RISPERDAL (risperidone) tablet
Janssen Pharmaceuticals, Inc.
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. RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1)]
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
See full prescribing information for complete boxed warning.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISPERDAL® is not approved for use in patients with dementia-related psychosis. (5.1)
| Dosage and Administration (2.6) | 3/2022 |
1 INDICATIONS AND USAGE
RISPERDAL® is an atypical antipsychotic indicated for:
1.1 Schizophrenia
RISPERDAL® (risperidone) is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults [see Clinical Studies (14.1)].
1.2 Bipolar Mania
Monotherapy
RISPERDAL® is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years) [see Clinical Studies (14.2)].
Adjunctive Therapy
RISPERDAL® adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults [see Clinical Studies (14.3)].
1.3 Irritability Associated with Autistic Disorder
RISPERDAL® is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years) [see Clinical Studies (14.4)].
2 DOSAGE AND ADMINISTRATION
| Initial Dose | Titration (Increments) | Target Dose | Effective Dose Range | |
|---|---|---|---|---|
| Schizophrenia: adults (2.1) | 2 mg | 1 to 2 mg | 4 to 8 mg | 4 to 16 mg |
| Schizophrenia: adolescents (2.2) | 0.5 mg | 0.5 to 1 mg | 3 mg | 1 to 6 mg |
| Bipolar mania: adults (2.2) | 2 to 3 mg | 1 mg | 1 to 6 mg | 1 to 6 mg |
| Bipolar mania: children and adolescents (2.2) | 0.5 mg | 0.5 to 1 mg | 1 to 2.5 mg | 1 to 6 mg |
| Irritability in autistic disorder (2.3) | 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) |
After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) |
0.5 mg: (body weight less than 20 kg) 1 mg: (body weight greater than or equal to 20 kg) |
0.5 to 3 mg |
Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.
- Recommended daily dosage:
| Initial Dose | Target Dose | Effective Dose Range | |
|---|---|---|---|
| Schizophrenia: adults (2.1) | 2 mg | 4 to 8 mg | 4 to 16 mg |
| Schizophrenia: adolescents (2.1) | 0.5 mg | 3 mg | 1 to 6 mg |
| Bipolar mania: adults (2.2) | 2 to 3 mg | 1 to 6 mg | 1 to 6 mg |
| Bipolar mania: in children and adolescents (2.2) | 0.5 mg | 1 to 2.5 mg | 1 to 6 mg |
| Irritability associated with autistic disorder (2.3) | 0.25 mg (Weight < 20 kg) 0.5 mg (Weight ≥20 kg) |
0.5 mg (<20 kg) 1 mg (≥20 kg) |
0.5 to 3 mg |
- Severe Renal or Hepatic Impairment in Adults: Use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of at least one week. (2.4)
- Oral Solution: Can be administered directly from calibrated oral dosing syringe or mixed with beverage (water, coffee, orange juice, or low-fat milk). (2.6)
- M-TAB Orally Disintegrating Tablets: Open the blister only when ready to administer, and immediately place tablet on the tongue. Can be swallowed with or without liquid. (2.7)
2.1 Schizophrenia
Adults
Usual Initial Dose
RISPERDAL® can be administered once or twice daily. Initial dosing is 2 mg per day. May increase the dose at intervals of 24 hours or greater, in increments of 1 to 2 mg per day, as tolerated, to a recommended dose of 4 to 8 mg per day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 mg to 16 mg per day. However, doses above 6 mg per 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 per day has not been evaluated in clinical trials [see Clinical Studies (14.1)].
Adolescents
The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to a recommended dose of 3 mg per day. Although efficacy has been demonstrated in studies of adolescent patients with schizophrenia at doses between 1 mg to 6 mg per day, no additional benefit was observed above 3 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per day have not been studied.
Patients experiencing persistent somnolence may benefit from administering half the daily dose twice daily.
