Risperidone tablet, film coated

Boxed warning section

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)

Spl unclassified section

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 (risperidone) is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions ( 5.1)]

Recent major changes

Warnings and Precautions ( 5.8) 02/2017

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

  • Recommended daily dosage:
Summary of Heart Protection Study Results

InitialDose
TargetDose
EffectiveDose



Range
Schizophrenia:
adults(2.1)
2mg
4to8mg
4to16mg
Schizophrenia:
adolescents
(2.1)
0.5mg
3mg
1to6mg
Bipolarmania:Adults(2.2)
2to3mg
1to6mg
1to6mg
Bipolarmania:in
childrenand
adolescents
(2.2)
0.5mg
1to2.5mg
1to6mg
Irritability
associatedwith
autisticdisorder
0.25mg
(Weight<20
kg)
0.5mg
(<20kg)
0.5to3mg
(2.3)

1mg


0.5mg
(Weight20
kg)
(20kg)

  • 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)

Spl unclassified section

Table 1Recommended Daily Dosage by Indication

Initial Dose
Titration
( Increments )
Target Dose
Effective Dose
Range
Schizophrenia : adults ( 2 . 1 )
2mg
1to2mg
4to8mg
4to16mg
Schizophrenia :
adolescents
( 2 . 2 )
0.5mg
0.5to1mg
3mg
1to6mg
Bipolar mania : adults ( 2 . 2 )
2to3mg
1mg
1to6mg
1to6mg
Bipolar mania :
children and
adolescents
( 2 . 2 )
0.5mg
0.5to1mg
1to2.5mg
1to6mg
Irritability in autistic
disorder ( 2 . 3 )
0.25mg
Canincreaseto
0.5mgbyDay4:
(bodyweightless
than20kg)

0.5mg
Canincreaseto
1mgbyDay4:
(bodyweight
greaterthanor
equalto20kg)
AfterDay4,at
intervalsof>2
weeks:
0.25mg
(bodyweightless
than20kg)

0.5mg
(bodyweight
greaterthanor
equalto20kg)
0.5mg:
(bodyweightless
than20kg)


1mg:
(bodyweight
greaterthanor
equalto20kg)
0.5to
3mg

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

3 dosage forms and strengths

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

Spl unclassified section

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".

4 contraindications

  • Known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERIDONE (4)

Spl unclassified section

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.

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)

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

  • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)
  • Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. ( 8.3)

8.1 pregnancy

Pregnancy Category C.

Risk Summary

Adequate and well controlled studies with RISPERIDONE have not been conducted in pregnant women. Neonates exposed to antipsychotic drugs (including RISPERIDONE) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There was no increase in the incidence of malformations in embryo-fetal studies in rats and rabbits at 0.4 to 6 times MHRD. Increased pup mortality was noted at all doses in peripostnatal studies in rats. RISPERIDONE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor neonates exhibiting extrapyramidal or withdrawal symptoms. Some neonates recover within hours or days without specific treatment; others may require prolonged hospitalization.

Data

Human Data

There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in neonates following in uteroexposure to antipsychotics in the third trimester. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

There was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERIDONE therapy is unknown

Animal Data

The teratogenic potential of risperidone was studied in three Segment II studies in Sprague- Dawley and Wistar rats (0.63 to 10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m 2body surface area basis) and in one Segment II study in New Zealand rabbits (0.31 to 5 mg/kg or 0.4 to 6 times the MRHD on a mg/m 2body surface area basis). There were no teratogenic effects in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m 2body surface area basis. In three reproductive studies in rats (two Segment III and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16 to 5 mg/kg or 0.1 to 3 times the MRHD on a mg/m 2body surface area basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

There was no no-effect dose for increased rat pup mortality. In one Segment III study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m 2body surface area basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups were observed, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control but reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m 2body surface area basis.Placental transfer of risperidone occurs in rat pups.

8.2 labor and delivery

The effect of RISPERIDONE on labor and delivery in humans is unknown.

8.3 nursing mothers

Risperidone and 9-hydroxyrisperidone are present in human breastmilk. Because of the potential for serious adverse reactions in nursing infants from risperidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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 for 40 weeks with oral risperidone doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone length and density were seen, with a no-effect dose of 0.31 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus its active metabolite paliperidone (9-hydroxy-risperidone) which were similar to those in children and adolescents receiving the maximum recommended human dose (MRHD) of 6 mg/day. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.

In a study in which juvenile rats were treated with oral risperidone from days 12 to 50 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0.63 mg/kg/day. This dose produced plasma levels (AUC) of risperidone plus paliperidone about half those observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest testable dose (1.25 mg/kg/day). This dose produced plasma levels (AUC) of risperidone plus paliperidone which were about two thirds of those observed in humans at the MRHD.

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 (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 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:

Structural Formula

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 unknown. However, it has been proposed that 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 [see CLINICAL PHARMACOLOGY ( 12.3)]. Antagonism at receptors other than D 2and 5HT 2[see CLINICAL PHARMACOLOGY ( 12.1)] may explain some of the other effects of RISPERIDONE.

12.2 pharmacodynamics

RISPERIDONE is a selective 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 acts as an antagonist at other receptors, but with lower potency. RISPERIDONE has 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

14 clinical studies

16 how supplied/storage and handling

17 patient counseling information

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

17.3 pregnancy

Advise patients and caregivers to notify their physician if the patient becomes pregnant or intends to become pregnant during therapy [see USE IN SPECIFIC POPULATIONS ( 8.1)].

Spl unclassified section

Manufactured by:

Cadila Healthcare Limited

India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 03/17

Ingredients and appearance - Product information

Risperidone tablet, film coated- Risperidone

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 49349-271
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Risperidone ( UNII: L6UH7ZF8HC)( Risperidone - UNII: L6UH7ZF8HC ) 2 mgin 1

Inactive Ingredients

Ingredient Name Code
Fd&c yellow no. 6 ( UNII: H77VEI93A8)
Hypromelloses ( UNII: 3NXW29V3WO)
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Magnesium stearate ( UNII: 70097M6I30)
Propylene glycol ( UNII: 6DC9Q167V3)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Titanium dioxide ( UNII: 15FIX9V2JP)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Starch, corn ( UNII: O8232NY3SJ)

Product Characteristics

Color orange (ORANGE) Shape ROUND (ROUND)
Size 8 mm Score 1
Imprint Code ZC;76

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 49349-271-02 30 in 1 BLISTER PACK 2009/12/24
2 NDC: 49349-271-06 28 in 1 BLISTER PACK 2018/09/17

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA078040 USA 2018/09/17

Labeler - REMEDYREPACK INC.( 829572556)