Risperidone tablet, film coated

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Spl product data elements section

Spl product data elements section

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Recent major changes

Warnings and Precautions ( 5.4) 07/2018

Boxed warning

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIARELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions ( 5.1)]

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS

WITH DEMENTIA-RELATED PSYCHOSIS

See full prescribing information for complete boxed warning.

  • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
  • Risperidone is not approved for use in patients with dementia-related psychosis. ( 5.1)

1 indications and usage

Risperidone is an 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)

2 dosage and administration

Table 1 Recommended Daily Dosage by Indication

Initial Dose
Titration
(Increments)
Target Dose
Effective Dose
Range
Schizophrenia: adults ( 2.1)
2 mg
1 to 2 mg
4 to 8 mg
4 to 16 mg
Schizophrenia:
adolescents
( 2.2)
0.5 mg
0.5 to 1 mg
3 mg
1 to 6 mg
Bipolar mania: adults ( 2.2)
2 to 3 mg
1 mg
1 to 6 mg
1 to 6 mg
Bipolar mania:
children and
adolescents
( 2.2)
0.5 mg
0.5 to 1 mg
1 to 2.5 mg
1 to 6 mg
Irritability in autistic
disorder ( 2.3)
0.25 mg
Can increase to
0.5 mg by Day 4:
(body weight less
than 20 kg)
0.5 mg
Can increase to
1 mg by Day 4:
(body weight
greater than or
equal to 20 kg)
After Day 4, at
intervals of > 2
weeks:
0.25 mg
(body weight less
than 20 kg)
0.5 mg
(body weight
greater than or
equal to 20 kg)
0.5 mg:
(body weight less
than 20 kg)
1 mg:
(body weight
greater than or
equal to 20 kg)
0.5 to
3 mg

Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily.

May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.

  • Recommended daily dosage:
Table 1 Recommended Daily Dosage by Indication

Initial Dose
Titration
(Increments)
Target Dose
Effective
Dose
Range
Schizophrenia: adults ( 2.1)
2 mg
1 to 2 mg
4 to 8 mg
4 to 16 mg
Schizophrenia: adolescents ( 2.2)
0.5 mg
0.5 to 1 mg
3 mg
1 to 6 mg
Bipolar mania: adults ( 2.2)
2 to 3 mg
1 mg
1 to 6 mg
1 to 6 mg
Bipolar mania: children and adolescents ( 2.2)
0.5 mg
0.5 to 1 mg
1 to 2.5 mg
1 to 6 mg
Irritability in autistic disorder ( 2.3)
0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg)
0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg)
After Day 4, at intervals of > 2 weeks: 0.25 mg
(body weight less than 20 kg)
0.5 mg (body weight greater than or equal to 20 kg)
0.5 mg: (body weight less than 20 kg)
1 mg: (body weight greater than or equal to 20 kg)
0.5 to 3 mg
  • Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. ( 2.4)

3 dosage forms and strengths

The round-shaped, film-coated tablets are available in the following strengths, colors and debossing: 0.25 mg - dark yellow and debossed with "Z" and "4"; 0.5 mg - red-brown, debossed with "Z" and "6"; 1 mg - white to off-white and debossed with "ZC 75"; 2 mg - orange and debossed with "ZC 76"; 3 mg yellow and debossed with "ZC 77" and 4 mg - green and debossed with "ZC 78".

  • Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg ( 3)

4 contraindications

Risperidone is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone 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 ( 4)

5 warnings and precautions

  • Cerebrovascular events, including stroke, in elderly patients with dementiarelated psychosis: risperidone is not approved for use in patients with dementia-related psychosis. ( 5.2)
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of risperidone and close monitoring. ( 5.3)
  • Tardive dyskinesia: Consider discontinuing risperidone 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 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)

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 (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [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)]

The most common adverse reactions in clinical trials (> 5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions ( 6.1)].