Maintenance Therapy
While it is unknown how long a patient with schizophrenia should remain on RISPERDAL®, the effectiveness of RISPERDAL® 2 mg per day to 8 mg per day at delaying relapse was demonstrated in a controlled trial in adult 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)]. Both adult and adolescent patients who respond acutely should generally be maintained on their effective dose beyond the acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment.
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 RISPERDAL®, 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 RISPERDAL®, or treating patients with concomitant antipsychotics.
2.2 Bipolar Mania
Usual Dose
Adults
The initial dose range is 2 mg to 3 mg per day. The dose may be adjusted at intervals of 24 hours or greater, in increments of 1 mg per day. The effective dose range is 1 mg to 6 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 mg to 6 mg per day [see Clinical Studies (14.2 , 14.3)]. RISPERDAL® doses higher than 6 mg per day were not studied.
Pediatrics
The initial dose is 0.5 mg once daily, administered as a single-daily dose in the morning or evening. The dose may be adjusted at intervals of 24 hours or greater, in increments of 0.5 mg or 1 mg per day, as tolerated, to the recommended target dose of 1 mg to 2.5 mg per day. Although efficacy has been demonstrated in studies of pediatric patients with bipolar mania at doses between 0.5 mg and 6 mg per day, no additional benefit was observed above 2.5 mg per day, and higher doses were associated with more adverse events. Doses higher than 6 mg per 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 RISPERDAL®. 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 RISPERDAL® in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use RISPERDAL® 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 dosage of RISPERDAL® should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL® can be administered once daily, or half the total daily dose can be administered twice daily.
For patients with body weight less than 20 kg, initiate dosing at 0.25 mg per day. For patients with body weight greater than or equal to 20 kg, initiate dosing at 0.5 mg per day. After a minimum of four days, the dose may be increased to the recommended dose of 0.5 mg per day for patients less than 20 kg and 1.0 mg per day for patients greater than or equal to 20 kg. Maintain this dose for a minimum of 14 days. In patients not achieving sufficient clinical response, the dose may be increased at intervals of 2 weeks or greater, in increments of 0.25 mg per day for patients less than 20 kg, or increments of 0.5 mg per day for patients greater than or equal to 20 kg. The effective dose range is 0.5 mg to 3 mg per day. No dosing data are available for children who weigh less than 15 kg.
Once sufficient clinical response has been achieved and maintained, consider gradually lowering the dose to achieve the optimal balance of efficacy and safety. The physician who elects to use RISPERDAL® 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 Dosing in Patients with Severe Renal or Hepatic Impairment
For patients with severe renal impairment (Clcr< 30 mL/min) or hepatic impairment (10–15 points on Child Pugh System), the initial starting dose is 0.5 mg twice daily. The dose may be increased in increments of 0.5 mg or less, administered twice daily. For doses above 1.5 mg twice daily, increase in intervals of one week or greater [see Use in Specific Populations (8.6 and 8.7)].
2.5 Dose Adjustments for Specific Drug Interactions
When RISPERDAL® is co-administered with enzyme inducers (e.g., carbamazepine), the dose of RISPERDAL® should be increased up to double the patient's usual dose. It may be necessary to decrease the RISPERDAL® dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of RISPERDAL® with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).
When fluoxetine or paroxetine is co-administered with RISPERDAL®, the dose of RISPERDAL® should be reduced. The RISPERDAL® dose should not exceed 8 mg per day in adults when co-administered with these drugs. When initiating therapy, RISPERDAL® should be titrated slowly. It may be necessary to increase the RISPERDAL® dose when enzyme inhibitors such as fluoxetine or paroxetine are discontinued [see Drug Interactions (7.1)].
2.6 Administration of RISPERDAL® Oral Solution
RISPERDAL® Oral Solution can be administered directly from the calibrated oral dosing syringe, or can be mixed with a beverage prior to administration. RISPERDAL® Oral Solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea.
2.7 Directions for Use of RISPERDAL® M-TAB® Orally Disintegrating Tablets
Tablet Accessing
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablets each.
Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet.
