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Risperdal

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RISPERDAL     (RISPERIDONE)

RISPERDAL M_TAB    (RISPERIDONE)      

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If you are taking Risperdal or thinking of taking Risperdal and you are wondering about side effects or the potential of side effects with using Risperdal, there is something you need to know. There is a way to predict adverse reactions with a very simple test.

Dr. Lester M. Crawford, Acting FDA Commissioner had this to say about this test on
Dec. 24, 2004. “Physicians can use the genetic information from this test to prevent harmful drug interactions and to assure drugs are used optimally, which in some cases will enable patients to avoid less effective or potentially harmful treatment choices,”

TABLETS/ORAL SOLUTION         ORALLY DISINTEGRATING TABLETS

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DESCRIPTION

The mechanism of action of RISPERDAL (risperidone), as with other drugs used to treat schizophrenia, is unknown.

Metabolism

Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite,

9-hydroxyrisperidone has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug (e.g., the active moiety) results from the combined concentrations of risperidone plus 9-hydroxyrisperidone.

CYP2D6, also called debrisoquin hydrozylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythimics, and other drugs, CYP 2D6 is subject to genetic polymorphism (about 6% -8% of Caucasians, and a very low percentage of Asians, have little or no activity and are “poor metabolizers”) and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety, after single and multiple doses, are similar in extensive and poor metabolizers.

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

In a drug interaction study in schizophrenic patients, 11 subjects received risperidone titrated to 6mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbanazepine did not appear to be affected. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and Phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment (see PRECAUTIONS – Drug Interactions and DOSAGE ADMINISTRATION – Co-Administration of RISPERDAL with Certain Other Medications).Fluoxetine (20mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma concentration of risperidone 2.5-238 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone an average of 13% (see PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION – Co-Administration of RISPERDAL with Certain Other Medications).

Special Populations

Renal Impairment. Back to top of page

In patients with moderate to severe renal disease, clearance of the sume of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. RISPERDAL doses should be reduced in patients with renal disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

While the pharmacokinetics of risperidone in subjects with liver disease were comparable to those in young healthy subjects, the mean free fraction of risperidone in plasma was increased by about 35% because of the diminished concentration of both albumin and or, -acid glycoprotien. Risperdal doses should be reduced in patients with liver disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Race and Gender Effects

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

WARNINGS Back to top of page

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipshychotic 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 antipshychotic 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 antipshychotic drug treatment after recover 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. Back to top of page

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinesia movements may develop in patients treated with antipshychotic 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 antipshychotic treatment, which patients are likely to develop the syndrome. Whether antipshychotic 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 antipshychotic 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 my remit, partially or completely, if antipshychotic 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, RISPERDAL (risperidone) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipshychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipshychotic 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 on RISPERDAL, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL despite the presence of the syndrome.

Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients With Dementia

Cerebrovascular Adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL is not approved for the treatment of patients with dementia-related psychosis.

Hyperglycemia and Diabetes Mellitus Back to top of page

Hyperglycemia, in some cases extreme and associated with detoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including RISPERDAL. Assessment of the relationship between atypical antipshychotic use and glucose abnormalities is complicated by the possibility of an increased background fisk 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 antipshychotic 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 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 should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

PRECAUTIONS Back to top of page

General

Orthostatic Hypotension

RISPERDAL (risperidone) may induce orthostatic hypotension associated with dizziness, tychycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflection its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of RISPERDAL treated patients in Phase 2 and 3 studies. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either QD or 1mg BID) in normal adults and 0.5 mg BID in the elderly and patients with renal or hepatic impairment (see DOSAGE AND ADMINISTRATION). 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 infraction or ischemia, heart failure, or condition 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 RISPERDAL and antihypertensive medication.

Seizures Back to top of page

During premarketing testing, 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.

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.

