RISPERIDONE (risperidone 1 mg) Dailymed
Generic: risperidone
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risperidone 3 mg oral tablet - ri5 oval orange
risperidone 3 mg - ri5 oval orange
Boxed Warning
Warning: Increased Mortality In Elderly Patients With Dementia-related Psychosis
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Recent Major Changes Section
Warnings and Precautions, Metabolic Changes (5.5 )Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â September 2011
Warning: Increased Mortality In Elderly Patients With Dementia-related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Risperidone tablets are 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 tablets are not approved for use in patients with dementia-related psychosis. (5.1 )
1 Indications And Usage
Risperidone tablets are an atypical antipsychotic agent indicated for:
- Treatment of schizophrenia in adults and adolescent aged 13-17 years (
1.1 )- Alone, or in combination with lithium or valproate, for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults, and alone in children and adolescent aged 10-17 years (
1.2 )- Treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years (
1.3 )1.1 Schizophrenia
Adults
Risperidone tablets are indicated for the acute and maintenance treatment of schizophrenia [see Clinical Studies (14.1)].Â
Adolescents
Risperidone tablets are indicated for the treatment of schizophrenia in adolescents aged 13–17 years [see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy - Adults and Pediatrics
Risperidone tablets are indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults [see Clinical Studies (14.2)].Â
Combination Therapy – Adults
The combination of risperidone tablets with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder [see Clinical Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder
Pediatrics
Risperidone tablets are indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5–16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see Clinical Studies (14.4)].
2 Dosage And Administration
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Initial Dose Titration Target Dose Effective Dose Range Schizophrenia - adults ( 2.1 )2 mg/day 1-2 mg daily 4-8 mg daily 4-16 mg/day Schizophrenia-adolescents ( 2.1 )0.5 mg/day 0.5-1 mg daily 3 mg/day 1-6 mg/day Bipolar mania - adults ( 2.2 )2-3 mg/day 1mg daily 1-6 mg/day 1-6 mg/day Bipolar mania in children/adolescents ( 2.2 )0.5 mg/day 0.5-1 mg daily 2.5 mg/day 0.5-6 mg/day Irritability associated with autistic disorder ( 2.3 )0.25 mg/day(<20 kg)0.5 mg/day(≥20 kg) 0.25-0.5 mgat ≥2 weeks 0.5 mg/day(<20 kg)1 mg/day(≥20 kg) 0.5-3 mg/day 2.1 Schizophrenia
Adults
Usual Initial Dose
Risperidone tablets can be administered once or twice daily. Initial dosing is generally 2 mg/day. Dose increases should then occur at intervals not less than 24 hours, in increments of 1-2 mg/day, as tolerated, to a recommended dose of 4-8 mg/day. In some patients, slower titration may be appropriate.Efficacy has been demonstrated in a range of 4-16 mg/day [see Clinical Studies (14.1)]. However, doses above 6 mg/day for twice daily dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are generally not recommended. In a single study supporting once-daily dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on risperidone tablets, the effectiveness of risperidone tablets 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years [see Clinical Studies (14.1)]. Patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.
Adolescents
The dosage of risperidone tablets should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 3 mg/day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 and 6 mg/day, no additional benefit was seen above 3 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
There are no controlled data to support the longer term use of risperidone tablets beyond 8 weeks in adolescents with schizophrenia. The physician who elects to use risperidone tablets for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term risk and benefits of the drug for the individual patient.
Reinitiation of Treatment in Patients Previously Discontinued
Although there are no data to specifically address reinitiation of treatment, it is recommended that after an interval off risperidone tablets, the initial titration schedule should be followed.
Switching From Other Antipsychotics
There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to risperidone tablets, or treating patients with concomitant antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. The period of overlapping antipsychotic administration should be minimized. When switching schizophrenic patients from depot antipsychotics, initiate risperidone tablets therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
2.2 Bipolar Mania
Usual Dose
Adults
Risperidone tablets should be administered on a once-daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1-6 mg per day [see Clinical Studies (14.2,14.3)]. Risperidone tablets doses higher than 6 mg per day were not studied.
Pediatrics
The dosage of risperidone tablets should be initiated at 0.5 mg once daily, administered as a single-daily dose in either the morning or evening. Dosage adjustments, if indicated, should occur at intervals not less than 24 hours, in increments of 0.5 or 1 mg/day, as tolerated, to a recommended dose of 2.5 mg/day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 and 6 mg/day, no additional benefit was seen above 2.5 mg/day, and higher doses were associated with more adverse events. Doses higher than 6 mg/day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
Maintenance Therapy
There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone tablets. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to support the use of risperidone tablets in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone tablets for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
2.3 Irritability Associated with Autistic Disorder - Pediatrics (Children and Adolescents)
The safety and effectiveness of risperidone tablets in pediatric patients with autistic disorder less than 5 years of age have not been established.
The dosage of risperidone tablets should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone tablets can be administered once daily, or half the total daily dose can be administered twice daily.
Dosing should be initiated at 0.25 mg per day for patients < 20 kg and 0.5 mg per day for patients ≥ 20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients < 20 kg and 1 mg per day for patients ≥ 20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at ≥2-week intervals in increments of 0.25 mg per day for patients < 20 kg or 0.5 mg per day for patients ≥ 20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg.
In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, [see Clinical Studies (14.4)]) received doses of risperidone tablets between 0.5 mg and 2.5 mg per day. The maximum daily dose of risperidone tablets in one of the pivotal trials, when the therapeutic effect reached plateau, was 1 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg, or 3 mg in patients > 45 kg. No dosing data is available for children who weighed less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use risperidone tablets for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Patients experiencing persistent somnolence may benefit from a once-daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.
2.4 Dosage in Special Populations
The recommended initial dose is 0.5 mg twice daily in patients who are elderly or debilitated, patients with severe renal or hepatic impairment, and patients either predisposed to hypotension or for whom hypotension would pose a risk. Dosage increases in these patients should be in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.
Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate risperidone tablets than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect [see Clinical Pharmacology (12.3) ]. Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored [see Warnings and Precautions (5.2 , 5.7 , 5.17 )]. If a once-daily dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-daily regimen for 2-3 days at the target dose. Subsequent switches to a once-daily dosing regimen can be done thereafter.
2.5 Co-Administration of Risperidone Tablets with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone tablets would be expected to cause decreases in the plasma concentrations of the sum of risperidone and 9-hydroxyrisperidone combined, which could lead to decreased efficacy of risperidone tablets treatment. The dose of risperidone tablets needs to be titrated accordingly for patients receiving these enzyme inducers, especially during initiation or discontinuation of therapy with these inducers [see Drug Interactions (7.11)].
Fluoxetine and paroxetine have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. The dose of risperidone tablets needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see Drug Interactions (7.10)].
3 Dosage Forms And Strengths
Risperidone tablets USP are available in the following strengths and colors: 0.25 mg (orange), 0.5 mg (orange), 1 mg (white), 2 mg (yellow), 3 mg (orange), and 4 mg (brown). 0.25 mg, 0.5 mg, 1 mg and 2 mg are circular shaped. 3 mg are capsule shaped and 4 mg in ovaloid shaped. Risperidone tablets USP are engraved with "RI1", "RI2", "RI3", "RI4", "RI5" and "RI6" on one side on "0.25", "0.5", "1", "2", "3" and "4" respectively and plain on other side.
- Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg (
3 )
4 Contraindications
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, risperidone tablets are contraindicated in patients with a known hypersensitivity to the product.
- Known hypersensitivity to the product (
4 )
5 Warnings And Precautions
- Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis. Risperidone tablets are not approved for use in patients with dementia-related psychosis (
5.2 )- Neuroleptic Malignant Syndrome (
5.3 )- Tardive dyskinesia (
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 (
5.6 )- Orthostatic hypotension (
5.7 )- Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including risperidone tablet. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone tablet should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. (
5.8 )- Potential for cognitive and motor impairment (
5.9 )- Seizures (
5.10 )- Dysphagia (
5.11 )- Priapism (
5.12 )- Thrombotic Thrombocytopenic Purpura (TTP) (
5.13 )- Disruption of body temperature regulation (
5.14 )- Antiemetic Effect (
5.15 )- Suicide (
5.16 )- Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies (
5.17 )- Diseases or conditions that could affect metabolism or hemodynamic responses (
5.17 )5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone tablets are not approved for the treatment of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone tablets are not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1)]
5.3 Neuroleptic Malignant Syndrome (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
5.4 Tardive Dyskinesia
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, risperidone tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with risperidone tablets, drug discontinuation should be considered. However, some patients may require treatment with risperidone tablets despite the presence of the syndrome.
5.5 Metabolic Changes
Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone tablets. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone tablets, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone tablets, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone tablets, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone tablets, were discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone tablets.
Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 1a.
Table 1a. Change in Random Glucose from Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects with Schizophrenia or Bipolar Mania RISPERIDONE TABLETS Placebo 1–8 mg/day >8–16 mg/day  Mean change from baseline (mg/dL) n=555 n=748 n=164 Serum Glucose - 1.4 0.8 0.6  Proportion of patients with shifts Serum Glucose(<140 mg/dL to ≥200 mg/dL) 0.6%(3/525) 0.4%(3/702) 0%(0/158)
In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).
Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 1b.
Table 1b. Change in Fasting Glucose from Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents with Schizophrenia (13–17 years of age), Bipolar Mania (10–17 years of age), or Autistic Disorder (5 to 17 years of age). RISPERIDONE TABLETS Placebo 0.5-6 mg/day  Mean change from baseline (mg/dL) n=76 n=135 Serum Glucose -1.3 2.6  Proportion of patients with shifts Serum Glucose(<100 mg/dL to ≥126 mg/dL) 0%(0/64) 0.8%(1/120)
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 2a.
Table 2a. Change in Random Lipids From Seven Placebo-Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERIDONE TABLETS Placebo 1–8 mg/day >8–16 mg/day  Mean change from baseline (mg/dL) Cholesterol n=559 n=742 n=156 Change from baseline 0.6 6.9 1.8 Triglycerides n=183 n=307 n=123 Change from baseline -17.4 -4.9 -8.3  Proportion of patients with shifts Cholesterol (<200 mg/dL to ≥240 mg/dL) 2.7%(10/368) 4.3%(22/516) 6.3%(6/96) Triglycerides 1.1% 2.7% 2.5% (<500 mg/dL to ≥500 mg/dL) (2/180) (8/301) (3/121)
In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).
Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 2b.
Table 2b. Change in Fasting Lipids From Three Placebo-Controlled, 3- to 6-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), or Autistic Disorder (5 to 17 Years of Age) RISPERIDONE TABLETS Placebo 0.5-6 mg/day  Mean change from baseline (mg/dL) Cholesetrol n=74 n=133 Change from baseline 0.3 -0.3 LDL n=22 n=22 Change from baseline 3.7 0.5 HDL n=22 n=22 Change from baseline 1.6 -1.9 Triglycerides n=77 n=138 Change from baseline -9.0 -2.6  Proportion of patients with shifts Cholesetrol 2.4% 3.8% (<170 mg/dL to ≥200 mg/dL) (1/42) (3/80) LDL 0% 0% (<110 mg/dL to ≥130 mg/dL) (0/16) (0/16) HDL 0% 10% (40 mg/dL to <40 mg/dL) (0/19) (2/20) Triglycerides 1.5% 7.1% (<150 mg/dL to ≥200 mg/dL) (1/65) (8/113)
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 3a.
Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥7% Gain in Body Weight From Seven Placebo- Controlled, 3- to 8-Week, Fixed- or Flexible-Dose Studies in Adult Subjects With Schizophrenia or Bipolar Mania RISPERIDONE TABLETS Placebon=597 1–8 mg/dayn=769 >8–16 mg/dayn=158 Weight (Kg)    Change from baseline -0.3 0.7 2.2 Weight Gain    ≥7% increase from baseline 2.9% 8.7% 20.9%
In longer-term, controlled and uncontrolled studies, risperidone tablets were associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).
Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 3b.
Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects With ≥7% Gain in Body Weight From Nine Placebo- Controlled, 3- to 8-Week, Fixed-Dose Studies in Children and Adolescents With Schizophrenia (13–17 Years of Age), Bipolar Mania (10–17 Years of Age), Autistic Disorder (5 to 17 Years of Age) or Other Psychiatric Disorders (5–17 Years of Age) RISPERIDONE TABLETS  Placebo(n=375) 0.5 – 6 mg/day(n=448) Weight (Kg)   Change from baseline 0.6 2.0 Weight Gain   ≥7% increase from baseline 6.9% 32.6%
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone tablets were associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, risperidone tablets elevates prolactin levels and the elevation persists during chronic administration. Risperidone tablets are associated with higher levels of prolactin elevation than other antipsychotic agents.
Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.
Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.
5.7 Orthostatic Hypotension
Risperidone tablets may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone tablets-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage & Administration (2.1, 2.4 ) ]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone tablets should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone tablets and antihypertensive medication.
5.8 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone tablets. Agranulocytosis has also been reported.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone tablets should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue risperidone tablets and have their WBC followed until recovery.
5.9 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with risperidone tablets treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checkul to detect adverse events, 41% of the high-dose patients (risperidone tablets 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone tablets 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since risperidone tablets has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone tablets therapy does not affect them adversely.
5.10 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone tablets-treated patients, two in association with hyponatremia. Risperidone tablets should be used cautiously in patients with a history of seizures.
5.11 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. Risperidone tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warning and Warning and Precautions (5.1)]
5.12 Priapism
Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.8) ]. Severe priapism may require surgical intervention.
5.13 Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year-old female patient receiving oral risperidone tablets in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to risperidone tablets therapy is unknown.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone tablets use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Antiemetic Effect
Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumor.
5.16 Suicide
The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for risperidone tablets should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.
5.17 Use in Patients with Concomitant Illness
Clinical experience with risperidone tablets in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson's Disease or Dementia with Lewy Bodies who receive antipsychotics, including risperidone tablets, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.
Caution is advisable in using risperidone tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone tablets has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing.
Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients [see Dosage and Administration (2.4) ].
5.18 Monitoring: Laboratory Tests
No specific laboratory tests are recommended.
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) ]
- Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8) ]
- Potential for cognitive and motor impairment [see Warnings and Precautions (5.9) ]
- Seizures [see Warnings and Precautions (5.10) ]
- Dysphagia [see Warnings and Precautions (5.11) ]
- Priapism [see Warnings and Precautions (5.12) ]
- Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13) ]
- Disruption of body temperature regulation [see Warnings and Precautions (5.14) ]
- Antiemetic effect [see Warnings and Precautions (5.15) ]
- Suicide [see Warnings and Precautions (5.16) ]
- Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.17) ]
- Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.17) ]
The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased appetite, fatigue,insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash.
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 (6.5) ].
The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of risperidone tablets for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received risperidone tablets while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone tablets 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 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.
Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of risperidone tablets (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for risperidone tablets often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The majority of all adverse reactions were mild to moderate in severity.Â
The most common adverse reactions in clinical trials (≥10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash. (6 )
The most common adverse reactions that were associated with discontinuation from clinical trials were nausea, somnolence, sedation, vomiting, dizziness, and akathisia. (6 )
To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Â
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia
Adult Patients with Schizophrenia
