Risperdal (Tablet, Orally Disintegrating)

dailymed-instance:drugs, http://www4.wiwiss.fu-berlin.de/drugbank/vocab/resource/class/Offer

Schizophrenia:<br/>Usual Initial Dose: RISPERDAL (risperidone) can be administered on either a BID or a QD schedule. In early clinical trials, RISPERDAL was generally administered at 1 mg BID initially, with increases in increments of 1 mg BID on the second and third day, as tolerated, to a target dose of 3 mg BID by the third day. Subsequent controlled trials have indicated that total daily risperidone doses of up to 8 mg ona QD regimen are also safe and effective. However, regardless of which regimen is employed, in some patients a slower titration may be medically appropriate. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for the active metabolite would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, small dose increments/decrements of 1���2 mg are recommended. Efficacy in schizophrenia was demonstrated in a dose range of 4 to 16 mg/day in the clinical trials supporting effectiveness of RISPERDAL; however, maximal effect was generally seen in a range of 4 to 8 mg/day. Doses above 6 mg/day for BID dosing were not demonstrated to be more efficacious than lower doses, were associated with more extrapyramidal symptoms and other adverse effects, and are not generally recommended. In a single study supporting QD dosing, the efficacy results were generally stronger for 8 mg than for 4 mg. The safety of doses above 16 mg/day has not been evaluated in clinical trials.<br/>Maintenance Therapy: While there is no body of evidence available to answer the question of how long the schizophrenic patient treated with RISPERDAL should remain on it, the effectiveness of RISPERDAL 2 mg/day to 8 mg/day at delaying relapse was demonstrated in a controlled trial in patients who had been clinically stable for at least 4 weeks and were then followed for a period of 1 to 2 years. In this trial, RISPERDAL was administered on a QD schedule, at 1 mg QD initially, with increases to 2 mg QD on the second day, and to a target dose of 4 mg QD on the third day (see CLINICAL PHARMACOLOGY���Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment with an appropriate dose.<br/>Reinitiation of Treatment in Patients Previously Discontinued: Although there are no data to specifically address reinitiation of treatment, it is recommended that when restarting patients who have had an interval off RISPERDAL, the initial titration schedule should be followed.<br/>Switching From Other Antipsychotics: There are no systematically collected data to specifically address switching schizophrenic patients from other antipsychotics to RISPERDAL, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some schizophrenic patients, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. Whenswitching schizophrenic patients from depot antipsychotics, if medically appropriate, initiate RISPERDAL therapy in place of the next scheduled injection. The need for continuing existing EPS medication should be re-evaluated periodically.<br/>Pediatric Use: The safety and effectiveness of RISPERDAL in pediatric patients with schizophrenia have not been established.<br/>Bipolar Mania:<br/>Usual Dose: Risperidone should be administered on a once daily schedule, starting with 2 mg to 3 mg per day. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments/decrements of 1 mg per day, as studied in the short-term, placebo-controlled trials. In these trials, short-term (3 week) anti-manic efficacy was demonstrated in a flexible dosage range of 1���6 mg per day (see CLINICAL PHARMACOLOGY���Clinical Trials). RISPERDAL doses higher than 6 mg per day were not studied.<br/>Maintenance Therapy: There is no body of evidence available from controlled trials to guide a clinician in the longer-term management of a patient who improves during treatment of an acute manic episode with risperidone. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no systematically obtained data to supportthe use of risperidone in such longer-term treatment (i.e., beyond 3 weeks).