Hyperprolactinemia Back to top of page

As with other drugs that antagonize dopamine D2 receptors, resperiodone elevates prolactin levels and the elevation persists during chronic administration. 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. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. As is common with compounds which increase prolactin release, an increase in pituitary gland, Mammary glend, and pancreatic islet cell hyperplasia and /or neoplasia was observed in the risperidone carcinogenicity studies conducted in mice and rats (see PRECAUTIONS – Carcinogenesis, Mutagenesis, Impairment of Fertility). However, 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.

Potential for Cognative and Motor Impairment

Somnolence was commonly reported adverse event associated with RISPERDAL 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 (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 16mg/day patients and 1% of placebo patients reported somnolence as an adverse event. 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.

Priapism Back to top of page

Rare cases of priapism have been reported. While the relationship of the events to RISPERDAL use has not been established, other drugs with alpha-adrenergic blocking effects have been reported to induce priapism, and it is possible that RISPERDAL may share this capacity. 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 RISPERDAL in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to RISPERDAL therapy is unknown.

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.

Body Temperature Regulation Back to top of page

Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral RISPERDAL us. Caution is advised when prescribing for pactients who will be exposed to temperature extremes.

Suicide

The possibility of suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for RISPERDAL 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 RISPERDAL in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using RISPERDAL in patients with disease of conditions that could affect metabolism or hemodynamic responses.

RISPERDAL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing.

Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients (seeDOSAGE AND ADMINISTRATION).

Information for Patients Back to top of page

Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL.

Orthostatic HypotensionPatients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.

Interference with Cognitive and Motor Performance

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.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Nursing Back to top of page

Patients should be advised not to breast-feed an infant if they are taking RISPERDAL

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.

Alcohol

Patients should be advised to avoid alcohol while taking RISPERDAL.

Phenylketonurics

Phenylalanine is a component of aspartame. Each 2 mg RISPERDAL M-TAB Orally Disintegrating Tablet contains 0.56mg phenylalanine; each 1mgRISPERDAL 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.

Laboratory Tests

No specific laboratory tests are recommended

Drug Interactions Back to top of page

The interactions of RISPERDAL and other drugs have not been systematically evaluated. Given the primary CNS effect of risperidone, caution should be used when RISPERDAL is taken in combination with other centrally acting drugs and alcohol.

Because of its potential for inducing hypotension. RISPERDAL may enhance the hypotensive effects of other therapeutic agents with this potential.

RISPERDAL may antagonize the effects of levodopa and dopamine agonists. Amtripyline does not affect the pharmacokinetics of risperidone of the active antipsychotic fraction. Cimetidine and ranitidine increased the bioavaiability of risperidone, but only marginally increased the plasma concentration of the active antipsychotic fraction.

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Carbamazepine and Other Enzyme Inducers

In a drug interaction study in scizophrenic patients, 11 subjects received risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. The does of risperidone may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known enzyme inducers) e.g., phenytoin, rifampin, and Phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of risperidone treatment.

Fluoxetine and Paroxetine Back to top of page

Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone an average of 13%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied

Lithium

Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUD) or peak plasma concentrations (C max) of lithium (n@13).

Valproate

Repeated oral doses of risperidone (4 mg QD) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000mg/day in three divided doses) compared to placebo (n+12). However, there was a 20% increase in valproate peak plasma concentration (C max) after concomitant administration of risperidone.

Digoxin Back to top of page

RISPERDAL (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Drugs That Inhibit CYP 2D6 and Other CYP Isozymes

Risperidone is metabolized to 9-hydroxyrisperidoneby CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs (see CLINICAL PHARMACOLOGY). Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n@70) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

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

There were no significant interactions between risperidone and erythromycin (see CLINICAL PHARMACOLOGY).