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg
RISPERDAL® M-TAB® Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistant pouch containing a blister with 1 tablet each.
The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT push the tablet through the foil, because this could damage the tablet.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL® M-TAB® Orally Disintegrating Tablet on the tongue. The RISPERDAL® M-TAB® Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL® M-TAB® Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.
3 DOSAGE FORMS AND STRENGTHS
RISPERDAL® Tablets are available in the following strengths and colors: 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green). All are capsule shaped, and imprinted with "JANSSEN" on one side and either "Ris 0.5", "R1", "R2", "R3", or "R4" on the other side according to their respective strengths.
RISPERDAL® Oral Solution is available in a 1 mg/mL strength.
RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in the following strengths, colors, and shapes: 0.5 mg (light coral, round), 1 mg (light coral, square), 2 mg (coral, square), 3 mg (coral, round), and 4 mg (coral, round). All are biconvex and etched on one side with "R0.5", "R1", "R2", "R3", or "R4" according to their respective strengths.
4 CONTRAINDICATIONS
RISPERDAL® is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the RISPERDAL® formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.
- Known hypersensitivity to risperidone, paliperidone, or to any excipients in RISPERDAL®. (4)
5 WARNINGS AND PRECAUTIONS
- Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis: RISPERDAL® is not approved for use in patients with dementia-related psychosis. (5.2)
- Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of RISPERDAL® and close monitoring. (5.3)
- Tardive dyskinesia: Consider discontinuing RISPERDAL® if clinically indicated. (5.4)
- Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/ cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. (5.5)
- Hyperglycemia and Diabetes Mellitus: Monitor patients for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes. (5.5)
- Dyslipidemia: Undesirable alterations have been observed in patients treated with atypical antipsychotics. (5.5)
- Weight Gain: Significant weight gain has been reported. Monitor weight gain. (5.5)
- Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. (5.6)
- Orthostatic hypotension: For patients at risk, consider a lower starting dose and slower titration. (5.7)
- Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts in patients with a history of clinically significant low white blood cell count (WBC). Consider discontinuing RISPERDAL® if a clinically significant decline in WBC occurs in the absence of other causative factors. (5.9)
- Potential for cognitive and motor impairment: Use caution when operating machinery. (5.10)
- Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. (5.11)
5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.
In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus RISPERDAL® when compared to patients treated with RISPERDAL® 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.
RISPERDAL® (risperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning].
5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis
Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73–97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL® is not approved for the treatment of patients with dementia-related psychosis. [see Boxed Warning and Warnings and Precautions (5.1)].
5.3 Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and 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.
If NMS is suspected, immediately discontinue RISPERDAL® and provide symptomatic treatment and monitoring.
5.4 Tardive Dyskinesia
Tardive dyskinesia, a syndrome consisting 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 predict which patients will 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, RISPERDAL® 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: (1) who suffer from a chronic illness that 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.
If signs and symptoms of tardive dyskinesia appear in a patient on RISPERDAL®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL® 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 RISPERDAL®. 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 RISPERDAL®, 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 RISPERDAL®, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISPERDAL®, 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 RISPERDAL®, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including RISPERDAL®, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of RISPERDAL®.
Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 2.
| RISPERDAL® | |||
|---|---|---|---|
| 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, RISPERDAL® was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50).
Data from the placebo-controlled 3- to 6-week study in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 3.
| RISPERDAL® | ||
|---|---|---|
| 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, RISPERDAL® was associated with a mean change in fasting glucose of +5.2 mg/dL at Week 24 (n=119).
Dyslipidemia
Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
Pooled data from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 4.
| RISPERDAL® | |||
|---|---|---|---|
| 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% | 4.3% | 6.3% |
| (10/368) | (22/516) | (6/96) | |
|
Triglycerides
(<500 mg/dL to ≥500 mg/dL) |
1.1% (2/180) |
2.7% (8/301) |
2.5% (3/121) |
In longer-term, controlled and uncontrolled studies, RISPERDAL® was associated with a mean change in (a) non-fasting cholesterol of +4.4 mg/dL at Week 24 (n=231) and +5.5 mg/dL at Week 48 (n=86); and (b) non-fasting triglycerides of +19.9 mg/dL at Week 24 (n=52).
