RISPERIDONE: 79,288 Adverse Event Reports & Safety Profile

Risperidone is an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 2 and its molecular weight is 410.49. The structural formula is: Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.

Risperidone

Tablets, USP, are for oral administration and are available in 0.25 mg (dark yellow), 0.5 mg (brownish red), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (white) strengths. Risperidone tablets contain the following inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and tartaric acid.

The

0.25 mg tablets also contain Opadry II yellow 85F12383, for purposes of coating, which contains the following: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide.

The

0.5 mg tablets also contain Opadry II red 85F15362, for purposes of coating, which contains the following: iron oxide red, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide.

The

1 mg and 4 mg tablets also contain Opadry II white 85F18422, for purposes of coating, which contains the following: polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide.

The

2 mg tablets also contain Opadry II red 85F15404, for purposes of coating, which contains the following: calcium carbonate, calcium sulfate, iron oxide red, polyethylene glycol 3350, polyvinyl alcohol, and talc.

The

3 mg tablets also contain Opadry II yellow 03B12447, for purposes of coating, which contains the following: hypromellose 2910 6cP, iron oxide red, iron oxide yellow, polyethylene glycol 400, and titanium dioxide.

Chemical

Structure

AND USAGE Risperidone orally disintegrating tablets are atypical antipsychotic indicated for: Treatment of schizophrenia ( 1.1 ) As monotherapy or adjunctive therapy with lithium or valproate, for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder ( 1.2) Treatment of irritability associated with autistic disorder ( 1.3 )

1.1 Schizophrenia Risperidone orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> .

1.2 Bipolar Mania Monotherapy Risperidone orally disintegrating tablets are indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> .

Adjunctive Therapy

Risperidone orally disintegrating tablets adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14.3) ] .

1.3 Irritability Associated with Autistic Disorder Risperidone orally disintegrating tablets are indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) <span class="opacity-50 text-xs">[see Clinical Studies (14.4) ]</span> .

AND ADMINISTRATION For patients who have never taken oral RISPERDAL, it is recommended to establish tolerability with oral RISPERDAL prior to initiating treatment with risperidone for extended-release injectable suspension. Risperidone for extended-release injectable suspension should be administered every 2 weeks by deep intramuscular (IM) deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle [see Dosage and Administration (2.8) ] . For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. Do not administer intravenously. For patients who have never taken oral RISPERDAL, tolerability should be established with oral RISPERDAL prior to initiating treatment with risperidone for extended-release injectable suspension. ( 2 ) Administer by deep intramuscular (IM) deltoid or gluteal injection. Each injection should be administered by a health care professional using the appropriate enclosed safety needle (1-inch for deltoid administration alternating injections between the two arms and 2-inch for gluteal administration alternating injections between the two buttocks). Do not administer intravenously. ( 2 ) 25 mg intramuscular (IM) every 2 weeks. Patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg every 2 weeks. ( 2 ) Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of risperidone for extended-release injectable suspension and continued for 3 weeks (and then discontinued) to ensure adequate therapeutic plasma concentrations from risperidone for extended-release injectable suspension. ( 2 ) Upward dose adjustment of risperidone for extended-release injectable suspension should not be made more frequently than every 4 weeks. Clinical effects of each upward dose adjustment should not be anticipated earlier than 3 weeks after injection. ( 2 ) Avoid inadvertent administration into a blood vessel. ( 5.16 )

See Full Prescribing Information Section

2.8 for instructions for use.

2.1 Schizophrenia The recommended dose for the treatment of schizophrenia is 25 mg IM (intramuscular) every 2 weeks. Although dose response for effectiveness has not been established for risperidone for extended-release injectable suspension, some patients not responding to 25 mg may benefit from a higher dose of 37.5 mg or 50 mg. The maximum dose should not exceed 50 mg risperidone for extended-release injectable suspension every 2 weeks. No additional benefit was observed with dosages greater than 50 mg risperidone for extended-release injectable suspension; however, a higher incidence of adverse effects was observed. The efficacy of risperidone for extended-release injectable suspension in the treatment of schizophrenia has not been evaluated in controlled clinical trials for longer than 12 weeks. Although controlled studies have not been conducted to answer the question of how long patients with schizophrenia should be treated with risperidone for extended-release injectable suspension, oral risperidone has been shown to be effective in delaying time to relapse in longer-term use. It is recommended that responding patients be continued on treatment with risperidone for extended-release injectable suspension at the lowest dose needed. The physician who elects to use risperidone for extended-release injectable suspension for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

2.2 Bipolar Disorder The recommended dose for monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder is 25 mg IM (intramuscular) every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above 50 mg have not been studied in this population. The physician who elects to use risperidone for extended-release injectable suspension for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

2.3 General Dosing Information A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic or renal impairment, for certain drug interactions that increase risperidone plasma concentrations <span class="opacity-50 text-xs">[see Drug Interactions (7.11) ]</span> or in patients who have a history of poor tolerability to psychotropic medications. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of risperidone for extended-release injectable suspension and continued for 3 weeks (and then discontinued) to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Upward dose adjustment should not be made more frequently than every 4 weeks. The clinical effects of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose. In patients with clinical factors such as hepatic or renal impairment or certain drug interactions that increase risperidone plasma concentrations <span class="opacity-50 text-xs">[see Drug Interactions (7.11) ]</span> , dose reduction as low as 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Do not combine two different dose strengths of risperidone for extended-release injectable suspension in a single administration. Discard unused portion.