Drugs Metabolized by CYP 2D6 Back to top of page

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

Carcinogenesis

Carcinogenicity studies were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and  for 25 months to rats. These doses are equivalent to 2.4, 9.4, and37.5 times the maximum recommended human dose (MRHD) (16 mg/day) on a mg/kg basis or 0.2, 0.75, and 3times the MRHD (mice) or 0.4, 1.5, and 6 times the MRHD (rats) on a mg/m2 basis. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The following table summarizes the multiples of the human dose on the mg/m2 (mg/mk) basis at which these tumors occurred.

Tumor Type                Species           Sex            Multiples of Maximum Human Dose

                                                                                       In mg/m2 (mg/kg)

                                                                              Lowest                  Highest

                                                                              Effect                    No-Effect

                                                                              Level                     Level

Pituitary adenomas        mouse              female        0.75 (9.4)               0.2 (2.4)

Endocrine pancreas      rat                    male           1.5  (9.4)                0.4 (2.4)

      Adenomas

Mammary gland            mouse              female        0.2 (2.4                  none

Adenocarcinomas        

                                    Rat                   female        0.4 (2.4)                 none

                                    Rat                   male           6.0 (37.5)               1.5 (9.4)

Mammary gland            rat                    male            1.5 (9.4)                0.4 (2.4)

Neoplasm, Total Back to top of page

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

Mutagenesis

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

Impairment of Fertility

Risperidone (0.16 to 5 mg/kg) was shown to impair mating, but not fertility, in Wistar rats in three reproductive studies (two Segment 1 and a muligenerational study) at doses 0.1 to 3 times the maximum recommended human dose (MRHD) on a mg/m2 basis. The effect appeared to be in females, since impaired mating behavior was not noted in the Segment 1 study in which sperm motility and concentration were decreased at doses 0.6 to 10 times the MRHD on a mg/m2 basis. Dose-related decreases were also noted in serum testosterone at the same doses. Serum testosterone and sperm parameters partially recovered, but remained decreased after treatment was discontinued. No no-effect doses were noted in either rat or dog.

Pregnancy Back to top of page

Pregnancy Category C

The teratogenic potential of risperidone was studied in three Segment 11 studies in Sprague-Dawley and Wistar rats (0.63-10mg/kg or 0.4 to 6 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and in one Segment 11 study in New Zealand rabbits (0.31-5 mg/kg or 0.4 to 6 times the MRHD on a mg/m2 basis). The incidence of malformations was not increased compared to control in offspring of rats or rabbits given 0.4 to 6 times the MRHD on a mg/m2 basis. In three reproductive studies in rats (two Segment 111 and a multigenerational study), there was an increase in pup deaths during the first 4 days of lactation at doses of 0.16-5 mg/kg or 0.1 to 3 times the MRHD on a mg/m2 basis. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams.

There was no no-effect dose for increased rat pup mortality. In one Segment 111 study, there was an increase in stillborn rat pups at a dose of 2.5 mg/kg or 1.5 times the MRHD on a mg/m2 basis. In a cross-fostering study in Wistar rats, toxic effects on the fetus or pups, as evidenced by a decrease in the number of live pups and an increase in the number of dead pups at birth (Day 0), and a decrease in birth weight in pups of drug-treated dams were observed. In addition, there was an increase in deaths by Day 1 among pups of drug-treated dams, regardless of whether or not the pups were cross-fostered. Risperidone also appeared to impair maternal behavior in that pup body weight gain and survival (from Day 1 to 4 of lactation) were reduced in pups born to control by reared by drug-treated dams. These effects were all noted at the one dose of risperidone tested, i.e., 5 mg/kg or 3 times the MRHD on a mg/m2 basis.

Placental transfer of risperidone occurs in rat pups. There are no adequate and well-controlled studies in pregnant women. However, there was one report of a case of agenesis of the corpus callosum in an infant exposed to risperidone in utero. The causal relationship to RISPERDAL therapy is unknown.

RISPERDAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery  Back to top of page

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

Nursing Mothers

In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving risperidone should not breast-feed.

