risperidone

Warnings and Precautions (5.6) 1/2025 Warnings and Precautions ( 5.6 ) 1/2025

1 INDICATIONS AND USAGE Risperidone for Extended-Release Injectable Suspension is an atypical antipsychotic indicated: for the treatment of schizophrenia. ( 1.1 ) as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder. ( 1.2 ) 1.1 Schizophrenia Risperidone for Extended-Release Injectable Suspension is indicated for the treatment of schizophrenia [see Clinical Studies ( 14.1 )] . 1.2 Bipolar Disorder Risperidone for Extended-Release Injectable Suspension is indicated as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of Bipolar I Disorder [see Clinical Studies ( 14.2 , 14.3 )] .

2 DOSAGE AND ADMINISTRATION For patients who have never taken oral risperidone, it is recommended to establish tolerability with oral risperidone 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 risperidone, tolerability should be established with oral risperidone 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 risperidone (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 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 intramuscular every 2 weeks. Some patients may benefit from a higher dose of 37.5 mg or 50 mg. Dosages above …

3 DOSAGE FORMS AND STRENGTHS Risperidone for Extended-Release Injectable Suspension is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, and 50 mg risperidone. It is provided as a single-dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for Risperidone for Extended-Release Injectable Suspension, a vial adapter, and two Terumo SurGuard ® 3 Needles for intramuscular injection (a 21 G UTW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration). Vial kits: 12.5 mg, 25 mg, 37.5 mg, and 50 mg ( 3 )

4 CONTRAINDICATIONS Risperidone for Extended-Release Injectable Suspension is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the Risperidone for Extended-Release Injectable Suspension 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. Known hypersensitivity to risperidone, paliperidone, or to any excipients in Risperidone for Extended-Release Injectable Suspension. ( 4 )

6 ADVERSE 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 2392 patients exposed to one or more doses of Risperidone for Extended-Release Injectable Suspension for the treatment of schizophrenia. Of these 2392 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 a …

7 DRUG 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 [see Adverse Reactions (6.2)] . 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 [see Clinical Pharmacology ( 12.3 )] . Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the p …

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. ( 8.1 ) Renal or Hepatic Impairment: dose appropriately with oral RISPERDAL ® prior to initiating treatment with risperidone for extended-release injectable suspension. A lower starting dose of risperidone for extended-release injectable suspension of 12.5 mg may be appropriate in some patients. ( 2.4 ) Pediatric Use: safety and effectiveness not established in patients less than 18 years of age. ( 8.4 ) Elderly: dosing for otherwise healthy elderly patients is the same as for healthy nonelderly. Elderly may be more predisposed to orthostatic effects than nonelderly. ( 8.5 ) 8.1 Pregnancy 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 risperidone 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 or bipolar I disorder and with exposure to antipsychotics, including risperidone for extended-release injectable suspension, during pregnancy (see Clinical Considerations) . Risperidone has been detected in plasma in adult subjects up to 8 weeks after a single-dose administration of risperidone for extended-release injectable suspension [see Clinical Pharmacology ( 12.3 )] . The clinical significance of risperidone for extended-release injectable suspension administered before pregnancy or anytime during pregnancy is not known. Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times the MRHD based on mg/m 2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m 2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, 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 risperidone for extended-release injectable suspension, 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 …

12.1 Mechanism of Action The mechanism of action of risperidone in schizophrenia is unclear. The drug’s therapeutic activity in schizophrenia could be mediated through a combination of dopamine Type 2 (D 2 ) and serotonin Type 2 (5HT 2 ) receptor antagonism. The clinical effect from risperidone results from the combined concentrations of risperidone and its major active metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3 )] . Antagonism at receptors other than D 2 and 5HT 2 may explain some of the other effects of risperidone [see Clinical Pharmacology ( 12.1 )] .