Table 4 uls the adverse reactions reported in 1% or more of risperidone tablets-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 4. Adverse Reactions in ≥1% of Risperidone Tablets-Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablets 2–8 mg per day(N=366) >8–16 mg per day(N=198) Placebo(N=225) *Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson's disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor. Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis. Blood and Lymphatic System Disorders  Anemia <1 1 0 Cardiac Disorders  Tachycardia 1 3 0 Ear and Labyrinth Disorders  Ear pain <1 1 0 Eye Disorders  Vision blurred 3 1 1 Gastrointestinal Disorders  Nausea 9 4 4  Constipation 8 9 6  Dyspepsia 8 6 5  Vomiting 7 5 7  Dry mouth 4 0 1  Abdominal discomfort 3 1 1  Salivary hypersecretion 2 1 <1  Diarrhea 2 1 1  Abdominal pain 1 1 0  Abdominal pain upper 1 1 0  Stomach discomfort 1 1 1 General Disorders  Fatigue 3 1 0  Chest pain 2 2 1  Asthenia 2 1 <1 Immune System Disorders  Hypersensitivity <1 1 0 Infections and Infestations  Nasopharyngitis 3 4 3  Upper respiratory tract infection 2 3 1  Sinusitis 1 2 1  Urinary tract infection 1 3 0 Investigations  Weight increased 1 1 0  Blood creatine phosphokinase increased 1 2 <1  Heart rate increased <1 2 0 Metabolism and Nutrition Disorders  Decreased appetite 1 0 <1 Musculoskeletal and Connective Tissue Disorders  Back pain 4 1 1  Arthralgia 2 3 <1  Pain in extremity 2 1 1  Joint stiffness 1 1 0 Nervous System Disorders  Parkinsonism* 14 17 8  Akathisia* 10 10 3  Dizziness 7 4 2  Somnolence 7 2 1  Dystonia* 3 4 2  Sedation 3 3 1  Tremor* 2 3 1  Dizziness postural 2 0 0  Dyskinesia* 1 2 2  Syncope 1 1 0 Psychiatric Disorders  Insomnia 32 25 27  Anxiety 16 11 11  Nervousness 1 1 <1 Renal and Urinary Disorders  Urinary incontinence 1 1 0 Reproductive System and Breast Disorders  Ejaculation failure <1 1 0 Respiratory, Thoracic and Mediastinal Disorders   Nasal congestion 4 6 2  Dyspnea 1 2 0  Epistaxis <1 2 0 Skin and Subcutaneous Tissue Disorders  Rash 1 4 1  Dry skin 1 3 0  Dandruff 1 1 0  Seborrheic dermatitis <1 1 0  Hyperkeratosis 0 1 1 Vascular Disorders  Orthostatic hypotension 2 1 0  Hypotension 1 1 0
Pediatric Patients with Schizophrenia
Table 5 uls the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Table 5. Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablets Placebo(N=54) 1–3 mg per day(N=55) 4–6 mg per day(N=51) *Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. Gastrointestinal Disorders  Salivary hypersecretion 0 10 2 Nervous System Disorders  Parkinsonism* 16 28 11  Sedation 13 8 2  Somnolence 11 4 2  Tremor 11 10 6  Akathisia* 9 10 4  Dizziness 7 14 2  Dystonia* 2 6 0 Psychiatric Disorders  Anxiety 7 6 0 6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Bipolar Mania
Adult Patients with Bipolar Mania
Table 6 uls the adverse reactions reported in 1% or more of risperidone tablets-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Table 6. Adverse Reactions in ≥ 1% of Risperidone Tablets-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablets1–6 mg per day(N=448) Placebo(N=424) *Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. Dyskinesia includes muscle twitching and dyskinesia. Cardiac Disorders  Tachycardia 1 <1 Eye Disorders  Vision blurred 2 1 Gastrointestinal Disorders  Nausea 5 2  Diarrhea 3 2  Salivary hypersecretion 3 1  Dyspepsia 2 2  Stomach discomfort 2 <1 General Disorders  Fatigue 2 1  Asthenia 1 1  Pyrexia 1 1 Infections and Infestations  Nasopharyngitis 1 1 Investigations  Aspartate aminotransferase increased 1 <1 Nervous System Disorders  Parkinsonism* 25 9  Akathisia* 9 3  Tremor* 6 3  Dizziness 6 5  Sedation 6 2  Somnolence 5 2  Dystonia* 5 1  Lethargy 2 1  Dyskinesia* 1 <1 Reproductive System and Breast Disorders  Galactorrhea 1 0 Skin and Subcutaneous Tissue Disorders  Acne 1 0
Table 7 uls the adverse reactions reported in 2% or more of risperidone tablets-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
Table 7. Adverse Reactions in ≥2% of Risperidone Tablets-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablets +Mood Stabilizer(N=127) Placebo + Mood Stabilizer(N=126) *Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. Cardiac Disorders  Palpitations 2 0 Gastrointestinal Disorders  Dyspepsia 9 8  Nausea 6 4  Diarrhea 6 4  Dry mouth 4 4  Vomiting 4 6  Constipation 3 3  Salivary hypersecretion 2 0 General Disorders  Chest pain 2 1  Fatigue 2 2 Infections and Infestations  Nasopharyngitis 2 3  Urinary tract infection 2 1 Investigations  Weight increased 2 2 Nervous System Disorders  Parkinsonism* 14 4  Headache 14 15  Akathisia* 8 0  Dizziness 7 2  Sedation 6 3  Tremor 6 2  Somnolence 3 1  Lethargy 2 1 Psychiatric Disorders  Insomnia 4 8  Anxiety 3 2 Respiratory, Thoracic and Mediastinal Disorders  Pharyngolaryngeal pain 5 2  Cough 2 0
Pediatric Patients with Bipolar Mania
Table 8 uls the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Table 8. Adverse Reactions in ≥5% of Risperidone Tablets-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablet Placebo(N=58) 0.5–2.5 mg per day(N=50) 3–6 mg per day(N=61) *Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. Eye Disorders  Vision blurred 4 7 0 Gastrointestinal Disorders  Abdominal pain upper 16 13 5  Nausea 16 13 7  Vomiting 10 10 5  Diarrhea 8 7 2  Dyspepsia 10 3 2  Stomach discomfort 6 0 2 General Disorders  Fatigue 18 30 3 Metabolism and Nutrition Disorders  Increased appetite 4 7 2 Nervous System Disorders  Somnolence 22 30 12  Sedation 20 23 7  Dizziness 16 13 5  Parkinsonism* 6 12 3  Dystonia* 6 5 0  Akathisia* 0 8 2 Psychiatric Disorders  Anxiety 0 8 3 Respiratory, Thoracic and Mediastinal Disorders   Pharyngolaryngeal pain 10 3 5 Skin and Subcutaneous Tissue Disorders  Rash 0 7 2 6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder
Table 9 uls the adverse reactions reported in 5% or more of risperidone tablets-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials.
Table 9. Adverse Reactions in ≥ 5% of Risperidone Tablets-Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials System/Organ Class Adverse Reaction Percentage of Patients Reporting Event Risperidone Tablets0.5–4.0 mg per day(N=76) Placebo(N=80) *Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. Cardiac Disorders  Tachycardia 5 0 Gastrointestinal Disorders  Vomiting 25 21  Constipation 21 8  Dry mouth 15 6  Salivary hypersecretion 9 0  Nausea 8 6 General Disorders    Fatigue 42 13  Feeling abnormal 5 0 Infections and Infestations  Nasopharyngitis 21 10  Rhinitis 13 10  Upper respiratory tract infection 8 3 Investigations  Weight increased 5 0 Metabolism and Nutrition Disorders  Increased appetite 47 19 Nervous System Disorders  Somnolence 49 18  Sedation 29 3  Drooling 16 5  Tremor 12 1  Parkinsonism* 11 1  Dizziness 9 3  Dyskinesia 7 3  Lethargy 5 3 Respiratory, Thoracic and Mediastinal Disorders  Cough 24 18  Rhinorrhea 16 13  Nasal congestion 13 5 Skin and Subcutaneous Tissue Disorders  Rash 11 8
In another study with patients treated for irritability associated with autistic disorder, headache (6%), epistaxis (6%) and pyrexia (6%) were also observed in risperidone tablets-treated pediatric subjects.