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use Back to top of page

Clinical studies of RISPERDAL did not include sufficient numbers of patients aged 65 and over to determine whether or not thy respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, a lower starting dose is recommended for an elderly patient, reflecting a decreased pharmacokinetic clearance in the elderly, as well as a greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTATION). While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg BID followed by careful titration (see PRECAUTIONS). Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

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

ADVERSE REACTIONS

The following findings are based on the short-term, placebo-controlled, North American, premarketing trial for schizophrenia and acute bipolar mania, In patients with Bipolar 1 Disorder, treatment-emergent adverse events are presented separately for risperidone as monotherapy and as adjunctive therapy to mood stabilizers.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia. However, this information is also generally applicable to bipolar mania.

Associated With Discontinuation of Treatment Back to top of page

Schizophrenia

Approximately 9% (244/2607 of RISPERDAL (risperidone)-treated patients in Phase 2 and 3 studies discontinued treatment due to an adverse event, compared with about 7% on placebo and 10% on active control drugs. The more common events (≥0.3%) associated with discontinuation and considered to be possibly or probably drug-related included:

            Adverse Event                                               RISPERDAL             Placebo

            Extrapyramidal symptoms                                        2.1%                          0%

            Dizziness                                                                 0.7%                          0%

            Hyperkinesia                                                           0.6%                          0%

            Somonlence                                                             0.5%                          0%

            Nausea                                                                    0.3%                          0% 

Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL- treated patients compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in RIPERDAL compared to placebo patients, it is unlikely that suicide attempt is a RISPERDAL-related adverse event (see PRECAUTIONS). Discontinuation for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 2 trials.

Bipolar Mania

In the US placebo-controlled trail with risperidone as monotherapy, approximately 8% (10/134) of RISPERDAL-treated patients discontinued treatment due to an adverse event, compared with approximately 6% (7/125) of placebo-treated patients. The adverse events associated with discontinuation and considered to be possibly, probably, or very likely drug-related included paroniria, somnolence, dizziness, extrapyramidal disorder and muscle contractions involuntary. Each of these events occurred in one RISPERDAL-treated patient (0.7%) and in no placebo-treated patients (0%)

In US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, there was no overall difference in the incidence of discontinuation due to adverse events (4% for RISPERDAL vs. 4% for placebo).

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

Schizophrenia Back to top of page

In tow 6-to 8-week placebo-controlled trials, spontaneously-reproted, treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL groups and at least twice that of placebo were anxiety, somnolence, extra-pyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.

Adverse events were also elicited in one of these two trails. (i.e., in the fixed-dose trial comparing RISPERDAL at doses of 2,6,10, and 16 mg/day with placebo) utilizing a checklist for detecting adverse events, a method that is more sensitive than spontaneous reporting. By this method, the following additional common and drug-related adverse events occurred at an incidence of at least 5% and twice the rate of placebo; increased dream activity, increased duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances, diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory dysfunction, and orgastic dysfunction.

Bipolar Mania Back to top of page

In the US placebo-controlled trial with risperidone as monotherapy, the most commonly observed adverse events associated with the use of RISPERDAL (incidence of 5% or greater and at least twice that of placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva increased. In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, the most commonly observed adverse events associated with the use of RISPERDAL were somnolence, dizziness, parkinsonism, saliva increased, akathisia, abdominal pain, and urinary incontinence.

Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL - Treated Patients - Schizophrenia

The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent among RISPERDAL – treated patients treated at doses of

≤10 mg/day than among placebo-treated patients in the pooled results of two 6- to 8- week controlled trials. Patients received RISPERDAL doses of 2,6,10, or 16 mg/day in the dose comparison trial, or up to a maximum dose of 10mg/day in the titration study. This table shows the percentage of patients in each dose group (≤10 mg/day or 16 mg/day) who spontaneously reported at least one episode of an event at some time during their treatment. Patients given doses of 2,6, or 10 mg did not differ materially in these rates, Reported adverse events were classified using the World Health Organization preferred terms. Back to top of page

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

Table 1.                                   Incidence of Treatment-Emergent Adverse Events

      In 6- to 8- Week Controlled Clinical Trials (1)

Body System                                                  RISPERDAL

    Preferred Term                  ≤10 mg/day                 16 mg/day                   Placebo

                                                   (N=324)                   (N=77)                       (N=142)

______________________________________________________________________

Psychiatric                                   26%                           23%                         19%

Insomnia                                        22%                           26%                          20%

Agitation                                        22%                           26%                          20%

Anxiety                             12%                           20%                          20%

Somnolence                                    3%                              8%                           1%

Aggressive reaction                         1%                              3%                            1%

Central &peripheral nervous system

Extapyramidal Symptoms               17%                           34%                          16%

Headache                                      14%                           12%                          12%

Dizziness                                         4%                             7%                           1%

Gastrointestinal

Constipation                                    7%                           13%                           3%     

Nausea                                            6%                             4%                           3%

Dyspepsia                                       5%                           10%                           4%

Vomiting                                          5%                             7%                           4%

Abdominal pain                               4%                             1%                           0%

Saliva increased                              2%                             0%                           1%

Toothache                                       2%                             0%                           0%

Respiratory system Back to top of page

Rhinitis                              10%                             8%                           4%

Coughing                                         3%                             3%                           1%

Sinusitis                                           2%                             1%                           1%

Pharyngitis                                       2%                             3%                           0%

Dyspnea                                          1%                             0%                           0%

Body as a whole – general

Back pain                                        2%                             0%                           1%

Chest pain                                       2%                             3%                           1%

Fever                                              2%                             3%                           0%

Dermatological Back to top of page

Rash                                                2%                             5%                           1%

Dry Skin                                          2%                             4%                           0%

Seborrhea                                       1%                             0%                           0%

Infections

Upper respiratory                            3%                             3%                            1%

Visual

Abnormal vision                               2%                             1%                            1%

Musculo-Skeletal      

Arthralgia                                        2%                              3%                           0%

Cardiovascular

Tachycardia                                     3%                              5%                           0%

(1)   Events reported by at least 1% of patients treated with RISPERDAL ≤10 mg/day are included, and are rounded to the nearest %. Comparative rates for RISPERDAL 16 mg/day and placebo are provided as well. Events for which the RISPERDAL incidence (in both dose groups) was equal to or less than placebo are not listed in the table, but included the following: nervousness, injury, and fugal infection.

(2)   Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesias, oculogyriccrisis, ataxia, abnormal gait, involuntary muscle contractions, hyporeglexia, akathisia, and extrapyramidal disorders. Although the incidence of ‘extrapyramidal symptoms’ does not appear to differ for the ’10 mg/day’ group and placebo, the data for individual dose groups in fixed dose trials do suggest a dose/response relationship (see ADVERSE REACTIONS- Dose Dependency of Adverse Events). Back to top of page

Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL – Treated Patients - Bipolar Mania

Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were more frequent among patients treated with flexible doses of RISPERDAL (1-6 mg daily as monotherapy and as adjunctive therapy to mood stabilizers, respectively_ than among patients treated with placebo. Reported adverse events were classified using the World Health Organization preferred terms.

Table 2.                       Incidence of Treatment-Emergent Adverse Events

            In a 3-Week, Placebo-Controlled Trial – Monotherapy in Bipolar Mania (1)

Body System/                                     RISPERDAL                         Placebo

    Preferred Term                                  (N=134)                              (N=125)__________

Central & peripheral nervous system

Dystonia                                               18%                                         6%

Akathisia                                              16%                                         6%

Dizziness                                              11%                                         9%

Parkinsonism                                        6%                                           3%

Hypoaesthesia                                      2%                                           1%

Psychiatric

Somnolence                                          28%                                         7%

A