extended-release tablets [see Warnings and Precautions (5.11)].

{ "type": "p", "children": [], "text": "Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking paliperidone extended-release tablets [see Warnings and Precautions (5.11)]." }

Hyperprolactinemia

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

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of paliperidone extended-release tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of paliperidone extended-release tablets. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)]." }

Interference with Cognitive and Motor Performance

{ "type": "p", "children": [], "text": "\nInterference with Cognitive and Motor Performance\n" }

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that paliperidone extended-release tablets therapy does not affect them adversely [see Warnings and Precautions (5.12)].

{ "type": "p", "children": [], "text": "Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that paliperidone extended-release tablets therapy does not affect them adversely [see Warnings and Precautions (5.12)]." }

Priapism

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

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.15)].

{ "type": "p", "children": [], "text": "Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.15)]." }

Heat Exposure and Dehydration

{ "type": "p", "children": [], "text": "\nHeat Exposure and Dehydration\n" }

Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.16)].

{ "type": "p", "children": [], "text": "Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.16)]." }

Concomitant Medication

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

Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)].

{ "type": "p", "children": [], "text": "Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)]." }

Alcohol

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

Advise patients to avoid alcohol while taking paliperidone extended-release tablets [see Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Advise patients to avoid alcohol while taking paliperidone extended-release tablets [see Drug Interactions (7.1)]." }

Administration

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

Patients should be informed that paliperidone extended-release tablets should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed [see Dosage and Administration (2.3)].

{ "type": "p", "children": [], "text": "Patients should be informed that paliperidone extended-release tablets should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed [see Dosage and Administration (2.3)]." }

Pregnancy

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

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with paliperidone extended-release tablets. Advise patients that paliperidone extended-release tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to paliperidone extended-release tablets during pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with paliperidone extended-release tablets. Advise patients that paliperidone extended-release tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to paliperidone extended-release tablets during pregnancy [see Use in Specific Populations (8.1)]." }

Lactation

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

Advise breastfeeding women using paliperidone extended-release tablets to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Advise breastfeeding women using paliperidone extended-release tablets to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]." }

Infertility

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

Advise females of reproductive potential that paliperidone extended-release tablets may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].

{ "type": "p", "children": [], "text": "Advise females of reproductive potential that paliperidone extended-release tablets may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].\n" }

All brands mentioned are trademarks of their respective owners.

{ "type": "p", "children": [], "text": "All brands mentioned are trademarks of their respective owners." }

Manufactured by:

{ "type": "p", "children": [], "text": "Manufactured by:" }

Alembic Pharmaceuticals Limited

{ "type": "p", "children": [], "text": "\nAlembic Pharmaceuticals Limited\n" }

(Formulation Division),

{ "type": "p", "children": [], "text": "(Formulation Division)," }

Panelav 389350, Gujarat, India

{ "type": "p", "children": [], "text": "Panelav 389350, Gujarat, India" }

Manufactured for:

{ "type": "p", "children": [], "text": "Manufactured for:" }

Alembic Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "\nAlembic Pharmaceuticals, Inc.\n" }

Bedminster, NJ 07921, USA

{ "type": "p", "children": [], "text": "Bedminster, NJ 07921, USA" }

Revised: 02/2025

{ "type": "p", "children": [], "text": "Revised: 02/2025" }

NDC 62332-803-30 Paliperidone Extended-Release Tablets 1.5 mg Tablets should be swallowed whole. Do not divide, crush, or chew. Paliperidone extended-release tablets should be taken once daily. Rx only

{ "type": "p", "children": [], "text": "\nNDC 62332-803-30 Paliperidone Extended-Release Tablets 1.5 mg Tablets should be swallowed whole. Do not divide, crush, or chew.\nPaliperidone extended-release tablets should be taken once daily.\n Rx only \n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets\n" }

Alembic

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

NDC 62332-804-30 Paliperidone Extended-Release Tablets 3 mg Tablets should be swallowed whole. Do not divide, crush, or chew. Paliperidone extended-release tablets should be taken once daily. Rx only

{ "type": "p", "children": [], "text": "\nNDC 62332-804-30 Paliperidone Extended-Release Tablets 3 mg Tablets should be swallowed whole. Do not divide, crush, or chew.\nPaliperidone extended-release tablets should be taken once daily.\n Rx only \n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets\n" }

Alembic

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

NDC 62332-805-30 Paliperidone Extended-Release Tablets 6 mg Tablets should be swallowed whole. Do not divide, crush, or chew. Paliperidone extended-release tablets should be taken once daily. Rx only

{ "type": "p", "children": [], "text": "\nNDC 62332-805-30 Paliperidone Extended-Release Tablets 6 mg Tablets should be swallowed whole. Do not divide, crush, or chew.\nPaliperidone extended-release tablets should be taken once daily.\n Rx only \n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets\n" }

Alembic

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

NDC 62332-806-30 Paliperidone Extended-Release Tablets 9 mg Tablets should be swallowed whole. Do not divide, crush, or chew. Paliperidone extended-release tablets should be taken once daily. Rx only

{ "type": "p", "children": [], "text": "\n NDC 62332-806-30 Paliperidone Extended-Release Tablets 9 mg Tablets should be swallowed whole. Do not divide, crush, or chew.\nPaliperidone extended-release tablets should be taken once daily.\n Rx only \n" }

30 Tablets

{ "type": "p", "children": [], "text": "\n30 Tablets\n" }

Alembic

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