6.4 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone
The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with risperidone tablets in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in risperidone tablets-treated patients who participated in other studies, including double-blind, active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia.
Blood and Lymphatic System Disorders: granulocytopenia, neutropenia
Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block
Ear and Labyrinth Disorders: tinnitus
Endocrine Disorders: hyperprolactinemia
Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced
Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism
General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness
Immune System Disorders: drug hypersensitivity
Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic
Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased
Metabolism and Nutrition Disorders: polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis
Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep disorder, ullessness, libido decreased, anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement
Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema
Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular
Vascular Disorders: flushing
6.5 Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of risperidone tablets-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone tablets-treated patients were:
Table 10. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Schizophrenia Trials Adverse Reaction Risperidone Tablets Placebo 2-8 mg/day >8-16 mg/day (N=366) (N=198) (N=225) Dizziness 1.4% 1.0% 0% Nausea 1.4% 0% 0% Vomiting 0.8% 0% 0% Parkinsonism 0.8% 0% 0% Somnolence 0.8% 0% 0% Dystonia 0.5% 0% 0% Agitation 0.5% 0% 0% Abdominal pain 0.5% 0% 0% Orthostatic hypotension 0.3% 0.5% 0% Akathisia 0.3% 2.0% 0%
Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.
Schizophrenia - Pediatrics
Approximately 7% (7/106), of risperidone tablet-treated patients discontinued treatment due to an adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone tablets-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
Bipolar Mania - Adults
In double-blind, placebo-controlled trials with risperidone tablets as monotherapy, approximately 6% (25/448) of risperidone tablets-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone tablets-treated patients were:
Table 11. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone Tablets-Treated Adult Patients in Bipolar Mania Clinical Trials Risperidone Tablets 1-6 mg/day Placebo Adverse Reaction (N=448) (N=424) Parkinsonism 0.4% 0% Lethargy 0.2% 0% Dizziness 0.2% 0% Alanine aminotransferase increased 0.2% 0.2% Aspartate aminotransferase increased 0.2% 0.2%
Bipolar Mania - Pediatrics
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone tablets-treated patients discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone tablets-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
Autistic Disorder - Pediatrics
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone tablets-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.
6.6 Dose Dependency of Adverse Reactions in Clinical Trials
Extrapyramidal Symptoms
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone tablets treatment. Â
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone tablets (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:
 Dose Groups Placebo Risperidone Tablets2 mg Risperidone Tablets6 mg Risperidone Tablets10 mg Risperidone Tablets16 mg Parkinsonism 1.2 0.9 1.8 2.4 2.6 EPS Incidence 13% 17% 21% 21% 35%
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone tablets (1, 4, 8, 12, and 16 mg/day):Â Â
Dose Groups Risperidone Tablets1 mg Risperidone Tablets4 mg Risperidone Tablets8Â mg Risperidone Tablets12Â mg Risperidone Tablets16Â mg Parkinsonism 0.6 1.7 2.4 2.9 4.1 EPS Incidence 7% 12% 17% 18% 20%
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Other Adverse Reactions
Adverse event data elicited by a checkul for side effects from a large study comparing 5 fixed doses of risperidone tablet (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.
6.7 Changes in ECG
Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone tablets and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate.When all risperidone tablets doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.
In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 – 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone tablets groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.
In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone tablets to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.
6.8 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention and water intoxication.
Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.
7 Drug Interactions
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. (7.6 )
Fluoxetine and paroxetine increase plasma concentrations of risperidone. (7.10 )
Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. (7.11 )
7.1 Centrally-Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when risperidone tablets is taken in combination with other centrally-acting drugs and alcohol.
7.2 Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, risperidone tablets may enhance the hypotensive effects of other therapeutic agents with this potential.
7.3 Levodopa and Dopamine Agonists
Risperidone tablets may antagonize the effects of levodopa and dopamine agonists.
7.4 Amitriptyline
Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.
7.5 Cimetidine and Ranitidine
Cimetidine and ranitidine increased the bioavailability of 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 Clozapine
Chronic administration of clozapine with risperidone tablets may decrease the clearance of risperidone.
7.7 Lithium
Repeated oral doses of risperidone tablets (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).
7.8 Valproate
Repeated oral doses of risperidone tablets (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 (Cmax) after concomitant administration of risperidone tablets.
7.9 Digoxin
Risperidone tablets (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.
7.10 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 plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n70) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.Â
In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.
Fluoxetine and Paroxetine
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of risperidone tablets. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Erythromycin
There were no significant interactions between risperidone and erythromycin.
7.11 Carbamazepine and Other Enzyme Inducers
Carbamazepine co-administration decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. The dose of risperidone may tablet need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone tablets may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone tablets treatment.
7.12 Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, risperidone tablets is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, risperidone tablets did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
8 Use In Specific Populations
Nursing Mothers: should not breast feed. (8.3 )
Pediatric Use: safety and effectiveness not established for schizophrenia less than 13 years of age, for bipolar mania less than 10 years of age, and for autistic disorder less than 5 years of age. (8.4 )
Elderly or debilitated; severe renal or hepatic impairment; predisposition to hypotension or for whom hypotension poses a risk: Lower initial dose (0.5 mg twice daily), followed by increases in dose in increments of no more than 0.5 mg twice daily. Increases to dosages above 1.5 mg twice daily should occur at intervals of at least 1 week. (8.5 ,2.4 )
8.1 Pregnancy
Pregnancy Category C.
