FULL PRESCRIBING INFORMATION
WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
Elderly patients with dementia-related psychosis treated with atypical 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 the 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 is not approved for the treatment of patients with dementia-related psychosis. [See WARNINGS AND PRECAUTIONS (5.1).]
Indications and Usage for Risperidone Orally Disintegrating
Schizophrenia
Adults
Risperidone is indicated for the acute and maintenance treatment of schizophrenia [see CLINICAL STUDIES (14.1)].
Adolescents
Risperidone is indicated for the treatment of schizophrenia in adolescents aged 13 to 17 years [see CLINICAL STUDIES (14.1)].
Bipolar Mania
Monotherapy - Adults
Risperidone is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults and in children and adolescents aged 10 to 17 years [see CLINICAL STUDIES (14.2)].
Combination Therapy – Adults
The combination of risperidone 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)].
Irritability Associated with Autistic Disorder
Pediatrics
Risperidone is indicated for the treatment of irritability associated with autistic disorder in children and adolescents aged 5 to 16 years, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods [see CLINICAL STUDIES (14.4)].
Risperidone Orally Disintegrating Dosage and Administration
Schizophrenia
Adults
Usual Initial Dose
Risperidone 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 to 2 mg/day, as tolerated, to a recommended dose of 4 to 8 mg/day. In some patients, slower titration may be appropriate. Efficacy has been demonstrated in a range of 4 to 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, the effectiveness of risperidone 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 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 beyond 8 weeks in adolescents with schizophrenia. The physician who elects to use risperidone for extended periods in adolescents with schizophrenia should periodically re-evaluate the long-term risks 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, 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, 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 therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.
Bipolar Mania
Usual Dose
Adults
Risperidone 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 to 6 mg per day [see CLINICAL STUDIES (14.2, 14.3)]. Risperidone doses higher than 6 mg per day were not studied.
Pediatrics
The dosage of risperidone 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. 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 in such longer-term treatment (i.e., beyond 3 weeks). The physician who elects to use risperidone for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Irritability Associated with Autistic Disorder – Pediatrics (Children and Adolescents)
The safety and effectiveness of risperidone in pediatric patients with autistic disorder less than 5 years of age have not been established.
The dosage of risperidone should be individualized according to the response and tolerability of the patient. The total daily dose of risperidone 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 between 0.5 mg and 2.5 mg per day. The maximum daily dose of risperidone 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 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.
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 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 to 3 days at the target dose. Subsequent switches to a once daily dosing regimen can be done thereafter.
Co-Administration of Risperidone with Certain Other Medications
Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone 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 treatment. The dose of risperidone 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 to 2.8 fold and 3 to 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 needs to be titrated accordingly when fluoxetine or paroxetine is co-administered [see DRUG INTERACTIONS (7.10)].
Directions for Use of Risperidone Orally Disintegrating Tablets
Tablet Accessing
Risperidone Orally Disintegrating Tablets 0.25 mg
Risperidone Orally Disintegrating Tablets 0.25 mg are supplied in cartons of 30 tablets with 5 blister packs of 6 (3 x 2) tablets.
Risperidone Orally Disintegrating Tablets 0.5 mg and 1 mg
Risperidone Orally Disintegrating Tablets 0.5 mg and 1 mg are supplied in cartons of 28 tablets with 7 blister packs of 4 (2x2) tablets, and in cartons of 30 tablets with 5 blister packs of 6 (3x2) tablets.
Risperidone Orally Disintegrating Tablets 2 mg, 3 mg and 4 mg
Risperidone Orally Disintegrating Tablets 3 mg and 4 mg are supplied in cartons of 28 tablets with 7 blister packs of 4 (2 x 2) tablets.
Do not open the blister until ready to administer. For single tablet removal, separate one of the four or six 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.
Tablet Administration
Using dry hands, remove the tablet from the blister unit and immediately place the entire Risperidone Orally Disintegrating Tablet on the tongue. The Risperidone Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. Risperidone 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.