The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in doubleblind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) doubleblind, 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 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

The most common adverse reactions in clinical trials (> 5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals

USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

7 drug interactions

  • Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the risperidone dose up to double the patient's usual dose. Titrate slowly. ( 7.1)
  • Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of risperidone. ( 7.1)

8 use in specific populations

8.1 pregnancy

Pregnancy Exposure Registry

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

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to 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, during pregnancy (see Clinical Considerations).

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 MRHD based on mg/m 2body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m 2body 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 2body 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 2body 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, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI 0.881.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.

Animal Data

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m 2body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m 2body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m 2body surface area; postnatal development and growth of the offspring were also delayed.

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the MRHD based on mg/m 2body surface area.

In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD based on mg/m 2and the only dose tested in the study.

8.4 pediatric use

Approved Pediatric Indications

Schizophrenia

The efficacy and safety of risperidone in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 to 17 years, in two short-term (6 and 8 weeks, respectively) doubleblind controlled trials [see Indications and Usage ( 1.1), Adverse Reactions ( 6.1), and Clinical Studies ( 14.1)]. Additional safety and efficacy information was also assessed in one long-term (6 month) open-label extension study in 284 of these adolescent patients with schizophrenia.

Safety and effectiveness of risperidone in children less than 13 years of age with schizophrenia have not been established.

Bipolar I Disorder

The efficacy and safety of risperidone in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 to 17 years, were demonstrated in one doubleblind, placebo-controlled, 3 week trial [see Indications and Usage ( 1.2), Adverse Reactions ( 6.1), and Clinical Studies ( 14.2)].

Safety and effectiveness of risperidone in children less than 10 years of age with bipolar disorder have not been established.

Autistic Disorder

The efficacy and safety of risperidone in the treatment of irritability associated with autistic disorder were established in two 8 week, doubleblind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage ( 1.3), Adverse Reactions ( 6.1) and Clinical Studies ( 14.4)]. Additional safety information was also assessed in a long-term study in patients with autistic disorder, or in short- and long-term studies in more than 1200 pediatric patients with psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania who were of similar age and weight, and who received similar dosages of risperidone as patients treated for irritability associated with autistic disorder.

A third study was a 6 week, multicenter, randomized, doubleblind, placebo-controlled, fixeddose study to evaluate the efficacy and safety of a lower than recommended dose of risperidone in subjects 5 to 17 years of age with autistic disorder and associated irritability, and related behavioral symptoms. There were two weight-based, fixed-doses of risperidone (high-dose and low-dose). The high dose was 1.25 mg per day for patients weighing 20 to < 45 kg, and it was 1.75 mg per day for patients weighing > 45 kg. The low dose was 0.125 mg per day for patients for patients weighing 20 to < 45 kg, and it was 0.175 mg per day for patients weighing > 45 kg. The study demonstrated the efficacy of high-dose risperidone, but it did not demonstrate efficacy for low-dose risperidone.

Adverse Reactions in Pediatric Patients

Tardive Dyskinesia

In clinical trials in 1885 children and adolescents treated with risperidone, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone treatment [see also Warnings and Precautions ( 5.4)].

Weight Gain

Weight gain has been observed in children and adolescents during treatment with risperidone. Clinical monitoring of weight is recommended during treatment.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for risperidone-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the risperidone group had weight gain > 7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48 [see Warnings and Precautions ( 5.5) and Adverse Reactions ( 6.1)].

Somnolence

Somnolence was frequently observed in placebo-controlled clinical trials of pediatric patients with autistic disorder. Most cases were mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first two weeks of treatment, and transient with a median duration of 16 days. Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents. As was seen in the autistic disorder trials, these adverse reactions were most often of early onset and transient in duration [see Adverse Reactions ( 6.1and 6.2)]. Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage and Administration ( 2.1, 2.2, and 2.3)].

Hyperprolactinemia

Risperidone has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions ( 5.6)]. In doubleblind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received risperidone had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82 to 87% of patients who received risperidone had elevated levels of prolactin compared to 3 to 7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.

In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of risperidone-treated patients and gynecomastia was reported in 2.3% of risperidone-treated patients.

