CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of RISPERDAL® (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 (D2) and serotonin Type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of the other effects of RISPERDAL®.
RISPERDAL® is a selective monoaminergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin Type 2 (5HT2), dopamine Type 2 (D2),α1 and α2 adrenergic, and H1 histaminergic receptors. RISPERDAL® acts as an antagonist at other receptors, but with lower potency. RISPERDAL® has low to moderate affinity (Ki of 47 to 253 nM) for the serotonin 5HT1C, 5HT1D, and 5HT1A receptors, weak affinity (Ki of 620 to 800 nM) for the dopamine D1 and haloperidol-sensitive sigma site, and no affinity (when tested at concentrations >10-5 M) for cholinergic muscarinic orβ1 and β2 adrenergic receptors.
Pharmacokinetics
Absorption
After a single intramuscular (gluteal) injection of RISPERDAL® CONSTA® (risperidone), there is a small initial release of the drug (<about 1% of the dose), followed by a lag time of 3 weeks. The main release of the drug starts from 3 weeks onward, is maintained from 4 to 6 weeks, and subsides by 7 weeks following the intramuscular (IM) injection. Therefore, oral antipsychotic supplementation should be given during the first 3 weeks of treatment with RISPERDAL® CONSTA® to maintain therapeutic levels until the main release of risperidone from the injection site has begun (see DOSAGE AND ADMINISTRATION ). Following single doses of RISPERDAL® CONSTA®, the pharmacokinetics of risperidone, 9-hydroxyrisperidone (the major metabolite), and risperidone plus 9-hydroxyrisperidone were linear in the dosing range of 12.5 mg to 50 mg.
The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of RISPERDAL® CONSTA® results in sustained therapeutic concentrations. Steady-state plasma concentrations are reached after 4 injections and are maintained for 4 to 6 weeks after the last injection. Following multiple doses of 25 mg to 50 mg RISPERDAL® CONSTA®, plasma concentrations of risperidone, 9-hydroxyrisperidone and risperidone plus 9-hydroxyrisperidone were linear.
Distribution
Once absorbed, risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is approximately 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 mcg/mL), warfarin (10 mcg/mL), and carbamazepine (10 mcg/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and of 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Metabolism and Drug Interactions
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.
CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, 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.
The interactions of RISPERDAL® CONSTA® and other drugs have not been systematically evaluated in human subjects. 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 notbeen 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 carbamazepine and other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone cause a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone (see PRECAUTIONS - Drug Interactions ). 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 suggests this is unlikely.
In a drug interaction study in schizophrenic patients, 11 subjects received oral 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. 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 AND ADMINISTRATION - Co-Administration of RISPERDAL® CONSTA® with Certain Other Medications ).
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 by about 10% (see PRECAUTIONS – Drug Interactions and DOSAGE AND ADMINISTRATION - Co-Administration of RISPERDAL®CONSTA® with Certain Other Medications ).
Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13) (see PRECAUTIONS - Drug Interactions ).
Repeated oral doses of risperidone (4 mg QD) 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 (Cmax) after concomitant administration of risperidone (see PRECAUTIONS – Drug Interactions ).
There were no significant interactions between oral risperidone (1 mg QD) and erythromycin (500 mg QID) (see PRECAUTIONS – Drug Interactions ).
Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased the AUC of the active moiety by 20%.
Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety.
In drug interaction studies, risperidone did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.
RISPERDAL® (0.25 mg BID) did not show a clinically relevant effect on the pharmacokinetics of digoxin.
Excretion
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. As illustrated by a mass balance study of a single 1 mg oral dose of 14C-risperidone administered as solution to three healthy male volunteers, total recovery of radioactivity at 1 week was 84%, including 70% in the urine and 14% in the feces.
The apparent half-life of risperidone plus 9-hydroxyrisperidone following RISPERDAL® CONSTA® administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone. The clearance of risperidone and risperidone plus 9-hydroxyrisperidone was 13.7 L/h and 5.0 L/h in extensive CYP 2D6 metabolizers, and 3.3 L/h and 3.2 L/h in poor CYP 2D6 metabolizers, respectively. No accumulation of risperidone was observed during long-term use (up to 12 months) in patients treated every 2 weeks with 25 mg or 50 mg RISPERDAL® CONSTA®. The elimination phase is complete approximately 7 to 8 weeks after the last injection.
Special Populations
Renal Impairment
In patients with moderate to severe renal disease treated with oral RISPERDAL®, clearance of the sum of risperidone and its active metabolite decreased by 60% compared with young healthy subjects. Although patients with renal impairment were not studied with RISPERDAL® CONSTA®, it is recommended that patients with renal impairment be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with renal impairment. (see PRECAUTIONS - Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION - Dosage in Special Populations). ).
Hepatic Impairment
While the pharmacokinetics of oral RISPERDAL® 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 α1-acid glycoprotein. Although patients with hepatic impairment were not studied with RISPERDAL® CONSTA®, it is recommended that patients with hepatic impairment be carefully titrated on oral RISPERDAL® before treatment with RISPERDAL® CONSTA® is initiated at a dose of 25 mg. A lower initial dose of 12.5 mg may be appropriate when clinical factors warrant dose adjustment, such as in patients with hepatic impairment. (see PRECAUTIONS - Use in Patients with Concomitant Illness and DOSAGE AND ADMINISTRATION - Dosage in Special Populations ).
Elderly
In an open-label trial, steady-state concentrations of risperidone plus 9-hydroxyrisperidone in otherwise healthy elderly patients (≥65 years old) treated with RISPERDAL® CONSTA® for up to 12 months fell within the range of values observed in otherwise healthy nonelderly patients. Dosing recommendations are the same for otherwise healthy elderly patients and nonelderly patients (see DOSAGE AND ADMINISTRATION ).
Race and Gender Effects
No specific pharmacokinetic 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 or not corrected for body weight) or race.
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