risperdal (risperidone)  tablet, orally disintegrating 
risperdal (risperidone)  tablet 
risperdal (risperidone)  solution 
risperdal m-tab (risperidone)  tablet, orally disintegrating 
[Janssen, L.P.]

DESCRIPTION

RISPERDAL® (risperidone) is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]- 6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:

Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1 N HCl.

RISPERDAL® tablets are available in 0.25 mg (dark yellow), 0.5 mg (red-brown), 1 mg (white), 2 mg (orange), 3 mg (yellow), and 4 mg (green) strengths. Inactive ingredients are colloidal silicon dioxide, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, propylene glycol, sodium lauryl sulfate, and starch (corn). Tablets of 0.25, 0.5, 2, 3, and 4 mg also contain talc and titanium dioxide. The 0.25 mg tablets contain yellow iron oxide; the 0.5 mg tablets contain red iron oxide; the 2 mg tablets contain FD&C Yellow No. 6 Aluminum Lake; the 3 mg and 4 mg tablets contain D&C Yellow No. 10; the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake.

RISPERDAL® is also available as a 1 mg/mL oral solution. The inactive ingredients for this solution are tartaric acid, benzoic acid, sodium hydroxide, and purified water.

RISPERDAL® M-TAB® Orally Disintegrating Tablets are available in 0.5 mg (light coral), 1 mg (light coral), 2 mg (light coral), 3 mg (coral) and 4 mg (coral) strengths.

RISPERDAL® M-TAB® Orally Disintegrating Tablets contain the following inactive ingredients: Amberlite® resin, gelatin, mannitol, glycine, simethicone, carbomer, sodium hydroxide, aspartame, red ferric oxide, and peppermint oil. In addition, the 3 mg and 4 mg RISPERDAL® M-TAB® Orally Disintegrating Tablets contain xanthan gum.

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 or β1 and β2 adrenergic receptors.

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.

Pharmacokinetic studies showed that RISPERDAL® M-TAB® Orally Disintegrating Tablets and RISPERDAL® Oral Solution are bioequivalent to RISPERDAL® Tablets.

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 solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5–6 days (measured in extensive metabolizers).

Food Effect

Food does not affect either the rate or extent of absorption of risperidone. Thus, risperidone can be given with or without meals.

Distribution

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 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 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 (e.g., 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.

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 eva luated, but observations in a modest number (n70) 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 phenobarbital) 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 suggests this is unlikely.

In a drug interaction study in schizophrenic 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. 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® 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® 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 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 were 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 was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of the active moiety, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Special Populations

Renal Impairment

In patients with moderate to severe renal disease, clearance of the sum 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 α1-acid glycoprotein. RISPERDAL® doses should be reduced in patients with liver disease (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Elderly

In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients (see DOSAGE AND ADMINISTRATION).

Pediatric

The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.

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 corrected for body weight or not) or race.

CLINICAL TRIALS

Schizophrenia

Short-Term Efficacy

The efficacy of RISPERDAL® in the treatment of schizophrenia was established in four short-term (4- to 8-week) controlled trials of psychotic inpatients who met DSM-III-R criteria for schizophrenia.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to eva luate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Positive and Negative Syndrome Scale (PANSS) and the Scale for Assessing Negative Symptoms (SANS) were employed.

The results of the trials follow:

(1)

In a 6-week, placebo-controlled trial (n=160) involving titration of RISPERDAL ® in doses up to 10 mg/day (BID schedule), RISPERDAL ® was generally superior to placebo on the BPRS total score, on the BPRS psychosis cluster, and marginally superior to placebo on the SANS.

(2)

In an 8-week, placebo-controlled trial (n=513) involving 4 fixed doses of RISPERDAL ® (2, 6, 10, and 16 mg/day, on a BID schedule), all 4 RISPERDAL ® groups were generally superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score; the 3 highest RISPERDAL ® dose groups were generally superior to placebo on the PANSS negative subscale. The most consistently positive responses on all measures were seen for the 6 mg dose group, and there was no suggestion of increased benefit from larger doses.