2.4 Dosage in Special Populations Elderly For elderly patients treated with risperidone for extended-release injectable suspension, the recommended dosage is 25 mg IM (intramuscular) every 2 weeks. Oral RISPERDAL (or another antipsychotic medication) should be given with the first injection of risperidone for extended-release injectable suspension and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Renal or Hepatic Impairment Patients with renal or hepatic impairment should be treated with titrated doses of oral RISPERDAL prior to initiating treatment with risperidone for extended-release injectable suspension. The recommended starting dose is 0.5 mg oral RISPERDAL twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a total daily dose of at least 2 mg oral RISPERDAL is well tolerated, an injection of 25 mg risperidone for extended-release injectable suspension can be administered every 2 weeks. Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun. In some patients, slower titration may be medically appropriate. Alternatively, a starting dose of risperidone for extended-release injectable suspension of 12.5 mg may be appropriate. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Patients with renal impairment may have less ability to eliminate risperidone than normal adults. Patients with impaired hepatic function may have an increase in the free fraction of the risperidone, possibly resulting in an enhanced effect <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Elderly patients and patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk should be instructed in nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). These patients should avoid sodium depletion or dehydration and circumstances that accentuate hypotension (alcohol intake, high ambient temperature, etc.). Monitoring of orthostatic vital signs should be considered <span class="opacity-50 text-xs">[see Warnings and Precautions (5.7) ]</span> .

2.5 Reinitiation of Treatment in Patients Previously Discontinued There are no data to specifically address reinitiation of treatment. When restarting patients who have had an interval off treatment with risperidone for extended-release injectable suspension, supplementation with oral RISPERDAL (or another antipsychotic medication) should be administered.

2.6 Switching from Other Antipsychotics There are no systematically collected data to specifically address switching patients from other antipsychotics to risperidone for extended-release injectable suspension, or concerning concomitant administration with other antipsychotics. Previous antipsychotics should be continued for 3 weeks after the first injection of risperidone for extended-release injectable suspension to ensure that therapeutic concentrations are maintained until the main release phase of risperidone from the injection site has begun <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . For patients who have never taken oral RISPERDAL, it is recommended to establish tolerability with oral RISPERDAL prior to initiating treatment with risperidone for extended-release injectable suspension. As recommended with other antipsychotic medications, the need for continuing existing EPS medication should be re-evaluated periodically.

2.7 Co-Administration of Risperidone for Extended-Release Injectable Suspension with Certain Other Medications Co-administration of carbamazepine and other CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of risperidone for extended-release injectable suspension treatment. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers <span class="opacity-50 text-xs">[see Drug Interactions (7.11) ]</span> . At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4 to 8 weeks, since the dose of risperidone for extended-release injectable suspension may need to be adjusted. A dose increase, or additional oral RISPERDAL, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of risperidone for extended-release injectable suspension should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of risperidone for extended-release injectable suspension between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg risperidone for extended-release injectable suspension and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the risperidone for extended-release injectable suspension dose to 12.5 mg or necessitates interruption of risperidone for extended-release injectable suspension treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. Fluoxetine and paroxetine, CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5 to 2.8 fold and 3 to 9 fold respectively. Fluoxetine did not affect the plasma concentration of 9- hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of risperidone for extended-release injectable suspension. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of risperidone for extended-release injectable suspension between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg risperidone for extended-release injectable suspension, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the risperidone for extended-release injectable suspension dose to 12.5 mg or necessitates interruption of risperidone for extended-release injectable suspension treatment. When risperidone for extended-release injectable suspension is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied <span class="opacity-50 text-xs">[see Drug Interactions (7.11) ]</span> .

2.8 Instructions for Use For deltoid or gluteal intramuscular injection only IMPORTANT RESOURCES For additional information, visit www.amneal.com or call Amneal Pharmaceuticals LLC at 1-877-835-5472.

Important Information

Risperidone for extended-release injectable suspension requires close attention to these step-by-step Instructions for Use to help ensure successful administration. Use components provided The components in this single-dose pack are specifically designed for use with risperidone for extended-release injectable suspension. Risperidone for extended-release injectable suspension must be reconstituted only in the diluent supplied in the single-dose pack. Do not substitute ANY components of the single-dose pack. Do not store suspension after reconstitution Administer dose as soon as possible after reconstitution to avoid settling. Proper dosing The entire contents of the vial must be administered to ensure intended dose of risperidone for extended-release injectable suspension is delivered. Do not reuse. Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single-dose only. Any attempt to re-process the device for subsequent re-use may adversely affect the integrity of the device or lead to deterioration in performance. Single-dose pack contents Vial Adapter Prefilled Syringe Vial Terumo SurGuard ® 3 Injection Needles Step 1: Assemble components Take out s ingle-dose pack Wait 30 minutes Remove single-dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting. Do not warm any other way. Connect vial adapter to vial Remove cap from vial Flip off colored cap from vial. Wipe top of the grey stopper with an alcohol swab . Allow to air dry. Do not remove grey rubber stopper. Prepare vial adapter Hold sterile blister as shown. Peel back and remove paper backing. Do not remove vial adapter from blister. Do not touch spike tip at any time. This will result in contamination. Connect vial adapter to vial Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place. Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial. Connect prefilled syringe to vial adapter Remove sterile blister Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove. Do not shake. Do not touch exposed luer opening on vial adapter. This will result in contamination. Use proper grip Hold by white collar at the tip of the syringe. Do not hold syringe by the glass barrel during assembly. Remove cap Holding the white collar, snap off the white cap. Do not twist or cut off the white cap. Do not touch syringe tip. This will result in contamination. The broken-off cap can be discarded. Connect syringe to vial adapter Hold vial adapter by skirt to keep stationary. Hold syringe by white collar then insert tip into the luer opening of the vial adapter. Do not hold the glass syringe barrel. This may cause the white collar to loosen or detach. Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug. Do not over-tighten. Over-tightening may cause the syringe tip to break.

