Paliperidone: Concomitant use of risperidone and paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive antipsychotic fraction exposure.
Furosemide: In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone when compared to patients treated with risperidone or furosemide alone. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings. No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use.
Centrally-acting drugs (e.g., opiates, antihistamines, benzodiazepines) and alcohol: Caution should be used when risperidone is taken in combination with other centrally-acting drugs and alcohol due to increased risk of sedation.
Drugs with blood pressure lowering effects: Because of its potential for inducing hypotension, risperidone may enhance the blood pressure lowering effects of other therapeutic agents.
Levodopa and dopamine agonists: Risperidone may antagonize the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed.
Cimetidine and ranitidine: Increased the bioavailability of 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%.
CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine): 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 physician should reevaluate the dosing of risperidone when either concomitant fluoxetine or paroxetine is initiated or discontinued.
CYP3A4 inhibitor (e.g., verapamil): Increases the plasma concentration of risperidone.
Carbamazepine: Coadministration of carbamazepine with risperidone decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. The dose of risperidone needs to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of the drug.
Phenytoin, rifampicin and phenobarbital: Coadministration of these drugs 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. The dose of risperidone needs to be titrated accordingly for patients receiving these enzyme inducers, particularly during initiation or discontinuation of therapy with these inducers.
Phenothiazines, TCAs and some beta-blockers: May increase the plasma concentrations of risperidone but not those of risperidone plus 9-hydroxyrisperidone.
Clozapine: Chronic administration with risperidone may decrease the clearance of risperidone.
Topiramate: Modestly reduced the bioavailability of risperidone, but not that of risperidone plus 9-hydroxyrisperidone. Therefore, this interaction is unlikely to be of clinical significance.
Valproate: Repeated oral doses of risperidone did not affect the pre-dose or average plasma concentrations and exposure of valproate compared to placebo. However, there was a 20% increase in valproate peak plasma concentration after concomitant use of risperidone.
Amitriptyline, digoxin, donepezil, erythromycin, galantamine, lithium, psychostimulants (e.g., methylphenidate): Did not affect the pharmacokinetics of risperidone.