(3)

In an 8-week, dose comparison trial (n=1356) involving 5 fixed doses of RISPERDAL ® (1, 4, 8, 12, and 16 mg/day, on a BID schedule), the four highest RISPERDAL ® dose groups were generally superior to the 1 mg RISPERDAL ® dosegroup on BPRS total score, BPRS psychosis cluster, and CGI severity score. None of the dose groups were superior to the 1 mg group on the PANSS negative subscale. The most consistently positive responses were seen for the 4 mg dose group.

In a 4-week, placebo-controlled dose comparison trial (n=246) involving 2 fixed doses of RISPERDAL ® (4 and 8 mg/day on a QD schedule), both RISPERDAL ® dose groups were generally superior to placebo on several PANSS measures, including a response measure (>20% reduction in PANSS total score), PANSS total score, and the BPRS psychosis cluster (derived from PANSS). The results were generally stronger for the 8 mg than for the 4 mg dose group.

(4)

Long-Term Efficacy

In a longer-term trial, 365 adult outpatients predominantly meeting DSM-IV criteria for schizophrenia and who had been clinically stable for at least 4 weeks on an antipsychotic medication were randomized to RISPERDAL® (2–8 mg/day) or to an active comparator, for 1 to 2 years of observation for relapse. Patients receiving RISPERDAL® experienced a significantly longer time to relapse over this time period compared to those receiving the active comparator.

Bipolar Mania

Monotherapy

The efficacy of RISPERDAL® in the treatment of acute manic or mixed episodes was established in 2 short-term (3-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, andinsight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:

(1)

In one 3-week placebo-controlled trial (n=246), limited to patients with manic episodes, which involved a dose range of RISPERDAL ® 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 4.1 mg/day), RISPERDAL ® was superior to placebo in the reduction of Y-MRS total score.

In another 3-week placebo-controlled trial (n=286), which involved a dose range of 1–6 mg/day, once daily, starting at 3 mg/day (mean modal dose was 5.6 mg/day), RISPERDAL ® was superior to placebo in the reduction of Y-MRS total score.

(2)

Combination Therapy

The efficacy of risperidone with concomitant lithium or valproate in the treatment of acute manic or mixed episodes was established in one controlled trial in patients who met the DSM-IV criteria for Bipolar I Disorder. This trial included patients with or without psychotic features and with or without a rapid-cycling course.

(1)

In this 3-week placebo-controlled combination trial, 148 in- or outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL ®, placebo, or an active comparator, in combination with their original therapy. RISPERDAL ®, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.8 mg/day), combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.4 mEq/L or 50 mcg/mL to 120 mcg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.

In a second 3-week placebo-controlled combination trial, 142 in- or outpatients on lithium, valproate, or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive RISPERDAL ® or placebo, in combination with their original therapy. RISPERDAL ®, in a dose range of 1–6 mg/day, once daily, starting at 2 mg/day (mean modal dose of 3.7 mg/day), combined with lithium, valproate, or carbamazepine (in therapeutic ranges of 0.6 mEq/L to 1.4 mEq/L for lithium, 50 mcg/mL to 125 mcg/mL for valproate, or 4–12 mcg/mL for carbamazepine, respectively) was not superior to lithium, valproate, or carbamazepine alone in the reduction of Y-MRS total score. A possible explanation for the failure of this trial was induction of risperidone and 9-hydroxyrisperidone clearance by carbamazepine, leading to subtherapeutic levels of risperidone and 9-hydroxyrisperidone.

(2)

Irritability Associated with Autistic Disorder

Short-Term Efficacy

The efficacy of RISPERDAL® in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in children and adolescents (aged 5 to 16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of these subjects were under 12 years of age and most weighed over 20 kg (16-104.3 kg).

Efficacy was eva luated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression - Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured the emotional and behavioral symptoms of autism, including aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

The results of these trials are as follows:

(1) In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=101), aged 5 to 16 years, received twice daily doses of placebo or RISPERDAL® 0.5-3.5 mg/day on a weight adjusted basis. RISPERDAL®, starting at 0.25 mg/day or 0.5 mg/day depending on baseline weight (< 20 kg and ≥ 20 kg, respectively) and titrated to clinical response (me