Risperdal Consta (Risperidone) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

The interactions of RISPERDAL^® CONSTA^® with coadministration of other drugs have not been systematically evaluated. The drug interaction data provided in this section is based on studies with oral RISPERDAL^®.

Centrally-Acting Drugs and Alcohol

Given the primary CNS effects of risperidone, caution should be used when RISPERDAL^® CONSTA^® is administered in combination with other centrally-acting drugs or alcohol.

Drugs with Hypotensive Effects

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

Levodopa and Dopamine Agonists

RISPERDAL^® CONSTA^® may antagonize the effects of levodopa and dopamine agonists.

Amitriptyline

Amitriptyline did not affect the pharmacokinetics of risperidone or of risperidone and 9-hydroxyrisperidone combined following concomitant administration with oral RISPERDAL^®.

Cimetidine and Ranitidine

Cimetidine and ranitidine increased the bioavailability of oral risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

Clozapine

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

Lithium

Repeated doses of oral RISPERDAL^® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (C_max) of lithium (n=13).

Valproate

Repeated doses of oral 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 (C_max) after concomitant administration of oral RISPERDAL^®.

Digoxin

Oral RISPERDAL^® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Topiramate

Oral RISPERDAL^® administered at doses from 1–6 mg/day concomitantly with topiramate 400 mg/day resulted in a 23% decrease in risperidone Cmax and a 33% decrease in risperidone AUC_{0–12 hour} at steady state. Minimal reductions in the exposure to risperidone and 9-hydroxyrisperidone combined, and no change for 9-hydroxyrisperidone were observed. This interaction is unlikely to be of clinical significance. There was no clinically relevant effect of oral RISPERDAL^® on the pharmacokinetics of topiramate.

Drugs That Inhibit CYP 2D6 and Other CYP Isozymes

Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see Clinical Pharmacology]. 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 patients) 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.

Fluoxetine and Paroxetine

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5–2.8 fold and 3–9 fold respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL^® CONSTA^®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL^® CONSTA^® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or paroxetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL^® CONSTA^®, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL^® CONSTA^® dose to 12.5 mg or necessitates interruption of RISPERDAL^® CONSTA^® treatment. When RISPERDAL^® CONSTA^® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [see also DOSAGE AND ADMINISTRATION]. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Erythromycin

There were no significant interactions between oral RISPERDAL^® and erythromycin.

Carbamazepine and Other CYP 3A4 Enzyme Inducers

Carbamazepine co-administration with oral RISPERDAL^® decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 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 RISPERDAL^® CONSTA^® treatment. At the initiation of therapy with carbamazepine or other known hepatic enzyme inducers, patients should be closely monitored during the first 4–8 weeks, since the dose of RISPERDAL^® CONSTA^® may need to be adjusted. A dose increase, or additional oral RISPERDAL^®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL^® CONSTA^® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL^® CONSTA^® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL^® CONSTA^® and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL^® CONSTA^® dose to 12.5 mg or necessitates interruption of RISPERDAL^® CONSTA^® treatment. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. [see also DOSAGE AND ADMINSTRATION]

Drugs Metabolized by CYP 2D6

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

OVERDOSAGE

Human Experience

No cases of overdose were reported in premarketing studies with RISPERDAL^® CONSTA^®. Because RISPERDAL^® CONSTA^® is to be administered by health care professionals, the potential for overdosage by patients is low.

In premarketing experience with oral RISPERDAL^®, there were eight reports of acute RISPERDAL^® overdosage, with estimated doses ranging from 20 to 300 mg and no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. One case, involving an estimated overdose of 240 mg, was associated with hyponatremia, hypokalemia, prolonged QT, and widened QRS. Another case, involving an estimated overdose of 36 mg, was associated with a seizure.

Postmarketing experience with oral RISPERDAL^® includes reports of acute overdose, with estimated doses of up to 360 mg. In general, the most frequently reported signs and symptoms are those resulting from an exaggeration of the drug's known pharmacological effects, i.e., drowsiness, sedation, tachycardia, hypotension, and extrapyramidal symptoms. Other adverse reactions reported since market introduction related to oral RISPERDAL^® overdose include prolonged QT interval and convulsions. Torsade de pointes has been reported in association with combined overdose of oral RISPERDAL^® and paroxetine.

Management of Overdosage

In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT prolonging effects that might be additive to those of risperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of risperidone, resulting in problematic hypotension.

There is no specific antidote to risperidone. Therefore, appropriate supportive measures should be instituted. The possibility of multiple drug involvement should be considered. Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

CONTRAINDICATIONS

RISPERDAL^® CONSTA^® (risperidone) is contraindicated in patients with a known hypersensitivity to the product.

DRUG ABUSE AND DEPENDENCE

Controlled Substance

RISPERDAL^® CONSTA^® (risperidone) is not a controlled substance.

Abuse

RISPERDAL^® CONSTA^® has not been systematically studied in animals or humans for its potential for abuse. Because RISPERDAL^® CONSTA^® is to be administered by health care professionals, the potential for misuse or abuse by patients is low.

Dependence

RISPERDAL^® CONSTA^® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.