Growth and Sexual Maturation

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

Juvenile Animal Studies

Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9hydroxy-risperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m 2body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

8.5 geriatric use

Clinical studies of risperidone in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3) and Dosage and Administration ( 2.4, 2.5)]. While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg twice daily followed by careful titration [see Warnings and Precautions ( 5.7)]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration ( 2.4)].

9 drug abuse and dependence

9.1 controlled substance

Risperidone is not a controlled substance.

9.2 abuse

Risperidone has not been systematically studied in animals or humans for its potential for abuse. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of risperidone misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3 dependence

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

10 overdosage

11 description

Risperidone Tablets 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-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23H 27FN 4O 2and its molecular weight is 410.49. The structural formula is:

Risperidone, USP 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 NHCl.

Each risperidone tablet intended for oral administration contains 0.25 mg or 0.5 mg or 1 mg or 2 mg or 3 mg or 4 mg of risperidone. Additionally each tablet also contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and titanium dioxide. Additionally each 0.25 mg tablet contains iron oxide red and iron oxide yellow, 0.5 mg tablet contains iron oxide red, 2 mg tablet contains FD&C yellow # 6/sunset yellow FCF aluminum lake, 3 mg tablet contains D&C yellow # 10 aluminum lake and 4 mg tablet contains D&C yellow # 10 aluminum lake and FD&C blue # 2/ indigo carmine aluminum lake.

12 clinical pharmacology

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 metabolite, 9-hydroxyrisperidone (paliperidone) [see Clinical Pharmacology ( 12.3)]. Antagonism at receptors other than D 2and 5HT 2may explain some of the other effects of risperidone [see Clinical Pharmacology ( 12.1)].

12.2 pharmacodynamics

Risperidone is a monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT 2), dopamine Type 2 (D 2), 1and 2adrenergic, and H 1histaminergic receptors. Risperidone showed low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT 1C, 5HT 1D, and 5HT 1Areceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D 1and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10 -5M) for cholinergic muscarinic or 1and 2adrenergic receptors.

12.3 pharmacokinetics

Absorption

Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Pharmacokinetic studies showed that Risperidone Orally Disintegrating Tablets and Risperidone Oral Solution are bioequivalent to Risperidone Tablets.

Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers).

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.

Distribution

Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and 1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.

Risperidone could be subject to two kinds of drug-drug interactions. First, inhibitors of CYP 2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone [see Drug Interactions ( 7)]. This occurs with quinidine, giving essentially all recipients a risperidone pharmacokinetic profile typical of poor metabolizers. The therapeutic benefits and adverse effects of risperidone in patients receiving quinidine have not been evaluated, but observations in a modest number (n@70) of poor metabolizers given risperidone do not suggest important differences between poor and extensive metabolizers. Second, co-administration of known enzyme inducers (e.g., carbamazepine, phenytoin, rifampin, and phenobarbital) with risperidone may cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone [see Drug Interactions ( 7)]. It would also be possible for risperidone to interfere with metabolism of other drugs metabolized by CYP 2D6. Relatively weak binding of risperidone to the enzyme suggests this is unlikely [see Drug Interactions (7)].

In vitrostudies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

In vitrostudies demonstrated that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Excretion

Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.

The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Drug-Drug Interaction Studies

[see Drug Interactions ( 7)] .

Specific Populations

Renal and Hepatic Impairment

[See Use in Specific Populations ( 8.6And 8.7)] .

Elderly

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients [see Use in Specific Populations ( 8.5)].

Pediatric

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.

Race and Gender Effects

No specific pharmacokinetic study was conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.

13 nonclinical toxicology

13.1 carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to approximately 0.2, 0.75, and 3 times (mice) and 0.4, 1.5, and 6 times (rats) the MRHD of 16 mg/day, based on mg/m 2body surface area. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The table below summarizes the multiples of the human dose on a mg/m 2(mg/kg) basis at which these tumors occurred.