The teratogenic potential of risperidone was studied in three Segment II studies in Sprague-Dawley and Wistar rats (0.63-10 mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in one Segment II study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m2 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 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 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/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, 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 were observed. 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/m2 basis.Â
Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, 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 tablets therapy is unknown.
Non-Teratogenic Effects
Neonates exposed to antipsychotic drugs (including risperidone tablets) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. 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.
Risperidone tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.2 Labor & Delivery
The effect of risperidone tablets on labor and delivery in humans is unknown.
8.3 Nursing Mothers
In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving risperidone tablets should not breast-feed.
8.4 Pediatric Use
The efficacy and safety of risperidone tablets in the treatment of schizophrenia were demonstrated in 417 adolescents, aged 13 – 17 years, in two short-term (6 and 8 weeks, respectively) double-blind 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 tablets in children less than 13 years of age with schizophrenia have not been established.
The efficacy and safety of risperidone tablets in the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in 169 children and adolescent patients, aged 10 – 17 years, were demonstrated in one double-blind, placebo-controlled, 3-week trial [see Indications and Usage (1.2), Adverse Reactions (6.2), and Clinical Studies (14.2)].
Safety and effectiveness of risperidone tablets in children less than 10 years of age with bipolar disorder have not been established.
The efficacy and safety of risperidone tablets in the treatment of irritability associated with autistic disorder were established in two 8-week, double-blind, placebo-controlled trials in 156 children and adolescent patients, aged 5 to 16 years [see Indications and Usage (1.3), Adverse Reactions (6.3)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 tablets as patients treated for irritability associated with autistic disorder.
The safety and effectiveness of risperidone tablets in pediatric patients less than 5 years of age with autistic disorder have not been established.
Tardive Dyskinesia
In clinical trials in 1885 children and adolescents treated with risperidone tablets, 2 (0.1%) patients were reported to have tardive dyskinesia, which resolved on discontinuation of risperidone tablets treatment [see also Warnings and Precautions (5.4)].
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 event 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 events were most often of early onset and transient in duration. [see also Adverse Reactions (6.1, 6.2, 6.3)] Patients experiencing persistent somnolence may benefit from a change in dosing regimen [see Dosage & Administration (2.1, 2.2, 2.3)].
Hyperprolactinemia, Growth, and Sexual Maturation
Risperidone tablet has been shown to elevate prolactin levels in children and adolescents as well as in adults [see Warnings and Precautions (5.6)]. In double-blind, 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 tablets 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, 82–87% of patients who received risperidone tablets had elevated levels of prolactin compared to 3–7% 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 tablets-treated patients and gynecomastia was reported in 2.3% of risperidone tablets-treated patients.
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.
The long-term effects of risperidone tablets on growth and sexual maturation have not been fully evaluated in children and adolescents.
8.5 Geriatric Use
Clinical studies of risperidone tablets 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 & 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 & Administration (2.4)].
Concomitant use with Furosemide in Elderly Patients with Dementia-Related Psychosis
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone tablets when compared to patients treated with risperidone tablets alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. An increase of mortality in elderly patients with dementia-related psychosis was seen with the use of risperidone tablets regardless of concomitant use with furosemide. Risperidone tablets is not approved for the treatment of patients with dementia-related psychosis. [See Boxed Warning and Warnings and Precautions (5.1)]
9 Drug Abuse And Dependence
9.1 Controlled Substance
Risperidone tablets are not a controlled substance.
9.2 Abuse
Risperidone tablets 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 tablets misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).
9.3 Dependence
Risperidone tablets has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.
10 Overdosage
10.1 Human Experience
Premarketing experience included eight reports of acute risperidone tablets 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 includes reports of acute risperidone tablets overdosage, 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 risperidone tablets overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of risperidone tablets and paroxetine.
10.2 Management of Overdosage
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.
The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately 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 tablets. 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.
11 Description
Risperidone tablets USP contain risperidone USP, a psychotropic agent 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 C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
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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 N HCl.
Risperidone tablets USP are available in 0.25 mg (orange), 0.5 mg (orange), 1 mg (white), 2 mg (yellow), 3 mg (orange), and 4 mg (brown) strengths. Risperidone tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, propylene glycol (except 1mg), sodium lauryl sulphate, sodium starch glycolate and polyethylene glycol (1mg). Tablets of 0.25 mg, 0.5 mg, 2 mg, 3 mg, and 4 mg also contain talc and titanium dioxide. 0.25 mg, 0.5 mg, and 3 mg tablets contain FD&C Yellow # 6 aluminum lake, the 2 mg tablets contain yellow iron oxide; the 4 mg tablets contain iron oxide red.
12 Clinical Pharmacology
12.1 Mechanism of Action
The mechanism of action of risperidone tablets, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.Â
Risperidone tablets are a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2), α1 and α2 adrenergic, and H1 histaminergic receptors. Risperidone tablets acts as an antagonist at other receptors, but with lower potency. Risperidone tablets has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic or ß1 and ß2 adrenergic receptors.
12.2 Pharmacodynamics
The clinical effect from risperidone tablets results from the combined concentrations of risperidone and its major metabolite, 9-hydroxyrisperidone [see Clinical Pharmacology (12.3)]. Antagonism at receptors other than D2 and 5HT2 [see Clinical Pharmacology (12.1)] may explain some of the other effects of risperidone tablets.
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.
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).Â
Food Effect
Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone tablets can be given with or without meals.Â
Distribution
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α1-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 (10mcg/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.Â
Metabolism and Drug Interactions
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 (7.12)]. 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 (n70) 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 (7.11)]. 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 (7.12)].