<br/>Pediatric Use: The safety and effectiveness of RISPERDAL in pediatric patients with bipolar mania have not been established.<br/>Irritability Associated with Autistic Disorder���Pediatrics (Children and Adolescents): The safety and effectiveness of RISPERDAL in pediatric patients with autistic disorder less than 5 years of age have not been established. The dosage of RISPERDAL should be individualized according to the response and tolerability of the patient. The total daily dose of RISPERDAL can be administered once daily, or half the total daily dose can be administered twice daily. Dosing should be initiated at 0.25 mg per day for patients<20 kg and 0.5 mg per day for patients���20 kg. After a minimum of four days from treatment initiation, the dose may be increased to the recommended dose of 0.5 mg per day for patients<20 kg and 1 mg per day for patients���20 kg. This dose should be maintained for a minimum of 14 days. In patients not achieving sufficient clinical response, dose increases may be considered at���2-week intervals in increments of 0.25 mg per day for patients<20 kg or 0.5 mg per day for patients���20 kg. Caution should be exercised with dosage for smaller children who weigh less than 15 kg. In clinical trials, 90% of patients who showed a response (based on at least 25% improvement on ABC-I, see CLINICAL PHARMACOLOGY���Clinical Trials) received doses of RISPERDAL between 0.5 mg and 2.5 mg per day. The maximum daily dose of RISPERDAL in one of the pivotal trials, when the therapeutic effect reached plateau, was 1.0 mg in patients<20 kg, 2.5 mg in patients���20 kg, or 3.0 mg in patients>45 kg. No dosing data is available for children who weighed less than 15 kg. Once sufficient clinical response has been achieved and maintained, consideration should be given to gradually lowering the dose to achieve the optimal balance of efficacy and safety. Patients experiencing persistent somnolence may benefit from a once daily dose administered at bedtime or administering half the daily dose twice daily, or a reduction of the dose.<br/>Dosage in Special Populations: 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 . 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 . 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.<br/>Co-Administration of RISPERDAL with Certain Other Medications: 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 . 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 by about 10%. The dose of risperidone needs to be titrated accordingly when fluoxetine or paroxetine is co-administered .<br/>Directions for Use of RISPERDAL' M-TAB' Orally Disintegrating Tablets:<br/>Tablet Accessing: RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg RISPERDAL M-TAB Orally Disintegrating Tablets 0.5 mg, 1 mg, and 2 mg are supplied in blister packs of 4 tablet units each. Do not open the blister until ready to administer. For single tablet removal, separate one of the four blister units by tearing apart at the perforations. Bend the corner where indicated. Peel back foil to expose the tablet. DO NOT push the tablet through the foil because this could damage the tablet. RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg RISPERDAL M-TAB Orally Disintegrating Tablets 3 mg and 4 mg are supplied in a child-resistent pouch containing a blister with 1 tablet each. The child-resistant pouch should be torn open at the notch to access the blister. Do not open the blister until ready to administer. Peel back foil from the side to expose the tablet. DO NOT put the tablet through the foil, because this could damage the tablet.<br/>Tablet Administration: Using dry hands, remove the tablet from the blister unit and immediately place the entire RISPERDAL M-TAB Orally Disintegrating Tablet on the tongue. The RISPERDAL M-TAB Orally Disintegrating Tablet should be consumed immediately, as the tablet cannot be stored once removed from the blister unit. RISPERDAL M-TAB Orally Disintegrating Tablets disintegrate in the mouth within seconds and can be swallowed subsequently with or without liquid. Patients should not attempt to split or to chew the tablet.