Multiples of Maximum
Human Dose in mg/m 2
(mg/kg)
Tumor Type
Species
Sex
Lowest
Highest No-
Effect Level
Effect Level
Pituitary adenomas
mouse
female
0.75 (9.4)
0.2 (2.4)
Endocrine pancreas adenomas
rat
male
1.5 (9.4)
0.4 (2.4)
Mammary gland adenocarcinomas
mouse
female
0.2 (2.4)
none
rat
female
0.4 (2.4)
none
rat
male
6 (37.5)
1.5 (9.4)
Mammary gland neoplasm, Total
rat
male
1.5 (9.4)
0.4 (2.4)

Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5-6 fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin-mediated. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear [see Warnings and Precautions ( 5.6)].

Mutagenesis

No evidence of mutagenic or clastogenic potential for risperidone was found in the in vitrotests of Ames gene mutation, the mouse lymphoma assay, rat hepatocyte DNA-repair assay, the chromosomal aberration test in human lymphocytes, Chinese hamster ovary cells, or in the in vivo oral micronucleus test in mice and the sex-linked recessive lethal test in Drosophila.

Impairment of Fertility

Oral risperidone (0.16 to 5 mg/kg) impaired mating, but not fertility, in rat reproductive studies at doses 0.1 to 3 times the MRHD of 16 mg/day based on mg/m 2body surface area. The effect appeared to be in females, since impaired mating behavior was not noted in the male fertility study. In a subchronic study in Beagle dogs in which risperidone was administered orally at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD based on mg/m 2body surface area. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. A no-effect dose could not be determined in either rat or dog.

14 clinical studies

16 how supplied/storage and handling

16.1 how supplied

Risperidone Tablets USP, 0.25 mg are dark yellow, round, biconvex film-coated tablets debossed with "Z" on one side and "4" on the other side and are supplied as follows:

NDC 65841-665-06in bottle of 30 tablets

NDC 65841-665-14 in bottle of 60 tablets

NDC 65841-665-16 in bottle of 90 tablets

NDC 65841-665-01 in bottle of 100 tablets

NDC 65841-665-05 in bottle of 500 tablets

NDC 65841-665-10 in bottle of 1000 tablets

Risperidone Tablets USP, 0.5 mg are red-brown colored, round, biconvex film-coated tablets debossed with "Z" on one side and "6" on other side and are supplied as follows:

NDC 65841-666-06 in bottle of 30 tablets

NDC 65841-666-14 in bottle of 60 tablets

NDC 65841-666-16 in bottle of 90 tablets

NDC 65841-666-01 in bottle of 100 tablets

NDC 65841-666-05 in bottle of 500 tablets

NDC 65841-666-10 in bottle of 1000 tablets

Risperidone Tablets USP, 1 mg are white to off-white, round, biconvex film-coated tablets debossed with "ZC 75" on one side and plain on other side and are supplied as follows:

NDC 65841-667-06 in bottle of 30 tablets

NDC 65841-667-14 in bottle of 60 tablets

NDC 65841-667-16 in bottle of 90 tablets

NDC 65841-667-01 in bottle of 100 tablets

NDC 65841-667-05 in bottle of 500 tablets

NDC 65841-667-10 in bottle of 1000 tablets

Risperidone Tablets USP, 2 mg are orange, round, biconvex film-coated tablets debossed with "ZC 76" on one side and plain on other side and are supplied as follows:

NDC 65841-668-06 in bottle of 30 tablets

NDC 65841-668-14 in bottle of 60 tablets

NDC 65841-668-16 in bottle of 90 tablets

NDC 65841-668-01 in bottle of 100 tablets

NDC 65841-668-05 in bottle of 500 tablets

NDC 65841-668-10 in bottle of 1000 tablets

Risperidone Tablets USP, 3 mg are yellow, round, biconvex film-coated tablets debossed with "ZC 77"on one side and plain on other side and are supplied as follows:

NDC 65841-669-06 in bottle of 30 tablets

NDC 65841-669-14 in bottle of 60 tablets

NDC 65841-669-16 in bottle of 90 tablets

NDC 65841-669-01 in bottle of 100 tablets

NDC 65841-669-05 in bottle of 500 tablets

NDC 65841-669-10 in bottle of 1000 tablets

Risperidone Tablets USP, 4 mg are green, round, biconvex film-coated tablets debossed with "ZC 78" on one side and plain on other side and are supplied as follows:

NDC 65841-670-06 in bottle of 30 tablets

NDC 65841-670-14 in bottle of 60 tablets

NDC 65841-670-16 in bottle of 90 tablets

NDC 65841-670-01 in bottle of 100 tablets

NDC 65841-670-05 in bottle of 500 tablets

NDC 65841-670-10 in bottle of 1000 tablets

16.2 storage and handling

Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature]. Protect from light and moisture.

Dispense in a tight, light-resistant container.

Keep out of reach of children.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

17 patient counseling information

Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone and their caregivers:

Orthostatic Hypotension

Advise patients and caregivers about the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions ( 5.7)].

Interference with Cognitive and Motor Performance

Inform patients and caregivers that risperidone has the potential to impair judgment, thinking, or motor skills. Advise caution about operating hazardous machinery, including automobiles, until patients are reasonably certain that risperidone therapy does not affect them adversely [see Warnings and Precautions ( 5.10)].

Concomitant Medication

Advise patients and caregivers to inform their physicians if the patient is taking, or plans to take, any prescription or over-the-counter drugs, because there is a potential for interactions [see Drug Interactions ( 7)].

Alcohol

Advise patients to avoid alcohol while taking risperidone [see Drug Interactions ( 7.2)].

Metabolic Changes

Inform patients and caregivers that treatment with risperidone can be associated with hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain [see Warnings and Precautions ( 5.5)].

Tardive Dyskinesia

Inform patients and caregivers about the risk of tardive dyskinesia [see Warnings and Precautions ( 5.4)].

Pregnancy

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

Lactation

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

Infertility

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

Brands listed are trademarks of their respective owners.

Spl unclassified section

Manufactured by:

Cadila Healthcare Limited

India

Rev.: 02/19

Ingredients and appearance - Product information

Risperidone tablet, film coated- Risperidone

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 65841-665
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Risperidone ( UNII: L6UH7ZF8HC)( Risperidone - UNII: L6UH7ZF8HC ) 0.25 mgin 1

Inactive Ingredients

Ingredient Name Code
Ferric oxide yellow ( UNII: EX438O2MRT)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propylene glycol ( UNII: 6DC9Q167V3)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Titanium dioxide ( UNII: 15FIX9V2JP)
Ferric oxide red ( UNII: 1K09F3G675)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Starch, corn ( UNII: O8232NY3SJ)

Product Characteristics

Color YELLOW (DARK YELLOW) Shape ROUND (ROUND)
Size 5 mm Score 1
Imprint Code Z;4

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA078040 USA

Labeler - Cadila Healthcare Limited( 918596198)

Establishment

Name ID/FEI Business Operations
Cadila Healthcare Limited 918596198 ANALYSIS( 65841-665, 65841-666, 65841-667, 65841-668, 65841-669, 65841-670), MANUFACTURE( 65841-665, 65841-666, 65841-667, 65841-668, 65841-669, 65841-670)

Package label.principal display panel

Risperidone Tablets USP, 0.25 mg

NDC 65841-665-14

60 tablets

Rx only

Risperidone Tablets USP, 0.5 mg

NDC 65841-666-14

60 tablets

Rx only

Risperidone Tablets USP, 1 mg

NDC 65841-667-14

60 Tablets

Rx only

Risperidone Tablets USP, 2 mg

NDC 65841-668-14

60 Tablets

Rx only

Risperidone Tablets USP, 3 mg

NDC 65841-669-14

60 Tablets

Rx only

Risperidone Tablets USP, 4 mg

NDC 65841-670-14

60 Tablets

Rx only