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.Â
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.Â
Renal Impairment
In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in patients with renal disease [see Dosage & Administration (2.4) and Warnings and Precautions (5.17)].Â
Hepatic Impairment
While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and α1-acid glycoprotein. Risperidone doses should be reduced in patients with liver disease [see Dosage & Administration (2.4) and Warnings and Precautions (5.17)].Â
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 Dosage & Administration (2.4)].Â
Pediatric
The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.Â
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
Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to mice and for 25 months to rats. These doses are equivalent to 2.4, 9.4, and 37.5 times the maximum recommended human dose (MRHD) for schizophrenia (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3 times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. 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 following table summarizes the multiples of the human dose on a mg/m2 (mg/kg) basis at which these tumors occurred.
   Multiples of MaximumHuman Dose in mg/m² (mg/kg) Tumor Type Species Sex Lowest Effect Level Highest No-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  6.0 (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 unknown [see Warnings and Precautions (5.6)].
Mutagenesis
No evidence of mutagenic potential for risperidone was found in the Ames reverse mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration test in human lymphocytes or Chinese hamster cells.
Impairment of Fertility
Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment I and a multigenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment I study in which males only were treated. In a subchronic study in Beagle dogs in which risperidone was administered at doses of 0.31 to 5 mg/kg, sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. 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. No no-effect doses were noted in either rat or dog.
14 Clinical Studies
14.1 Schizophrenia
Adults
Short-Term Efficacy
The efficacy of risperidone tablets in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-li inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed.Â
The results of the trials follow:
In a 6-week, placebo-controlled trial (n=160) involving titration of risperidone tablets in doses up to 10 mg/day (twice-daily schedule), risperidone tablets were generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.Â
In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of risperidone tablets (2 mg/day, 6 mg/day, 10 mg/day, and 16 mg/day, on a twice-daily schedule), all 4 risperidone tablets groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest risperidone tablets dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses.Â
In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of risperidone tablets (1 mg/day, 4 mg/day, 8 mg/day, 12 mg/day, and 16 mg/day, on a twice-daily schedule), the four highest risperidone tablets dose groups were generally superior to the 1 mg risperidone tablets dose group on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group.Â
In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of risperidone tablets (4 and 8 mg/day on a once-daily schedule), both risperidone tablets dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group.Â
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Long-Term Efficacy
In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to risperidone tablets (2-8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving risperidone tablets experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.Â
Pediatrics
The efficacy of risperidone tablets in the treatment of schizophrenia in adolescents aged 13–17 years was demonstrated in two short-term (6 and 8 weeks), double-blind controlled trials. All patients met DSM-IV diagnostic criteria for schizophrenia and were experiencing an acute episode at time of enrollment. In the first trial (study #1), patients were randomized into one of three treatment groups: Risperidone tablets 1-3 mg/day (n = 55, mean modal dose = 2.6 mg), risperidone tablets 4-6 mg/day (n = 51, mean modal dose = 5.3 mg), or placebo (n = 54). In the second trial (study #2), patients were randomized to either risperidone tablets 0.15-0.6 mg/day (n = 132, mean modal dose = 0.5 mg) or risperidone tablets 1.5–6 mg/day (n = 125, mean modal dose = 4 mg). In all cases, study medication was initiated at 0.5 mg/day (with the exception of the 0.15-0.6 mg/day group in study #2, where the initial dose was 0.05 mg/day) and titrated to the target dosage range by approximately Day 7. Subsequently, dosage was increased to the maximum tolerated dose within the target dose range by Day 14. The primary efficacy variable in all studies was the mean change from baseline in total PANSS score.
Results of the studies demonstrated efficacy of risperidone tablets in all dose groups from 1-6 mg/day compared to placebo, as measured by significant reduction of total PANSS score. The efficacy on the primary parameter in the 1-3 mg/day group was comparable to the 4-6 mg/day group in study #1, and similar to the efficacy demonstrated in the 1.5–6 mg/day group in study #2. In study #2, the efficacy in the 1.5-6 mg/day group was statistically significantly greater than that in the 0.15-0.6 mg/day group. Doses higher than 3 mg/day did not reveal any trend towards greater efficacy.
14.2 Bipolar Mania - Monotherapy
Adults
The efficacy of risperidone tablets in the treatment of acute manic or mixed episodes was established in two short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS), an 11-li clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the YMRS total score. The results of the trials follow:
- In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of risperidone tablets 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), risperidone tablets were superior to placebo in the reduction of YMRS total score.
- In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1-6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), risperidone tablets were superior to placebo in the reduction of YMRS total score.
Pediatrics
The efficacy of risperidone tablets in the treatment of mania in children or adolescents with Bipolar I disorder was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multicenter trial including patients ranging in ages from 10 to 17 years who were experiencing a manic or mixed episode of bipolar I disorder. Patients were randomized into one of three treatment groups: Risperidone tablets 0.5-2.5 mg/day (n = 50, mean modal dose = 1.9 mg), risperidone tablets 3-6 mg/day (n = 61, mean modal dose = 4.7 mg), or placebo (n = 58). In all cases, study medication was initiated at 0.5 mg/day and titrated to the target dosage range by Day 7, with further increases in dosage to the maximum tolerated dose within the targeted dose range by Day 10. The primary rating instrument used for assessing efficacy in this study was the mean change from baseline in the total YMRS score.
Results of this study demonstrated efficacy of risperidone tablets in both dose groups compared with placebo, as measured by significant reduction of total YMRS score. The efficacy on the primary parameter in the 3-6 mg/day dose group was comparable to the 0.5-2.5 mg/day dose group. Doses higher than 2.5 mg/day did not reveal any trend towards greater efficacy.
14.3 Bipolar Mania - Combination Therapy
The efficacy of risperidone tablets with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in adult patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.Â
In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone tablets, placebo, or an active comparator, in combination with their original therapy. Risperidone tablets, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of YMRS total score.Â
In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive risperidone tablets or placebo, in combination with their original therapy. Risperidone tablets, in a dose range of 1-6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4-12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of YMRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.