Step

2: Reconstitute microspheres Inject diluent Inject entire amount of diluent from syringe into the vial. Suspend microspheres in diluent Continuing to hold down the plunger rod, shake vigorously for at least 10 seconds , as shown. Check the suspension . When properly mixed, the suspension appears uniform, thick and milky in color. Microspheres will be visible in the liquid. Immediately proceed to the next step so suspension does not settle. Transfer suspension to syringe Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe. Remove vial adapter Hold white collar on the syringe and unscrew from vial adapter. Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes. Discard both vial and vial adapter appropriately.

Step

3: Attach needle Select appropriate needle Choose needle based on injection location (gluteal or deltoid). Attach needle Peel blister pouch open part way and use to grasp the base of the needle, as shown. Holding the white collar on the syringe , attach syringe to needle luer connection with a firm clockwise twisting motion until snug. Do not touch needle luer opening. This will result in contamination. Resuspend microspheres Fully remove the blister pouch. Just before injection, shake syringe vigorously again, as some settling will have occurred.

Step

4: Inject dose Remove transparent needle protector Move the needle safety device back towards the syringe, as shown. Then hold white collar on syringe and carefully pull the transparent needle protector straight off. Do not twist transparent needle protector, as the luer connection may loosen. Remove air bubbles Hold needle upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air.

Inject

Immediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient. Gluteal injection should be made into the upper-outer quadrant of the gluteal area. Do not administer intravenously. Secure needle in safety device Using one hand , place needle safety device at a 45-degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device. Avoid needle stick injury: Do not use two hands. Do not intentionally disengage or mishandle the needle safety device. Do not attempt to straighten the needle or engage the safety device if the needle is bent or damaged. Properly dispose of needles Check to confirm needle safety device is fully engaged. Discard in an approved sharps container. Also discard the unused needle provided in the single-dose pack. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Risperidone Tablets, Oral Solution, or Orally Disintegrating Tablets are contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the Risperidone Tablets, Oral Solution, or Orally Disintegrating Tablets formulations. 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. Known hypersensitivity to risperidone, paliperidone, or to any excipients in Risperidone Tablets, Oral Solution, or Orally Disintegrating Tablets. ( 4 )

REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ]. Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2) ]. Neuroleptic malignant syndrome [see Warnings and Precautions (5.3) ]. Tardive dyskinesia [see Warnings and Precautions (5.4) ]. Metabolic changes [see Warnings and Precautions (5.5) ]. Hyperprolactinemia [see Warnings and Precautions (5.6) ]. Orthostatic hypotension [see Warnings and Precautions (5.7) ]. Falls [see Warnings and Precautions (5.8) ]. Leukopenia/Neutropenia and Agranulocytosis [see Warnings and Precautions (5.9) ]. Potential for cognitive and motor impairment [see Warnings and Precautions (5.10) ]. Seizures [see Warnings and Precautions (5.11) ]. Dysphagia [see Warnings and Precautions (5.12) ]. Priapism [see Warnings and Precautions (5.13) ]. Disruption of body temperature regulation [see Warnings and Precautions (5.14) ]. Avoidance of inadvertent injection into a blood vessel [see Warnings and Precautions (5.15) ]. Osteodystrophy and tumors in animals [see Warnings and Precautions (5.16) ]. The most common adverse reactions in clinical trials in patients with schizophrenia (≥ 5%) were: headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity and dry mouth. The most common adverse reactions in the double-blind, placebo-controlled periods of the bipolar disorder trials were weight increased (5% in the monotherapy trial) and tremor and parkinsonism (≥ 10% in the adjunctive treatment trial). The most common adverse reactions that were associated with discontinuation from the 12-week double-blind, placebo-controlled trial in patients with schizophrenia (causing discontinuation in ≥ 1% of patients) were agitation, depression, anxiety and akathisia. Adverse reactions that were associated with discontinuation from the double-blind, placebo-controlled periods of the bipolar disorder trials were hyperglycemia (one patient in the monotherapy trial) and hypokinesia and tardive dyskinesia (one patient each in the adjunctive treatment trial). The data described in this section are derived from a clinical trial database consisting of 2,392 patients exposed to one or more doses of risperidone for extended-release injectable suspension for the treatment of schizophrenia. Of these 2,392 patients, 332 were patients who received risperidone for extended-release injectable suspension while participating in a 12-week double-blind, placebo-controlled trial. Two hundred two (202) of the 332 were schizophrenia patients who received 25 mg or 50 mg risperidone for extended-release injectable suspension. The conditions and duration of treatment with risperidone for extended-release injectable suspension in the other clinical trials varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients and short-term (up to 12 weeks) and longer-term (up to 4 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses and ECGs. In addition to the studies in patients with schizophrenia, safety data are presented from a trial assessing the efficacy and safety of risperidone for extended-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I and who were stable on risperidone (oral or long-acting injection), were stable on other antipsychotics or mood stabilizers, or were experiencing an acute episode. After a 3-week period of treatment with open-label oral risperidone (N=440), subjects who demonstrated an initial response to oral risperidone in this period and those who were stable on risperidone (oral or long-acting injection) at study entry entered into a 26-week stabilization period of open-label risperidone for extended-release injectable suspension (N=501). Subjects who demonstrated a maintained response during this period were then randomized into a 24-month double-blind, placebo-controlled period in which they received risperidone for extended-release injectable suspension (N=154) or placebo (N=149) as monotherapy. Subjects who relapsed or who completed the double-blind period could choose to enter an 8-week open-label risperidone for extended-release injectable suspension extension period (N=160). Safety data are also presented from a trial assessing the efficacy and safety of risperidone for extended-release injectable suspension when administered as adjunctive maintenance treatment in patients with bipolar disorder. The subjects in this multi-center, double-blind, placebo-controlled study were adult patients who met DSM-IV criteria for Bipolar Disorder Type I or Type II and who experienced at least 4 episodes of mood disorder requiring psychiatric/clinical intervention in the previous 12 months, including at least 2 episodes in the 6 months prior to the start of the study. At the start of this study, all patients (N=275) entered into a 16-week open-label treatment phase in which they received risperidone for extended-release injectable suspension in addition to continuing their treatment as usual, which consisted of various mood stabilizers (primarily lithium and valproate), antidepressants and/or anxiolytics. Patients who reached remission at the end of this 16-week open-label treatment phase (N=139) were then randomized into a 52-week double-blind, placebo-controlled phase in which they received risperidone for extended-release injectable suspension (N=72) or placebo (n=67) as adjunctive treatment in addition to continuing their treatment as usual. Patients who did not reach remission at the end of the 16-week open-label treatment phase could choose to continue to receive risperidone for extended-release injectable suspension as adjunctive therapy in an open-label manner, in addition to continuing their treatment as usual, for up to an additional 36 weeks as clinically indicated for a total period of up to 52 weeks; these patients (N=70) were also included in the evaluation of safety. 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 risperidone for extended-release injectable suspension (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for risperidone for extended-release injectable suspension 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. The majority of all adverse reactions were mild to moderate in severity. The most common adverse reactions in clinical trials in patients with schizophrenia (≥ 5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in extremity and dry mouth. The most common adverse reactions in clinical trials in patients with bipolar disorder were weight increased (5% in monotherapy trial) and tremor and parkinsonism (≥ 10% in adjunctive therapy trial). ( 6 ) The most common adverse reactions that were associated with discontinuation from clinical trials in patients with schizophrenia were agitation, depression, anxiety and akathisia. Adverse reactions that were associated with discontinuation from bipolar disorder trials were hyperglycemia (one subject monotherapy trial) and hypokinesia and tardive dyskinesia (one subject each in adjunctive therapy trial). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia Table 4 lists the adverse reactions reported in 2% or more of risperidone for extended-release injectable suspension-treated patients with schizophrenia in one 12-week double-blind, placebo-controlled trial.

Table

4: Adverse Reactions in ≥ 2% of Risperidone for Extended-Release Injectable Suspension -Treated Patients with Schizophrenia in a 12-Week Double-Blind, Placebo-Controlled Trial System/Organ Class Percentage of Patients Reporting Event Risperidone for Extended-Release Injectable Suspension Placebo 25 mg 50 mg Adverse Reaction (N=99) (N=103) (N=98) Eye disorders Vision blurred 2 3 0 Gastrointestinal disorders Constipation 5 7 1 Dry mouth 0 7 1 Dyspepsia 6 6 0 Nausea 3 4 5 Toothache 1 3 0 Salivary hypersecretion 4 1 0 General disorders and administration site conditions Fatigue * 3 9 0 Edema peripheral 2 3 1 Pain 4 1 0 Pyrexia 2 1 0 Infections and infestations Upper respiratory tract infection 2 0 1 Investigations Weight increased 5 4 2 Weight decreased 4 1 1 Musculoskeletal and connective tissue disorders Pain in extremity 6 2 1 Nervous system disorders Headache 15 21 12 Parkinsonism * 8 15 9 Dizziness 7 11 6 Akathisia * 4 11 6 Sedation * 5 6 3 Tremor 0 3 0 Syncope 2 1 0 Hypoesthesia 2 0 0 Respiratory, thoracic and mediastinal disorders Cough 4 2 3 Sinus congestion 2 0 0 Skin and subcutaneous tissue disorders Acne 2 2 0 Dry skin 2 0 0 * Fatigue includes fatigue and asthenia. Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, muscle rigidity and bradykinesia. Akathisia includes akathisia and restlessness. Sedation includes sedation and somnolence. Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Disorder Table 5 lists the treatment-emergent adverse reactions reported in 2% or more of risperidone for extended-release injectable suspension-treated patients in the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone for extended-release injectable suspension when administered as monotherapy for maintenance treatment in patients with Bipolar I Disorder.