Pooled data from 3 placebo-controlled, 3- to 6-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), or autistic disorder (5–17 years of age) are presented in Table 5.
| RISPERDAL® | ||
|---|---|---|
| Placebo | 0.5–6 mg/day | |
| Mean change from baseline (mg/dL) | ||
| Cholesterol | n=74 | n=133 |
| Change from baseline | 0.3 | -0.3 |
| LDL | n=22 | n=22 |
| Change from baseline | 3.7 | 0.5 |
| HDL | n=22 | n=22 |
| Change from baseline | 1.6 | -1.9 |
| Triglycerides | n=77 | n=138 |
| Change from baseline | -9.0 | -2.6 |
| Proportion of patients with shifts | ||
|
Cholesterol
(<170 mg/dL to ≥200 mg/dL) |
2.4% (1/42) |
3.8% (3/80) |
|
LDL
(<110 mg/dL to ≥130 mg/dL) |
0% (0/16) |
0% (0/16) |
|
HDL
(≥40 mg/dL to <40 mg/dL) |
0% (0/19) |
10% (2/20) |
|
Triglycerides
(<150 mg/dL to ≥200 mg/dL) |
1.5% (1/65) |
7.1% (8/113) |
In longer-term, uncontrolled, open-label extension pediatric studies, RISPERDAL® was associated with a mean change in (a) fasting cholesterol of +2.1 mg/dL at Week 24 (n=114); (b) fasting LDL of -0.2 mg/dL at Week 24 (n=103); (c) fasting HDL of +0.4 mg/dL at Week 24 (n=103); and (d) fasting triglycerides of +6.8 mg/dL at Week 24 (n=120).
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of 7% or greater of body weight from 7 placebo-controlled, 3- to 8- week, fixed- or flexible-dose studies in adult subjects with schizophrenia or bipolar mania are presented in Table 6.
| RISPERDAL® | |||
|---|---|---|---|
| Placebo (n=597) |
1–8 mg/day (n=769) |
>8–16 mg/day (n=158) |
|
| Weight (kg) | |||
| Change from baseline | -0.3 | 0.7 | 2.2 |
| Weight Gain | |||
| ≥7% increase from baseline | 2.9% | 8.7% | 20.9% |
In longer-term, controlled and uncontrolled studies, RISPERDAL® was associated with a mean change in weight of +4.3 kg at Week 24 (n=395) and +5.3 kg at Week 48 (n=203).
Data on mean changes in body weight and the proportion of subjects meeting the criterion of ≥7% gain in body weight from nine placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13–17 years of age), bipolar mania (10–17 years of age), autistic disorder (5–17 years of age), or other psychiatric disorders (5–17 years of age) are presented in Table 7.
| Placebo (n=375) |
RISPERDAL® 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, RISPERDAL® was associated with a mean change in weight of +5.5 kg at Week 24 (n=748) and +8.0 kg at Week 48 (n=242).
In a long-term, open-label extension study in adolescent patients with schizophrenia, weight increase was reported as a treatment-emergent adverse event in 14% of patients. In 103 adolescent patients with schizophrenia, a mean increase of 9.0 kg was observed after 8 months of RISPERDAL® treatment. The majority of that increase was observed within the first 6 months. The average percentiles at baseline and 8 months, respectively, were 56 and 72 for weight, 55 and 58 for height, and 51 and 71 for body mass index.
In long-term, open-label trials (studies in patients with autistic disorder or other psychiatric disorders), a mean increase of 7.5 kg after 12 months of RISPERDAL® treatment was observed, which was higher than the expected normal weight gain (approximately 3 to 3.5 kg per year adjusted for age, based on Centers for Disease Control and Prevention normative data). The majority of that increase occurred within the first 6 months of exposure to RISPERDAL®. The average percentiles at baseline and 12 months, respectively, were 49 and 60 for weight, 48 and 53 for height, and 50 and 62 for body mass index.
