RISPERDAL^®
(risperidone)
TABLETS/ORAL SOLUTION
RISPERDAL^® M-TAB^®
(risperidone)
ORALLY DISINTEGRATING TABLETS

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10 week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. RISPERDAL^® (risperidone) is not approved for the treatment of patients with Dementia-Related Psychosis.

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, 1 mg, and 2 mg strengths and are light coral in color.

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.

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 5HT_1C, 5HT_1D, and 5HT_1A 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.

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).

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 evaluated, 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 an average of 13% (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 (C_max) 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 (C_max) 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).

RISPERDAL^® (risperidone) is indicated for the treatment of schizophrenia.

The efficacy of RISPERDAL^® in schizophrenia was established in short-term (6- to 8-weeks) controlled trials of schizophrenic inpatients (see CLINICAL PHARMACOLOGY).

The efficacy of RISPERDAL^® in delaying relapse was demonstrated in schizophrenic patients who had been clinically stable for at least 4 weeks before initiation of treatment with RISPERDAL^® or an active comparator and who were then observed for relapse during a period of 1 to 2 years (see CLINICAL PHARMACOLOGY - Clinical Trials). Nevertheless, the physician who elects to use RISPERDAL^® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

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

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. RISPERDAL^®(risperidone) is not approved for the treatment of dementia-related psychosis (see Boxed Warning).

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. 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 creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

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. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

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. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, RISPERDAL^® (risperidone) should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. 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.

If signs and symptoms of tardive dyskinesia appear in a patient treated with RISPERDAL^®, drug discontinuation should be considered. However, some patients may require treatment with RISPERDAL^® despite the presence of the syndrome.

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. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL^® is not approved for the treatment of patients with dementia-related psychosis. (See also Boxed WARNING, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including RISPERDAL^®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Physicians are advised to discuss the following issues with patients for whom they prescribe RISPERDAL^®:

No specific laboratory tests are recommended.

The interactions of RISPERDAL^® and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when RISPERDAL^® is taken in combination with other centrally acting drugs and alcohol.

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

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

Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine increased the bioavailability of risperidone, but only marginally increased the plasma concentration of the active antipsychotic fraction.

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone. Topiramate modestly reduced the bioavailability of risperidone, but not that of active antipsychotic fraction. Therefore this interaction is unlikely to be of clinical significance.

The effect of RISPERDAL^® on labor and delivery in humans is unknown.

In animal studies, risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone are also excreted in human breast milk. Therefore, women receiving risperidone should not breast-feed.

Safety and effectiveness of RISPERDAL^® in pediatric patients with schizophrenia or acute mania associated with Bipolar I Disorder have not been established.

Clinical studies of RISPERDAL^® in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. 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 (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION). While elderly patients exhibit a greater tendency to orthostatic hypotension, its risk in the elderly may be minimized by limiting the initial dose to 0.5 mg BID followed by careful titration (see PRECAUTIONS). Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern.

This drug is substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

In placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75–97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70–96) or furosemide alone (4.1%; mean age 80 years, range 67–90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials.

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 should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia-related psychosis. RISPERDAL^® is not approved for the treatment of patients with dementia-related psychosis. (See also Boxed Warning, WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis.)

The following findings are based on the short-term, placebo-controlled, North American, premarketing trials for schizophrenia and acute bipolar mania. In patients with Bipolar I Disorder, treatment-emergent adverse events are presented separately for risperidone as monotherapy and as adjunctive therapy to mood stabilizers.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia. However, this information is also generally applicable to bipolar mania.

During its premarketing assessment, multiple doses of RISPERDAL^® were administered to 2607 patients in Phase 2 and 3 studies. The conditions and duration of exposure to RISPERDAL^® varied greatly, and included (in overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term exposure. In most studies, untoward events associated with this exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In two large studies, adverse events were also elicited utilizing the UKU (direct questioning) side effect rating scale, and these events were not further categorized using standard terminology. (Note: These events are marked with an asterisk in the ulings that follow.)

In the ulings that follow, spontaneously reported adverse events were classified using World Health Organization (WHO) preferred terms. The frequencies presented, therefore, represent the proportion of the 2607 patients exposed to multiple doses of RISPERDAL^® who experienced an event of the type cited on at least one occasion while receiving RISPERDAL^®. All reported events are included, except those already uled in Table 1, those events for which a drug cause was remote, and those event terms which were so general as to be uninformative. It is important to emphasize that, although the events reported occurred during treatment with RISPERDAL^®, they were not necessarily caused by it.