Dosage Forms and Strengths
Risperidone Orally Disintegrating Tablets are available in the following strengths: 0.25 mg,
0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg. All are round shaped, white in color and imprinted with “P” on one side and either “212”, “311”, “315”, “401”, “402”, or “403” on the other side according to their respective strengths.
Contraindications
Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone. Therefore, risperidone is contraindicated in patients with a known hypersensitivity to the product.
Warnings and Precautions
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 is not approved for the treatment of dementia-related psychosis [see BOXED WARNING].
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 to 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 is not approved for the treatment of patients with dementia-related psychosis. [See also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1).]
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 creatinine 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.
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 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, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome.
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. 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, 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, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone , 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, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Pooled data from three double-blind, placebo-controlled schizophrenia studies and four double-blind, placebo-controlled bipolar monotherapy studies are presented in Table 1a.
| Placebo | Risperidone 1-8 mg/day | Risperidione >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 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 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 1b.
| Placebo | Risperidone 0.5-6mg/day | |
| Mean change from basline (mgdL) | ||
| N=76 | N=135 | |
| Serum Glucose | -1.3 | 2.6 |
| Proportion of patients with shifts | ||
| Serum Glucose (>100mg/dL to ≥126 mg/dL) | 0% (0/64) | 0.8% (1/120) |
In longer-term, uncontrolled, open-label extension pediatric studies, risperidone was associated with a mean change in fasting glucose of +5.2mg/dL at Week 24 (N=119).
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.
| Placebo | Risperidone 1-8 mg/day | Risperidone > 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 (<200mg/dL to ≥240 mg/dL) | 2.7% (10/368) | 4.3% (22/516) | 6.3% (6/96) |
| Triglycerides (<500mg/dL to ≥500 mg/dL) | 1.1% (2/180) | 2.7% (8/301) | 2.5% (3/121) |
In longer-term, controlled and uncontrolled studies, risperidone 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 to 17 years of age), bipolar mania (10 to 17 years of age), or autistic disorder (5 to 17 years of age) are presented in Table 2b.
| Placebo | Risperidone 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 < 40mg/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, risperidone 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 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 adults with schizophrenia or bipolar mania are presented in Table 3a.
| Placebo (N=597) | Risperidone 1-8 mg/day (N=769) | Risperidone >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, risperidone was associated with a mean change in weight of +4.3kg at Week 24 (N=395) and +5.3kg 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 9 placebo-controlled, 3- to 8-week, fixed-dose studies in children and adolescents with schizophrenia (13 to 17 years of age), bipolar mania (10 to 17 years of age), autistic disorder (5 to 17 years of age), or other psychiatric disorders (5 to 17 years of age) are presented in Table 3b.
| Placebo (N=375) | Risperidone 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 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).
Hyperprolactinemia
As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone 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.
Orthostatic Hypotension
Risperidone 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-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. Risperidone 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 and antihypertensive medication.
Leukopenia, Neutropenia, and Agranulocytosis
Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropinia have been reported temporally related to antipsychotic agents, including risperidone. 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 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 symptms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue risperidone and have their WBC followed until recovery.
Potential for Cognitive and Motor Impairment
Somnolence was a commonly reported adverse event associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 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 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since risperidone 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 therapy does not affect them adversely.
Seizures
During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures.
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 and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1).]
Priapism
Priapism has been reported during postmarketing surveillance [see ADVERSE REACTIONS (6.9)]. Severe priapism may require surgical intervention.
Thrombotic Thrombocytopenic Purpura (TTP)
A single case of TTP was reported in a 28 year old female patient receiving oral risperidone 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 therapy is unknown.
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 use. Caution is advised when prescribing for patients who will be exposed to temperature extremes.
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.
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 should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness
Clinical experience with risperidone in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies who receive antipsychotics, including risperidone, 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 in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone 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