In one 3-week, placebo-controlled trial in children and adolescent patients with acute manic or mixed episodes of bipolar I disorder, increases in body weight were higher in the RISPERDAL® groups than the placebo group, but not dose related (1.90 kg in the RISPERDAL® 0.5–2.5 mg group, 1.44 kg in the RISPERDAL® 3–6 mg group, and 0.65 kg in the placebo group). A similar trend was observed in the mean change from baseline in body mass index.
When treating pediatric patients with RISPERDAL® for any indication, weight gain should be assessed against that expected with normal growth.
5.6 Hyperprolactinemia
As with other drugs that antagonize dopamine D2 receptors, RISPERDAL® elevates prolactin levels and the elevation persists during chronic administration. RISPERDAL® is 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 Nonclinical 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
RISPERDAL® 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 RISPERDAL®-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 and 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. RISPERDAL® 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, and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of RISPERDAL® and antihypertensive medication.
5.8 Falls
Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including RISPERDAL®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
5.9 Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including RISPERDAL®. 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 RISPERDAL® 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 RISPERDAL® and have their WBC followed until recovery.
5.10 Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse reaction associated with RISPERDAL® treatment, especially when ascertained by direct questioning of patients. This adverse reaction is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (RISPERDAL® 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 RISPERDAL® 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse reaction. Since RISPERDAL® 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 RISPERDAL® therapy does not affect them adversely.
5.11 Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of RISPERDAL®-treated patients, two in association with hyponatremia. RISPERDAL® should be used cautiously in patients with a history of seizures.
5.12 Dysphagia
Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. RISPERDAL® and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [see Boxed Warning and Warnings and Precautions (5.1)].
5.13 Priapism
Priapism has been reported during postmarketing surveillance. Severe priapism may require surgical intervention.
5.14 Body Temperature Regulation
Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL® use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.
5.15 Patients with Phenylketonuria
Inform patients that RISPERDAL® M-TAB® Orally Disintegrating Tablets contain phenylalanine. Phenylalanine is a component of aspartame. Each 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.84 mg phenylalanine; each 3 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.63 mg phenylalanine; each 2 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.42 mg phenylalanine; each 1 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.28 mg phenylalanine; and each 0.5 mg RISPERDAL® M-TAB® Orally Disintegrating Tablet contains 0.14 mg phenylalanine.
6 ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions (5.2)]
- Neuroleptic malignant syndrome [see Warnings and Precautions (5.3)]
- Tardive dyskinesia [see Warnings and Precautions (5.4)]
- Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions (5.5)]
- Hyperprolactinemia [see Warnings and Precautions (5.6)]
- Orthostatic hypotension [see Warnings and Precautions (5.7)]
- Falls [see Warnings and Precautions (5.8)]
- Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.9)]
- Potential for cognitive and motor impairment [see Warnings and Precautions (5.10)]
- Seizures [see Warnings and Precautions (5.11)]
- Dysphagia [see Warnings and Precautions (5.12)]
- Priapism [see Warnings and Precautions (5.13)]
- Disruption of body temperature regulation [see Warnings and Precautions (5.14)]
- Patients with Phenylketonuria [see Warnings and Precautions (5.15)].
The most common adverse reactions in clinical trials (>5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.
The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions, Discontinuations Due to Adverse Reactions (6.1)].
The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL® 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.
The most common adverse reactions in clinical trials (≥5% and twice placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Clinical Trials Experience
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.