Table

5: Adverse Reactions in ≥ 2% of Patients with Bipolar I Disorder Treated with Risperidone for Extended-Release Injectable Suspension as Monotherapy in a 24-Month Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone for Extended-Release Injectable Suspension (N=154) Placebo (N=149)

Investigations

Weight increased 5 1 Nervous system disorders Dizziness 3 1 Vascular disorders Hypertension 3 1 Table 6 lists the treatment-emergent adverse reactions reported in 4% or more of patients in the 52-week double-blind, placebo-controlled treatment phase of a trial assessing the efficacy and safety of risperidone for extended-release injectable suspension when administered as adjunctive maintenance treatment in patients with bipolar disorder.

Table

6: Adverse Reactions in ≥ 4% of Patients with Bipolar Disorder Treated with Risperidone for Extended-Release Injectable Suspension as Adjunctive Therapy in a 52-Week Double-Blind, Placebo-Controlled Trial System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone for Extended-Release Injectable Suspension+ Treatment as Usual a (N=72) Placebo + Treatment as Usual a (N=67) General disorders and administration site conditions Gait abnormal 4 0 Infections and infestations Upper respiratory tract infection 6 3 Investigations Weight increased 7 1 Metabolism and nutrition disorders Decreased appetite 6 1 Increased appetite 4 0 Musculoskeletal and connective tissue disorders Arthralgia 4 3 Nervous system disorders Tremor 24 16 Parkinsonism b 15 6 Dyskinesia b 6 3 Sedation c 7 1 Disturbance in attention 4 0 Reproductive system and breast disorders Amenorrhea 4 1 Respiratory, thoracic and mediastinal disorders Cough 4 1 a Patients received double-blind risperidone for extended-release injectable suspension or placebo in addition to continuing their treatment as usual, which included mood stabilizers, antidepressants and/or anxiolytics. b Parkinsonism includes muscle rigidity, hypokinesia, cogwheel rigidity and bradykinesia. Dyskinesia includes muscle twitching and dyskinesia. c Sedation includes sedation and somnolence.

Other Adverse Reactions Observed

During the Clinical Trial Evaluation of Risperidone The following additional adverse reactions occurred in < 2% of the risperidone for extended-release injectable suspension-treated patients in the above schizophrenia double-blind, placebo-controlled trial dataset, in < 2% of the risperidone for extended-release injectable suspension-treated patients in the above double-blind, placebo-controlled period of the monotherapy bipolar disorder trial dataset, or in < 4% of the risperidone for extended-release injectable suspension-treated patients in the above double-blind, placebo-controlled period of the adjunctive treatment bipolar disorder trial dataset. The following also includes additional adverse reactions reported at any frequency in risperidone for extended-release injectable suspension-treated patients who participated in the open-label phases of the above bipolar disorder studies and in other studies, including double-blind, active controlled and open-label studies in schizophrenia and bipolar disorder. Blood and lymphatic system disorders: anemia, neutropenia Cardiac disorders: tachycardia, atrioventricular block first degree, palpitations, sinus bradycardia, bundle branch block left, bradycardia, sinus tachycardia, bundle branch block right Ear and labyrinth disorders: ear pain, vertigo Endocrine disorders: hyperprolactinemia Eye disorders: conjunctivitis, visual acuity reduced Gastrointestinal disorders: diarrhea, vomiting, abdominal pain upper, abdominal pain, stomach discomfort, gastritis General disorders and administration site conditions: injection site pain, chest discomfort, chest pain, influenza like illness, sluggishness, malaise, induration, injection site induration, injection site swelling, injection site reaction, face edema Immune system disorders: hypersensitivity Infections and infestations: nasopharyngitis, influenza, bronchitis, urinary tract infection, rhinitis, respiratory tract infection, ear infection, pneumonia, lower respiratory tract infection, pharyngitis, sinusitis, viral infection, infection, localized infection, cystitis, gastroenteritis, subcutaneous abscess Injury and poisoning: fall, procedural pain Investigations: blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, gamma-glutamyl transferase increased, blood glucose increased, hepatic enzyme increased, aspartate aminotransferase increased, electrocardiogram QT prolonged, glucose urine present Metabolism and nutritional disorders: anorexia, hyperglycemia Musculoskeletal, connective tissue and bone disorders: posture abnormal, myalgia, back pain, buttock pain, muscular weakness, neck pain, musculoskeletal chest pain Nervous system disorders: coordination abnormal, dystonia, tardive dyskinesia, drooling, paresthesia, dizziness postural, convulsion, akinesia, hypokinesia, dysarthria Psychiatric disorders: insomnia, agitation, anxiety, sleep disorder, depression, initial insomnia, libido decreased, nervousness Renal and urinary disorders: urinary incontinence Reproductive system and breast disorders: galactorrhea, oligomenorrhea, erectile dysfunction, sexual dysfunction, ejaculation disorder, gynecomastia, breast discomfort, menstruation irregular, menstruation delayed, menstrual disorder, ejaculation delayed Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, dyspnea, rhinorrhea Skin and subcutaneous tissue disorders: rash, eczema, pruritus generalized, pruritus Vascular disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported with Oral RISPERDAL The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral RISPERDAL, regardless of frequency of occurrence: Blood and Lymphatic Disorders: granulocytopenia Cardiac Disorders: atrioventricular block Ear and Labyrinth Disorders: tinnitus Eye Disorders: ocular hyperemia, eye discharge, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma Gastrointestinal Disorders: abdominal pain upper, dysphagia, fecaloma, abdominal discomfort, fecal incontinence, lip swelling, cheilitis, aptyalism General Disorders: thirst, feeling abnormal, gait disturbance, pitting edema, edema, chills, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: tonsillitis, eye infection, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, heart rate increased, eosinophil count increased, white blood cell count decreased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia Musculoskeletal, Connective Tissue and Bone Disorders: joint swelling, joint stiffness, rhabdomyolysis, torticollis Nervous System Disorders: hypertonia, balance disorder, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, parkinsonian rest tremor, transient ischemic attack, cerebrovascular accident, masked facies, speech disorder, loss of consciousness, muscle contractions involuntary, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: blunted affect, confusional state, middle insomnia, listlessness, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: vaginal discharge, retrograde ejaculation, ejaculation disorder, ejaculation failure, breast enlargement Respiratory, Thoracic and Mediastinal Disorders: epistaxis, wheezing, pneumonia aspiration, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, skin disorder, rash erythematous, rash papular, hyperkeratosis, dandruff, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders: flushing Discontinuations Due to Adverse Reactions Schizophrenia Approximately 11% (22/202) of risperidone for extended-release injectable suspension-treated patients in the 12-week double-blind, placebo-controlled schizophrenia trial discontinued treatment due to an adverse event, compared with 13% (13/98) who received placebo. The adverse reactions associated with discontinuation in two or more risperidone for extended-release injectable suspension-treated patients were: agitation (3%), depression (2%), anxiety (1%) and akathisia (1%).