14.4 Irritability Associated with Autistic Disorder
Short-Term Efficacy
The efficacy of risperidone tablets in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16-104.3 kg).
Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checkul (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
The results of these trials are as follows:
- In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or risperidone tablets 0.5-3.5 mg/day on a weight-adjusted basis. Risperidone tablets, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day), significantly improved scores on the ABC-I subscale and on the CGI-C scale compared with placebo.
- In the other 8-week, placebo-controlled trial in children with autistic disorder (n=55), aged 5 to 12 years, risperidone tablets 0.02 to 0.06 mg/kg/day given once or twice daily, starting at 0.01 mg/kg/day and titrated to clinical response (mean modal dose of 0.05 mg/kg/day, equivalent to 1.4 mg/day), significantly improved scores on the ABC-I subscale compared with placebo.
Long-Term Efficacy
Following completion of the first 8-week double-blind study, 63 patients entered an open-label study extension where they were treated with risperidone tablets for 4 or 6 months (depending on whether they received risperidone tablets or placebo in the double-blind study). During this open-label treatment period, patients were maintained on a mean modal dose of risperidone tablets of 1.8-2.1 mg/day (equivalent to 0.05 - 0.07 mg/kg/day).
Patients who maintained their positive response to risperidone tablets (response was defined as ≥ 25% improvement on the ABC-I subscale and a CGI-C rating of 'much improved' or 'very much improved') during the 4-6 month open-label treatment phase for about 140 days, on average, were randomized to receive risperidone tablets or placebo during an 8-week, double-blind withdrawal study (n=39 of the 63 patients). A pre-planned interim analysis of data from patients who completed the withdrawal study (n=32), undertaken by an independent Data Safety Monitoring Board, demonstrated a significantly lower relapse rate in the risperidone tablets group compared with the placebo group. Based on the interim analysis results, the study was terminated due to demonstration of a statistically significant effect on relapse prevention. Relapse was defined as ≥ 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline of the randomized withdrawal phase).
16 How Supplied/storage And Handling
Risperidone Tablets
Risperidone Tablets USP 0.25 mg are orange, circular, biconvex, film coated tablets, engraved with 'RI1' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-316-06
Bottles of 100's NDC 51991-316-01
Bottles of 500's NDC 51991-316-05
Bottles of 1000's NDC 51991-316-10
Risperidone Tablets USP 0.5 mg are orange, circular, biconvex, film coated tablets, engraved with 'RI2' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-317-06
Bottles of 100's NDC 51991-317-01
Bottles of 500's NDC 51991-317-05
Bottles of 1000's NDC 51991-317-10
Risperidone Tablets USP 1 mg are white to off white, circular, biconvex, film coated tablets, engraved with 'RI3' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-318-06
Bottles of 100's NDC 51991-318-01
Bottles of 500's NDC 51991-318-05
Bottles of 1000's NDC 51991-318-10
Risperidone Tablets USP 2 mg are yellow, circular, biconvex film coated tablets, engraved with 'RI4' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-319-06
Bottles of 100's NDC 51991-319-01
Bottles of 500's NDC 51991-319-05
Bottles of 1000's NDC 51991-319-10
Risperidone Tablets USP 3 mg are orange, capsule shaped, biconvex film coated tablets, engraved with 'RI5' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-320-06
Bottles of 100's NDC 51991-320-01
Bottles of 500's NDC 51991-320-05
Bottles of 1000's NDC 51991-320-10
Risperidone Tablets USP 4 mg are brown, ovaloid, biconvex, film coated tablets, engraved with 'RI6' on one side and plain on other and are supplied as follows:
Bottles of 60's NDC 51991-321-06
Bottles of 100's NDC 51991-321-01
Bottles of 1000's NDC 51991-321-10
Storage and Handling
Risperidone Tablets should be stored at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.
Keep out of reach of children.
17 Patient Counseling Information
Physicians are advised to discuss the following issues with patients for whom they prescribe risperidone tablets:
17.1 Orthostatic Hypotension
Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration [see Warnings and Precautions (5.7)].
17.2 Interference with Cognitive and Motor Performance
Since risperidone tablets has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone tablets therapy does not affect them adversely [see Warnings and Precautions (5.9)].
17.3 Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].
17.4 Nursing
Patients should be advised not to breast-feed an infant if they are taking risperidone tablets [see Use in Specific Populations (8.3)].
17.5 Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)].
17.6 Alcohol
Patients should be advised to avoid alcohol while taking risperidone tablets [see Drug Interactions (7.1)].
Revised:Â March 2012
Distributed by:
Breckenridge Pharmaceutical, Inc.
Boca Raton, FL33487.
Risperidone Tablets are manufactured by:
Ajanta Pharma Limited
B-4/5/6, MIDC Area, Paithan 431 128, India.
Package Label Principal Display Panel 0.25 Mg Bottle Label
NDC 51991-316-06
60 Tablets
risperiDONE Tablets USP 0.25 mg
0.25 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
Package Label Principal Display Panel 0.5 Mg Bottle Label
NDC 51991-317-06
60 Tablets
risperiDONE Tablets USP 0.5 mg
0.5 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
Package Label Principal Display Panel 1mg Bottle Label
NDC 51991-318-06
60 Tablets
risperiDONE Tablets USP 1 mg
1 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
Package Label Principal Display Panel 2mg Bottle Label
NDC 51991-319-06
60 Tablets
risperiDONE Tablets USP 2 mg
2 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
Package Label Principal Display Panel 3mg Bottle Label
NDC 51991-320-06
60 Tablets
risperiDONE Tablets USP 3 mg
3 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
Package Label Principal Display Panel 4mg Bottle Label
NDC 51991-321-06
60 Tablets
risperiDONE Tablets USP 4 mg
4 mg
Rx only
Breckenridge Pharmaceutical, Inc.
![]()
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