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia
Adult Patients with Schizophrenia
Table 8 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
| Percentage of Patients Reporting Reaction | |||
|---|---|---|---|
| RISPERDAL® | |||
| System/Organ Class Adverse Reaction |
2–8 mg per day (N=366) |
>8–16 mg per day (N=198) |
Placebo (N=225) |
| Cardiac Disorders | |||
| Tachycardia | 1 | 3 | 0 |
| Eye Disorders | |||
| Vision blurred | 3 | 1 | 1 |
| Gastrointestinal Disorders | |||
| Nausea | 9 | 4 | 4 |
| Constipation | 8 | 9 | 6 |
| Dyspepsia | 8 | 6 | 5 |
| Dry mouth | 4 | 0 | 1 |
| Abdominal discomfort | 3 | 1 | 1 |
| Salivary hypersecretion | 2 | 1 | <1 |
| Diarrhea | 2 | 1 | 1 |
| General Disorders | |||
| Fatigue | 3 | 1 | 0 |
| Chest pain | 2 | 2 | 1 |
| Asthenia | 2 | 1 | <1 |
| 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 | |||
| Blood creatine phosphokinase increased | 1 | 2 | <1 |
| Heart rate increased | <1 | 2 | 0 |
| Musculoskeletal and Connective Tissue Disorders | |||
| Back pain | 4 | 1 | 1 |
| Arthralgia | 2 | 3 | <1 |
| Pain in extremity | 2 | 1 | 1 |
| Nervous System Disorders | |||
| ParkinsonismParkinsonism 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. | 14 | 17 | 8 |
| Akathisia | 10 | 10 | 3 |
| Sedation | 10 | 5 | 2 |
| Dizziness | 7 | 4 | 2 |
| Dystonia | 3 | 4 | 2 |
| Tremor | 2 | 3 | 1 |
| Dizziness postural | 2 | 0 | 0 |
| Psychiatric Disorders | |||
| Insomnia | 32 | 25 | 27 |
| Anxiety | 16 | 11 | 11 |
| 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 |
| Vascular Disorders | |||
| Orthostatic hypotension | 2 | 1 | 0 |
Pediatric Patients with Schizophrenia
Table 9 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
| Percentage of Patients Reporting Reaction | |||
|---|---|---|---|
| RISPERDAL® | |||
| System/Organ Class Adverse Reaction |
1–3 mg per day (N=55) |
4–6 mg per day (N=51) |
Placebo (N=54) |
| Gastrointestinal Disorders | |||
| Salivary hypersecretion | 0 | 10 | 2 |
| Nervous System Disorders | |||
| Sedation | 24 | 12 | 4 |
| ParkinsonismParkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. | 16 | 28 | 11 |
| Tremor | 11 | 10 | 6 |
| Akathisia | 9 | 10 | 4 |
| Dizziness | 7 | 14 | 2 |
| Dystonia | 2 | 6 | 0 |
| Psychiatric Disorders | |||
| Anxiety | 7 | 6 | 0 |
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania
Adult Patients with Bipolar Mania
Table 10 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
| Percentage of Patients Reporting Reaction | ||
|---|---|---|
| System/Organ Class Adverse Reaction |
RISPERDAL®
1–6 mg per day (N=448) |
Placebo (N=424) |
| Eye Disorders | ||
| Vision blurred | 2 | 1 |
| Gastrointestinal Disorders | ||
| Nausea | 5 | 2 |
| Diarrhea | 3 | 2 |
| Salivary hypersecretion | 3 | 1 |
| Stomach discomfort | 2 | <1 |
| General Disorders | ||
| Fatigue | 2 | 1 |
| Nervous System Disorders | ||
| ParkinsonismParkinsonism 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. | 25 | 9 |
| Sedation | 11 | 4 |
| Akathisia | 9 | 3 |
| Tremor | 6 | 3 |
| Dizziness | 6 | 5 |
| Dystonia | 5 | 1 |
| Lethargy | 2 | 1 |
Table 11 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
| Percentage of Patients Reporting Reaction | ||
|---|---|---|
| System/Organ Class | RISPERDAL® + Mood Stabilizer | Placebo + Mood Stabilizer |
| Adverse Reaction | (N=127) | (N=126) |
| Cardiac Disorders | ||
| Palpitations | 2 | 0 |
| Gastrointestinal Disorders | ||
| Dyspepsia | 9 | 8 |
| Nausea | 6 | 4 |
| Diarrhea | 6 | 4 |
| Salivary hypersecretion | 2 | 0 |
| General Disorders | ||
| Chest pain | 2 | 1 |
| Infections and Infestations | ||
| Urinary tract infection | 2 | 1 |
| Nervous System Disorders | ||
| ParkinsonismParkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. | 14 | 4 |
| Sedation | 9 | 4 |
| Akathisia | 8 | 0 |
| Dizziness | 7 | 2 |
| Tremor | 6 | 2 |
| Lethargy | 2 | 1 |
| Psychiatric Disorders | ||
| Anxiety | 3 | 2 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Pharyngolaryngeal pain | 5 | 2 |
| Cough | 2 | 0 |
Pediatric Patients with Bipolar Mania
Table 12 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