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 (D) and serotonin Type 2 (5HT) receptor antagonism. Antagonism at receptors other than Dand 5HTmay 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 (5HT), dopamine Type 2 (D),��and��adrenergic, and Hhistaminergic 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, 5HT, and 5HTreceptors, weak affinity (Ki of 620 to 800 nM) for the dopamine Dand haloperidol-sensitive sigma site, and no affinity (when tested at concentrations>10M) for cholinergic muscarinic or��and��adrenergic receptors.<br/>Pharmacokinetics:<br/>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).<br/>Distribution: Risperidone is rapidly distributed. The volume of distribution is 1���2 L/kg. In plasma, risperidone is bound to albumin and��-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.<br/>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 . 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 risperidonetreatment (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% . Repeated oral doses of risperidone (3 mg BID) did not affect the exposure (AUC) or peak plasma concentrations (C) of lithium (n=13) . 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) after concomitant administration of risperidone . 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.<br/>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.<br/>Special Populations:<br/>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 .<br/>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��-acid glycoprotein. RISPERDAL doses should be reduced in patients with liver disease .<br/>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).<br/>Pediatric: The pharmacokinetics of risperidone and 9-hydroxyrisperidone in children were similar to those in adults after correcting for the difference in body weight.<br/>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.

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

http://www4.wiwiss.fu-berlin.de/drugbank/resource/drugs/DB00734

dailymed-ingredient:risperidone

diseasome-diseases:1025, diseasome-diseases:1032, diseasome-diseases:1377, diseasome-diseases:1460, diseasome-diseases:1984, diseasome-diseases:2216, diseasome-diseases:261, diseasome-diseases:3423, diseasome-diseases:347, diseasome-diseases:3734, diseasome-diseases:3841, diseasome-diseases:3852, diseasome-diseases:54, diseasome-diseases:852, diseasome-diseases:94, diseasome-diseases:989