Bipolar

Disorder In the 24-month double-blind, placebo-controlled treatment period of the trial assessing the efficacy and safety of risperidone for extended-release injectable suspension when administered as monotherapy for maintenance treatment in patients with bipolar I disorder, 1 (0.6%) of 154 risperidone for extended-release injectable suspension-treated patients discontinued due to an adverse reaction (hyperglycemia). In the 52-week double-blind phase of the placebo-controlled trial in which risperidone for extended-release injectable suspension was administered as adjunctive therapy to patients with bipolar disorder in addition to continuing with their treatment as usual, approximately 4% (3/72) of risperidone for extended-release injectable suspension-treated patients discontinued treatment due to an adverse event, compared with 1.5% (1/67) of placebo-treated patients. Adverse reactions associated with discontinuation in risperidone for extended-release injectable suspension-treated patients were: hypokinesia (one patient) and tardive dyskinesia (one patient).

Dose

Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week double-blind, placebo-controlled trial comparing three doses of risperidone for extended-release injectable suspension (25 mg, 50 mg and 75 mg) with placebo in patients with schizophrenia, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS). As shown in Table 1, the overall incidence of EPS-related adverse reactions (akathisia, dystonia, parkinsonism and tremor) in patients treated with 25 mg risperidone for extended-release injectable suspension was comparable to that of patients treated with placebo; the incidence of EPS-related adverse reactions was higher in patients treated with 50 mg risperidone for extended-release injectable suspension. The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with risperidone for extended-release injectable suspension compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group).

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. Changes in ECG The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg risperidone for extended-release injectable suspension and 98 schizophrenic patients treated with placebo in the 12-week double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for extended-release injectable suspension. The electrocardiograms of 227 patients with Bipolar I Disorder were evaluated in the 24-month double-blind, placebo-controlled period. There were no clinically relevant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for extended-release injectable suspension compared to placebo. The electrocardiograms of 85 patients with bipolar disorder were evaluated in the 52-week double-blind, placebo-controlled trial. There were no statistically significant differences in QTc intervals (using Fridericia’s and linear correction factors) during treatment with risperidone for extended-release injectable suspension 25 mg, 37.5 mg, or 50 mg when administered as adjunctive treatment in addition to continuing treatment as usual compared to placebo.

Pain

Assessment and Local Injection Site Reactions The mean intensity of injection pain reported by patients with schizophrenia 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: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg risperidone for extended-release injectable suspension experienced redness, swelling, or induration at the injection site. In a separate study to observe local-site tolerability in which risperidone for extended-release injectable suspension was administered into the deltoid muscle every 2 weeks over a period of 8 weeks, no patient discontinued treatment due to local injection site pain or reaction. Clinician ratings indicated that only mild redness, swelling, or induration at the injection site was observed in subjects treated with 37.5 mg or 50 mg risperidone for extended-release injectable suspension at 2 hours after deltoid injection. All ratings returned to baseline at the pre-dose assessment of the next injection 2 weeks later. No moderate or severe reactions were observed in any subject.