Events are further categorized by body system and uled in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already uled in the tabulated results from placebo-controlled trials appear in this uling); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Adverse events reported since market introduction which were temporally (but not necessarily causally) related to RISPERDAL^® therapy, include the following: anaphylactic reaction, angioedema, apnea, atrial fibrillation, benign pituitary adenomas, cerebrovascular disorder, including cerebrovascular accident, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pulmonary embolism. There have been rare reports of sudden death and/or cardiopulmonary arrest in patients receiving RISPERDAL^®. A causal relationship with RISPERDAL^® has not been established. It is important to note that sudden and unexpected death may occur in psychotic patients whether they remain untreated or whether they are treated with other antipsychotic drugs.

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

RISPERDAL^® has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of RISPERDAL^® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Premarketing experience included eight reports of acute RISPERDAL^® (risperidone) 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 includes reports of acute RISPERDAL^® overdosage, 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 events reported since market introduction which were temporally (but not necessarily causally) related to RISPERDAL^® overdose, include torsade de pointes, prolonged QT interval, convulsions, cardiopulmonary arrest, and rare fatality associated with multiple drug overdose.

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. Because of the rapid disintegration of RISPERDAL^® M-TAB^®Orally Disintegrating Tablets, pill fragments may not appear in gastric spans obtained with lavage.

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. 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 RISPERDAL^®. 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.

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. Increases to dosages above 1.5 mg BID should generally occur at intervals of at least 1 week. In some patients, slower titration may be medically appropriate.

Elderly or debilitated patients, and patients with renal impairment, may have less ability to eliminate RISPERDAL^® than normal adults. Patients with impaired hepatic function may have increases in the free fraction of risperidone, possibly resulting in an enhanced effect (see CLINICAL PHARMACOLOGY). Patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk likewise need to be titrated cautiously and carefully monitored (see PRECAUTIONS). If a once-a-day dosing regimen in the elderly or debilitated patient is being considered, it is recommended that the patient be titrated on a twice-a-day regimen for 2–3 days at the target dose. Subsequent switches to a once-a-day dosing regimen can be done thereafter.

Co-administration of carbamazepine and other enzyme inducers (e.g., phenytoin, rifampin, phenobarbital) with risperidone would be expected to cause decreases in the plasma concentrations of active moiety (the sum 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, especially during initiation or discontinuation of therapy with these inducers (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

Fluoxetine and paroxetine 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 an average of 13%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

RISPERDAL^® M-TAB^® Orally Disintegrating Tablets are supplied in buler packs of 4 tablet units each.

RISPERDAL^® (risperidone) tablets are imprinted "JANSSEN", and either "Ris" and the strength "0.25", "0.5", or "R" and the strength "1", "2", "3", or "4".

0.25 mg dark yellow tablet: bottles of 60 NDC 50458-301-04, bottles of 500 NDC 50458-301-50, hospital unit dose packs of 100 NDC 50458-301-01.

0.5 mg red-brown tablet: bottles of 60 NDC 50458-302-06, bottles of 500 NDC 50458-302-50, hospital unit dose packs of 100 NDC 50458-302-01.

1 mg white tablet: bottles of 60 NDC 50458-300-06, buler pack of 100 NDC 50458-300-01, bottles of 500 NDC 50458-300-50.

2 mg orange tablet: bottles of 60 NDC 50458-320-06, buler pack of 100 NDC 50458-320-01, bottles of 500 NDC 50458-320-50.

3 mg yellow tablet: bottles of 60 NDC 50458-330-06, buler pack of 100 NDC 50458-330-01, bottles of 500 NDC 50458-330-50.

4 mg green tablet: bottles of 60 NDC 50458-350-06, buler pack of 100 NDC 50458-350-01.

RISPERDAL^® (risperidone) 1 mg/mL oral solution (NDC 50458-305-03) is supplied in 30 mL bottles with a calibrated (in milligrams and milliliters) pipette. The minimum calibrated volume is 0.25 mL, while the maximum calibrated volume is 3 mL.

Tests indicate that RISPERDAL^® (risperidone) oral solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; it is NOT compatible with either cola or tea, however.

RISPERDAL^® M-TAB^® (risperidone) Orally Disintegrating Tablets are etched on one side with "R0.5", "R1", and "R2", respectively, and are packaged in buler packs of 4 (2 X 2) tablets.

0.5 mg light coral, round, biconvex tablets: 7 buler packages per box, NDC 50458-395-28, long-term care packaging of 30 tablets NDC 50458-395-30.

1 mg light coral, square, biconvex tablets: 7 buler packages per box, NDC 50458-315-28, long-term care packaging of 30 tablets NDC 50458-315-30.

2 mg light coral, round, biconvex tablets: 7 buler packages per box, NDC 50458-325-28.

RISPERDAL^® tablets should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and moisture.

Keep out of reach of children.

RISPERDAL^® 1 mg/mL oral solution should be stored at controlled room temperature 15°–25°C (59°–77°F). Protect from light and freezing.

Keep out of reach of children.

RISPERDAL^® M-TAB^® Orally Disintegrating Tablets should be stored at controlled room temperature 15°–25°C (59°–77°F).

Keep out of reach of children.