11 DESCRIPTION Risperidone for extended-release injectable suspension contains risperidone, 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-4-Hpyrido[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 Risperidone is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl. Risperidone for extended-release injectable suspension is a combination of extended-release microspheres for injection and diluent for parenteral use. The extended-release microspheres formulation is an off-white to slightly yellow, free flowing sterile powder that is available in dosage strengths of 25 mg, 37.5 mg or 50 mg risperidone per vial. Risperidone is micro-encapsulated in 7525 polylactide-co-glycolide (PLG) at a concentration of 381 mg risperidone per gram of microspheres. The diluent for parenteral use is a clear, colorless, sterile solution. Composition of the diluent includes 1 mg/mL citric acid anhydrous, 1.27 mg/mL disodium hydrogen phosphate dihydrate, 1 mg/mL polysorbate 20, 22.5 mg sodium carboxymethyl cellulose, 6 mg/mL sodium chloride, 0.54 mg/mL sodium hydroxide, and water for injection. The microspheres are suspended in the diluent prior to injection. Risperidone for extended-release injectable suspension is provided as a single dose pack, consisting of a vial containing the microspheres, a pre-filled syringe containing the diluent, a vial adapter, and two Terumo SurGuard ® 3 Needles (a 21 G UTW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration). Risperidone

10 OVERDOSAGE 10.1 Human Experience No cases of overdose were reported in premarketing studies with risperidone for extended-release injectable suspension. Because risperidone for extended-release injectable suspension is to be administered by health care professionals, the potential for overdosage by patients is low. In premarketing experience with oral RISPERDAL ® , there were eight reports of acute RISPERDAL ® overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure. Postmarketing experience with oral RISPERDAL ® includes reports of acute overdose, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to oral RISPERDAL ® overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral RISPERDAL ® and paroxetine. 10.2 Management of Overdosage In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension. There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. 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 risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

16 HOW SUPPLIED/STORAGE AND HANDLING Risperidone for Extended-Release Injectable Suspension is available in dosage strengths of 12.5 mg, 25 mg, 37.5 mg, or 50 mg risperidone, USP. It is provided as a single-dose pack, consisting of a vial containing the risperidone microspheres, a pre-filled syringe containing 2 mL of diluent for risperidone for extended-release injectable suspension, a vial adapter and two Terumo SurGuard ® 3 Needles for intramuscular injection (a 21 G TW 1-inch needle with needle protection device for deltoid administration and a 20 G TW 2-inch needle with needle protection device for gluteal administration). They are available as below: 12.5 mg vial/kit: Contains 41 mg risperidone microspheres (equivalent to 12.5 mg of risperidone, USP) is a white to off-white powder provided in a clear glass vial with a purple flip-off seal cap. 12.5 mg Vial: NDC 70121-1350-1 12.5 mg Kit: NDC 70121-2625-5 25 mg vial/kit: Contains 78 mg risperidone microspheres (equivalent to 25 mg of risperidone, USP) is a white to off-white powder provided in a clear glass vial with a red flip-off seal cap. 25 mg Vial: NDC 70121-1351-1 25 mg Kit: NDC 70121-2626-5 37.5 mg vial/kit: Contains 116 mg risperidone microspheres (equivalent to 37.5 mg of risperidone, USP) is a white to off-white powder provided in a clear glass vial with a green flip-off seal cap. 37.5 mg Vial: NDC 70121-1352-1 37.5 mg Kit: NDC 70121-2627-5 50 mg vial/kit: Contains 152 mg risperidone microspheres (equivalent to 50 mg of risperidone, USP) is a white to off-white powder provided in a clear glass vial with a blue flip-off seal cap. 50 mg Vial: NDC 70121-1353-1 50 mg Kit: NDC 70121-2628-5 Storage and Handling The entire single-dose pack should be stored in the refrigerator (36°F to 46°F; 2°C to 8°C) and protected from light. If refrigeration is unavailable, risperidone for extended-release injectable suspension can be stored at temperatures not exceeding 77°F (25°C) for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 77°F (25°C). Keep out of reach of children.