| Percentage of Patients Reporting Reaction | |||
|---|---|---|---|
| RISPERDAL® | |||
| System/Organ Class Adverse Reaction |
0.5–2.5 mg per day (N=50) |
3–6 mg per day (N=61) |
Placebo (N=58) |
| 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 | |||
| Sedation | 42 | 56 | 19 |
| Dizziness | 16 | 13 | 5 |
| ParkinsonismParkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. | 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 |
Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder
Table 13 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.
| Percentage of Patients Reporting Reaction | ||
|---|---|---|
|
System/Organ Class |
RISPERDAL®
0.5–4.0 mg/day |
Placebo |
| Adverse Reaction | (N=107) | (N=115) |
| Gastrointestinal Disorders | ||
| Vomiting | 20 | 17 |
| Constipation | 17 | 6 |
| Dry mouth | 10 | 4 |
| Nausea | 8 | 5 |
| Salivary hypersecretion | 7 | 1 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 31 | 9 |
| Pyrexia | 16 | 13 |
| Thirst | 7 | 4 |
| Infections and Infestations | ||
| Nasopharyngitis | 19 | 9 |
| Rhinitis | 9 | 7 |
| Upper respiratory tract infection | 8 | 3 |
| Investigations | ||
| Weight increased | 8 | 2 |
| Metabolism and Nutrition Disorders | ||
| Increased appetite | 44 | 15 |
| Nervous System Disorders | ||
| Sedation | 63 | 15 |
| Drooling | 12 | 4 |
| Headache | 12 | 10 |
| Tremor | 8 | 1 |
| Dizziness | 8 | 2 |
| ParkinsonismParkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. | 8 | 1 |
| Renal and Urinary Disorders | ||
| Enuresis | 16 | 10 |
| Respiratory, Thoracic and Mediastinal Disorders | ||
| Cough | 17 | 12 |
| Rhinorrhea | 12 | 10 |
| Nasal congestion | 10 | 4 |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 8 | 5 |
Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone
The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of RISPERDAL® in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, 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: ear pain, 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, feeling abnormal
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: decreased appetite, polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint stiffness, 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, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, 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, acne, hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Additional Adverse Reactions Reported with RISPERDAL CONSTA®
The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL CONSTA®, regardless of frequency of occurrence:
Cardiac Disorders: bradycardia
Ear and Labyrinth Disorders: vertigo
Eye Disorders: blepharospasm
Gastrointestinal Disorders: toothache, tongue spasm
General Disorders and Administration Site Conditions: pain
Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess
Injury and Poisoning: fall
Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased
Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain
Nervous System Disorders: convulsion, paresthesia
Psychiatric Disorders: depression
Skin and Subcutaneous Tissue Disorders: eczema
Vascular Disorders: hypertension
Discontinuations Due to Adverse Reactions
Schizophrenia - Adults
Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more RISPERDAL®-treated patients were:
| RISPERDAL® | |||
|---|---|---|---|
| Adverse Reaction | 2–8 mg/day (N=366) |
>8–16 mg/day (N=198) |
Placebo (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 RISPERDAL®-treated patients discontinued treatment due to an adverse reaction 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 RISPERDAL®-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 RISPERDAL® as monotherapy, approximately 6% (25/448) of RISPERDAL®-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 RISPERDAL®-treated patients were:
| Adverse Reaction | RISPERDAL®
1–6 mg/day (N=448) |
Placebo (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 RISPERDAL®-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one RISPERDAL®-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 RISPERDAL®-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.