6.2 Post-marketing Experience The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, catatonia, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention and water intoxication. In addition, the following adverse reactions have been observed during postapproval use of risperidone for extended-release injectable suspension: cerebrovascular disorders, including cerebrovascular accidents and diabetes mellitus aggravated. Retinal artery occlusion after injection of risperidone for extended-release injectable suspension has been reported during post-marketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis. Serious injection site reactions including abscess, cellulitis, cyst, hematoma, necrosis, nodule and ulcer have been reported with risperidone for extended-release injectable suspension during post-marketing surveillance. Isolated cases required surgical intervention. Very rarely, cases of anaphylactic reaction after injection with risperidone for extended-release injectable suspension have been reported during post-marketing experience in patients who have previously tolerated oral risperidone. Post-marketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis: Risperidone tablets are not approved for use in patients with dementia-related psychosis ( 5.2 )

Neuroleptic Malignant

Syndrome: Manage with immediate discontinuation of risperidone tablets and close monitoring. ( 5.3 ) Tardive dyskinesia: Consider discontinuing risperidone tablets if clinically indicated. ( 5.4 )

Metabolic

Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular / cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia and weight gain. ( 5.5 ) Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. ( 5.5 ) Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. ( 5.5 )

Weight

Gain : Significant weight gain has been reported. Monitor weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. ( 5.6 ) Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC). Consider discontinuing risperidone tablets if a clinically significant decline in WBC occurs in the absence of other causative factors. ( 5.9 ) Potential for cognitive and motor impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 )

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis 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. In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone tablets when compared to patients treated with risperidone tablets alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. Risperidone tablets are not approved for the treatment of dementia-related psychosis <span class="opacity-50 text-xs">[see Boxed Warning ]</span> .

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone tablets are not approved for the treatment of patients with dementia-related psychosis. <span class="opacity-50 text-xs">[see Boxed Warning and Warnings and Precautions (5.1) ]</span>

5.3 Neuroleptic Malignant Syndrome Antipsychotic drugs including risperidone tablets can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS are include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome 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, prescribe risperidone tablets 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: (1) 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, 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 risperidone tablets, consider drug discontinuation. However, some patients may require treatment with risperidone tablets despite the presence of the syndrome.

5.5 Metabolic Changes 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 atypical antipsychotics including risperidone 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. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone tablets, 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, including risperidone tablets, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone tablets, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone tablets, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone tablets. Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.

Table

2. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Tablets Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL)

Serum

Glucose n=555 - 1.4 n=748 0.8 n=164

0.6 Proportion of patients with shifts Serum Glucose (&lt;140 mg/dL to ≥200 mg/dL) 0.6% (3/525) 0.4% (3/702) 0% (0/158) In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50). Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.

Table

3. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age)

Risperidone Tablets Placebo

0.5-6 mg/day Mean change from baseline (mg/dL)

Serum

Glucose n=76 -1.3 n=135

2.6 Proportion of patients with shifts Serum Glucose (&lt;100 mg/dL to ≥126 mg/dL) 0% (0/64) 0.8% (1/120) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.

Table

4. Change in Random Lipids from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible -Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania Risperidone Tablets Placebo 1–8 mg/day >8–16 mg/day Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9

1.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4 -4.9 -8.3 Proportion of patients with shifts Cholesterol (&lt;200 mg/dL to ≥240 mg/dL) 2.7% (10/368) 4.3% (22/516) 6.3% (6/96)

Triglycerides

1.1% 2.7% 2.5% (<500 mg/dL to ≥500 mg/dL) (2/180) (8/301) (3/121) In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52). Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.

Table

5. Change in Fasting Lipids from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age)

Risperidone Tablets Placebo

0.5-6 mg/day Mean change from baseline (mg/dL) Cholesterol n=74 n=133 Change from baseline 0.3 -0.3 LDL n=22 n=22 Change from baseline 3.7

0.5 HDL n=22 n=22 Change from baseline 1.6 -1.9 Triglycerides n=77 n=138 Change from baseline -9.0 -2.6 Proportion of patients with shifts Cholesterol 2.4% 3.8% (&lt;170 mg/dL to ≥200 mg/dL) (1/42) (3/80) LDL 0% 0% (&lt;110 mg/dL to ≥130 mg/dL) (0/16) (0/16) HDL 0% 10% (≥40 mg/dL to &lt;40 mg/dL) (0/19) (2/20)

Triglycerides

1.5% 7.1% (<150 mg/dL to ≥200 mg/dL) (1/65) (8/113) In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).

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% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.

Table

6.

Mean

Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania Risperidone Tablets Placebo (n=597) 1–8 mg/day (n=769) >8–16 mg/day (n=158) Weight (kg) Change from baseline -0.3 0.7

2.2 Weight Gain ≥7% increase from baseline 2.9% 8.7% 20.9% In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203). Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.

Table

7.

Mean

Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo-Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age)

Placebo Risperidone Tablets

0.5–6 mg/day (n=375) (n=448) Weight (kg) Change from baseline 0.6

2.0 Weight Gain ≥7% increase from baseline 6.9% 32.6% In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242). In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients.

