CLINICAL PHARMACOLOGY:

The mechanism of action of Risperidone, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D ₂ ) and serotonin Type 2 (5HT ₂ ) receptor antagonism. Antagonism at receptors other than D ₂ and 5HT ₂ may explain some of the other effects of Risperidone.

Pharmacokinetics

Absorption: Risperidone is well absorbed. The absolute oral bioavailability of Risperidone is 70% (CV=25%). The relative oral bioavailability of Risperidone from a tablet is 94% (CV=10%) when compared to a solution. Plasma concentrations of Risperidone, its major metabolite, 9-hydroxyRisperidone, and Risperidone plus 9-hydroxyRisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg BID). Following oral administration of tablet, mean peak plasma concentrations of Risperidone occurred at about 1 hour.

Food Effect: Food does not affect either the rate or extent of absorption of Risperidone.

Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, Risperidone is bound to albumin and (alpha) ₁ -acid glycoprotein. The plasma protein binding of Risperidone is 90%, and that of its major metabolite, 9-hydroxyRisperidone, is 77%.

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 (i.e., the active moiety) results from the combined concentrations of Risperidone plus 9-hydroxyRisperidone.

Excretion: Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces.

Special Populations

Renal Impairment: Risperidone doses should be reduced in patients with renal disease.

Hepatic Impairment: Risperidone doses should be reduced in patients with liver disease.

Elderly: Dosing should be modified accordingly in the elderly patients.

WARNINGS:

Neuroleptic Malignant Syndrome (NMS): Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The 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.

Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. 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. 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.

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.

Potential for Proarrhythmic Effects: Risperidone and/or 9-hydroxyrisperidone appear to lengthen the QT interval in some patients, although there is no average increase in treated patients, even at 12-16 mg/day, well above the recommended dose.

PRECAUTIONS:

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.

Seizures: Risperidone should be used cautiously in patients with a history of seizures.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, Risperidone elevates prolactin levels and the elevation persists during chronic administration.

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. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of Risperidone 16 mg/day patients.

Priapism: Rare cases of priapism have been reported.

Antiemetic Effect: Risperidone has an antiemetic effect in humans, and may mask signs and symptoms of overdosage.

Body Temperature Regulation: Disruption of body temperature regulation has been attributed to antipsychotic agents.

Suicide: The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high-risk patients should accompany drug therapy.

Use in Patients With Concomitant Illness: Caution is advisable in using Risperidone in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

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

Nursing Mothers: Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving Risperidone should not breast-feed. Geriatric Use: 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

Drug Interactions:

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

Risperidone may antagonize the effects of levodopa and dopamine agonists.

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

Carbamazepine and Other Enzyme Inducers: 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 dose 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: Fluoxetine (20 mg QD) has been shown to increase the plasma concentration of Risperidone 2.5-2.8 fold, while the plasma concentration of 9-hydroxyrisperidone was not affected.

Drugs That Inhibit CYP 2D6 and Other CYP Isozymes: Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs. 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.

OVERDOSAGE:

Human Experience: acute Risperidone overdosage with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. Other adverse events reported since market introduction which were temporally, (but not necessarily causally) related to Risperidone overdose, include prolonged QT interval, convulsions, cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.

Management of Overdosage: In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. There is no specific antidote to Risperidone. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of Risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

DOSAGE AND ADMINISTRATION:

Usual Initial Dose: Risperidone can be administered on either a BID or a QD schedule. Subsequent controlled trials have indicated that total daily Risperidone doses of up to 8 mg on a QD regimen are also safe and effective. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, When dosage adjustments are necessary, small dose increments/decrements of 1-2 mg are recommended. Efficacy in schizophrenia was demonstrated maximal effect was generally seen in a range of 4 to 8 mg/day.

Pediatric Use:  Safety and effectiveness of Risperidone in pediatric patients have not been established.

Dosage in Special Populations: The recommended initial dose is 0.5 mg BID 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 BID.

How Supplied: Each Package of Ruz-Risperidone 1, 2, 3, 4 mg tablets contains 20 white, oblong tablets in 3 blisters.

storage: store at controlled room temperature 15°-25°C. Protect from light and moisture. Keep out of reach of children.

Reference: PDR 2000, page 1453-57

                USPDI Vol for Professional Health Care, 2004, Page 2477-83

                   Martindale 2005, Page 719-21