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 RISPERDAL® treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL® (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 | RISPERDAL® 2 mg | RISPERDAL® 6 mg | RISPERDAL® 10 mg | RISPERDAL® 16 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 RISPERDAL® (1, 4, 8, 12, and 16 mg/day):
| Dose Groups | RISPERDAL® 1 mg | RISPERDAL® 4 mg | RISPERDAL® 8 mg | RISPERDAL® 12 mg | RISPERDAL® 16 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 checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL® (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.
Changes in Body Weight
Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [see Warnings and Precautions (5.5), Adverse Reactions (6), and Use in Specific Populations (8.4)].
Changes in ECG Parameters
Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL® 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 RISPERDAL® 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 RISPERDAL® 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.
6.2 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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.
Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.
7 DRUG INTERACTIONS
- Carbamazepine and other enzyme inducers decrease plasma concentrations of risperidone. Increase the RISPERDAL® dose up to double the patient's usual dose. Titrate slowly. (7.1)
- Fluoxetine, paroxetine, and other CYP 2D6 enzyme inhibitors increase plasma concentrations of risperidone. Reduce the initial dose. Do not exceed a final dose of 8 mg per day of RISPERDAL®. (7.1)
7.1 Pharmacokinetic-related Interactions
The dose of RISPERDAL® should be adjusted when used in combination with CYP2D6 enzyme inhibitors (e.g., fluoxetine, and paroxetine) and enzyme inducers (e.g., carbamazepine) [see Table 18 and Dosage and Administration (2.5)]. Dose adjustment is not recommended for RISPERDAL® when co-administered with ranitidine, cimetidine, amitriptyline, or erythromycin [see Table 18].
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference) | Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
Effect of Risperidone on Other Drugs
Lithium
Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13). Dose adjustment for lithium is not recommended.
Valproate
Repeated oral doses of RISPERDAL® (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 RISPERDAL®. Dose adjustment for valproate is not recommended.
Digoxin
RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin. Dose adjustment for digoxin is not recommended.
7.2 Pharmacodynamic-related Interactions
Centrally Acting Drugs and Alcohol
Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is taken in combination with other centrally acting drugs and alcohol.
Drugs with Hypotensive Effects
Because of its potential for inducing hypotension, RISPERDAL® may enhance the hypotensive effects of other therapeutic agents with this potential.
Levodopa and Dopamine Agonists
RISPERDAL® may antagonize the effects of levodopa and dopamine agonists.
Methylphenidate
Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS). Monitor for symptoms of EPS with concomitant use of RISPERDAL® and methylphenidate [see Adverse Reactions (6.2)].
Clozapine
Chronic administration of clozapine with RISPERDAL® may decrease the clearance of risperidone.
8 USE IN SPECIFIC POPULATIONS
- Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. (8.1)
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RISPERDAL®, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.
Risk Summary
Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall, available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including RISPERDAL®, during pregnancy (see Clinical Considerations).
Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4-times MRHD based on mg/m2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6-times the MRHD based on mg/m2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5-times the MRHD based on mg/m2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6-times the MRHD and offspring mortality increased at doses 0.1 to 3 times the MRHD based on mg/m2 body surface area.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide. Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors.
Fetal/Neonatal Adverse Reactions
Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including RISPERDAL®, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization.
Data
Human Data
Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR=1.26, 95% CI 1.02–1.56) and of cardiac malformations (RR=1.26, 95% CI 0.88–1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates.
Animal Data
Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the MRHD of 16 mg/day based on mg/m2 body surface area: maternal toxicity occurred at 4 times the MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the MRHD of 16 mg/day risperidone based on mg/m2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD based on mg/m2 body surface area; postnatal development and growth of the offspring were also delayed.
Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the MRHD