In

103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of risperidone tablets treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index. In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of risperidone tablets treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to risperidone tablets. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index. In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the risperidone tablets groups than the placebo group, but not dose related (1.90 kg in the risperidone tablets 0.5–2.5 mg group, 1.44 kg in the risperidone tablets 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index. When treating pediatric patients with risperidone tablets for any indication, weight gain should be assessed against that expected with normal growth.

5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone tablets elevates prolactin levels and the elevation persists during chronic administration. Risperidone tablets are associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin 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 contemplated in a patient with previously detected breast cancer. An increase in 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology (13.1) ]</span> . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

5.7 Orthostatic Hypotension Risperidone tablets may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone tablets-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.4 ) ]</span> . Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone tablets should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone tablets and antihypertensive medication.

5.8 Falls Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including risperidone 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.

5.9 Leukopenia, Neutropenia, and Agranulocytosis Class Effect : In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone tablets. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone tablets should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count &lt;1000/mm 3 ) should discontinue risperidone tablets and have their WBC followed until recovery.

5.10 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse reactions associated with risperidone tablets treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone tablets 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone tablets 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reation. Since risperidone tablets have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone tablets therapy does not affect them adversely.

5.11 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone tablets-treated patients, two in association with hyponatremia. Risperidone tablets should be used cautiously in patients with a history of seizures.

5.12 Dysphagia 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. Risperidone tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. <span class="opacity-50 text-xs">[see Boxed Warning and Warnings and Precautions (5.1) ]</span>

5.13 Priapism Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.

5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone tablets use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.

INTERACTIONS The interactions of Risperidone for Extended-Release Injectable Suspension with coadministration of other drugs have not been systematically evaluated. The drug interaction data provided in this section is based on studies with oral risperidone. Due to CNS effects, use caution when administering with other centrally-acting drugs. Avoid alcohol. ( 7.1 ) Due to hypotensive effects, hypotensive effects of other drugs with this potential may be enhanced. ( 7.2 ) Effects of levodopa and dopamine agonists may be antagonized. ( 7.3 ) Cimetidine and ranitidine increase the bioavailability of risperidone. ( 7.5 ) Clozapine may decrease clearance of risperidone. ( 7.7 ) Fluoxetine and paroxetine increase plasma concentrations of risperidone. ( 7.12 ) Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. ( 7.13 )

7.1 Centrally-Acting Drugs and Alcohol Given the primary CNS effects of risperidone, caution should be used when Risperidone for Extended-Release Injectable Suspension is administered in combination with other centrally-acting drugs or alcohol.

7.2 Drugs with Hypotensive Effects Because of its potential for inducing hypotension, Risperidone for Extended-Release Injectable Suspension may enhance the hypotensive effects of other therapeutic agents with this potential.

7.3 Levodopa and Dopamine Agonists Risperidone for Extended-Release Injectable Suspension may antagonize the effects of levodopa and dopamine agonists.

7.4 Amitriptyline Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral risperidone.

7.5 Cimetidine and Ranitidine Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

7.6 Methylphenidate Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of Risperidone for Extended-Release Injectable Suspension and methylphenidate <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> .

7.7 Clozapine Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

7.8 Lithium Repeated doses of oral risperidone (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C max ) of lithium (N=13).

7.9 Valproate Repeated doses of oral risperidone (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (N=21). However, there was a 20% increase in valproate peak plasma concentration (C max ) after concomitant administration of oral risperidone.

7.10 Digoxin Oral risperidone (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

7.11 Topiramate Oral risperidone administered at doses from 1 to 6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone C max and a 33% decrease in risperidone AUC 0-12 hour at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral risperidone on the pharmacokinetics of topiramate.

7.12 Drugs That Inhibit CYP 2D6 and Other CYP Isozymes Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n≅70 patients) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made. In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism. Fluoxetine and Paroxetine Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5 to 2.8 fold and 3 to 9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of Risperidone for Extended-Release Injectable Suspension. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of Risperidone for Extended-Release Injectable Suspension between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg Risperidone for Extended-Release Injectable Suspension, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the Risperidone for Extended-Release Injectable Suspension dose to 12.5 mg or necessitates interruption of Risperidone for Extended-Release Injectable Suspension treatment.

When

Risperidone for Extended-Release Injectable Suspension is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials [see also Dosage and Administration ( 2.5 )] . The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Erythromycin

There were no significant interactions between oral risperidone and erythromycin.

7.13 Carbamazepine and Other CYP 3A4 Enzyme Inducers Carbamazepine coadministration with oral risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Coadministration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of Risperidone for Extended-Release Injectable Suspension treatment. At the initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4 to 8 weeks, since the dose of Risperidone for Extended-Release Injectable Suspension may need to be adjusted. A dose increase, or additional oral risperidone, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of Risperidone for Extended-Release Injectable Suspension should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of Risperidone for Extended-Release Injectable Suspension between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg Risperidone for Extended-Release Injectable Suspension and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25 mg dose unless clinical judgment necessitates lowering the Risperidone for Extended-Release Injectable Suspension dose to 12.5 mg or necessitates interruption of Risperidone for Extended-Release Injectable Suspension treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials <span class="opacity-50 text-xs">[see also Dosage and Administration ( 2.5 )]</span>

7.14 Drugs Metabolized by CYP 2D6 In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, Risperidone for Extended-Release Injectable Suspension is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, oral risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.