risperidone

The following findings are based on the short-term, placebo-controlled, North American, premarketing trials for schizophrenia and acute bipolar mania, and are followed by a description of adverse events and other safety measures in short-term, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder. In patients with Bipolar I Disorder, treatment-emergent adverse events are presented separately for risperidone as monotherapy and as adjunctivetherapy 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 and pediatric patients with autistic disorder.<br/>Associated With Discontinuation of Treatment:<br/>Schizophrenia: Approximately 9% (244/2607) of RISPERDAL (risperidone)-treated patients in Phase 2 and 3 studies discontinued treatment due to an adverse event, compared with about 7% on placebo and 10% on active control drugs. The more common events (���0.3%) associated with discontinuation and considered to be possibly or probably drug-related included: Suicide attempt was associated with discontinuation in 1.2% of RISPERDAL-treated patients compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in RISPERDAL compared to placebo patients, it is unlikely that suicide attempt is a RISPERDAL-related adverse event . Discontinuation for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 3 trials.<br/>Bipolar Mania: In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, there was no overall difference in the incidence of discontinuation due to adverse events (4% for RISPERDAL vs. 4% for placebo).<br/>Incidence in Controlled Trials:<br/>Commonly Observed Adverse Events in Controlled Clinical Trials:<br/>Adverse Events Occurring at an Incidence of 1% or More Among RISPERDAL-Treated Patients - Schizophrenia: The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent among RISPERDAL-treated patients treated at doses of���10 mg/day than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials. Patients received RISPERDAL doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or up to a maximum dose of 10 mg/day in the titration study. This table shows the percentage of patients in each dose group (���10 mg/day or 16 mg/day) who spontaneously reported at least one episode of an event at some time during their treatment. Patients given doses of 2, 6, or 10 mg did not differ materially in these rates. Reported adverse events were classified using the World Health Organization preferred terms. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.<br/>Adverse Events Occurring at an Incidence of 2% or More Among RISPERDAL-Treated Patients - Bipolar Mania: Tables 2 and 3 display adverse events that occurred at an incidence of 2% or more, and were more frequent among patients treated with flexible doses of RISPERDAL (1���6 mg daily as monotherapy and as adjunctive therapy to mood stabilizers, respectively) than among patients treated with placebo. Reported adverse events were classified using the World Health Organization preferred terms.<br/>Dose Dependency of Adverse Events:<br/>Other Adverse Events: Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse events: sleepiness, increased duration of sleep, accommodation disturbances, orthostatic dizziness, palpitations, weight gain, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, asthenia/lassitude/increased fatigability, and increased pigmentation.<br/>Vital Sign Changes: RISPERDAL is associated with orthostatic hypotension and tachycardia .<br/>Weight Changes: The proportions of RISPERDAL and placebo-treated patients meeting a weight gain criterion of���7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for RISPERDAL (18%) compared to placebo (9%).<br/>Laboratory Changes: A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically significant RISPERDAL/placebo differences in the proportions of patients experiencing potentially important changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no RISPERDAL/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis. However, RISPERDAL administration was associated with increases in serum prolactin .<br/>ECG Changes: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8���16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4���6 beats per minute).<br/>Adverse Events and Other Safety Measures in Pediatric Patients With Autistic Disorder: In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), two patients (one treated with RISPERDAL and one treated with placebo) discontinued treatment due to an adverse event. In addition to spontaneous reporting, in one of the studies, adverse events were also elicited from a checklist for detecting selected events, a method that is more sensitive than spontaneous reporting. The most common adverse events with RISPERDAL that occurred at an incidence equal to or greater than 5% and at a rate of at least twice that of placebo are shown in Table 4. Weight increase was reported more frequently with RISPERDAL than with placebo. The average weight increase over 8 weeks was 2.6 kg in patients treated with RISPERDAL compared with 0.9 kg in patients treated with placebo. There was a higher incidence of adverse events reflecting extrapyramidal symptoms (EPS) in the RISPERDAL group (27.6%) compared with the placebo group (10.0%). In addition, between-group comparison of the severity of EPS were assessed objectively by the following rating instruments: the Simpson-Angus Rating Scale (SARS) and the Abnormal Involuntary Movement Scale (AIMS) in one study, and the Extrapyramidal Symptom Rating Scale (ESRS) in the other study. The mean changes between baseline and endpoint in the total ESRS score were���0.3 in the RISPERDAL group and���0.4 in the placebo group. The median change from baseline to endpoint was 0 in both treatment groups for each EPS rating scale. Somnolence was the most frequent adverse event, and was reported at a higher incidence in the RISPERDAL group compared with the placebo group. The vast majority of cases (96%) were either mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first 2 weeks of treatment, and median duration was 16 days. Patients experiencing persistent somnolence may benefit from a change in dosing regimen (see DOSAGE AND ADMINISTRATION���Irritability Associated with Autistic Disorder���Pediatrics [Children and Adolescents]).<br/>Other Events Observed During the Premarketing Evaluation of RISPERDAL: During its premarketing assessment, multiple doses of RISPERDAL were administered to 2607 adult patients with schizophrenia and 1923 pediatric 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 listings that follow.) In the listings 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 adult or 1923 pediatric patients exposed to multiple doses of RISPERDAL who experienced anevent of the type cited on at least one occasion while receiving RISPERDAL. All reported events are included, except those already listed 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. Serious adverse reactions experienced by the pediatric population were similar to those seen in theadult population (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS). Events are further categorized by body system and listed 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 listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurringin fewer than 1/1000 patients.<br/>Psychiatric Disorders: Frequent: increased dream activity, diminished sexual desire, nervousness. Infrequent: impaired concentration, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia. Rare: emotional lability, nightmares, delirium, withdrawal syndrome, yawning.<br/>Central and Peripheral Nervous System Disorders: Frequent: increased sleep duration. Infrequent: dysarthria, vertigo, stupor, paraesthesia, confusion. Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis.<br/>Gastrointestinal Disorders: Frequent: anorexia, reduced salivation. Infrequent: flatulence, diarrhea, increased appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis. Rare: fecal incontinence, eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis.<br/>Body as a Whole/General Disorders: Frequent: fatigue. Infrequent: edema, rigors, malaise, influenza-like symptoms. Rare: pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing.<br/>Respiratory System Disorders: Infrequent: hyperventilation, bronchospasm, pneumonia, stridor. Rare : asthma, increased sputum, aspiration.<br/>Skin and Appendage Disorders: Frequent: increased pigmentation, photosensitivityInfrequent: increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation. Rare: bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria.<br/>Cardiovascular Disorders: Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction. Rare: ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles, ST depression, myocarditis.<br/>Vision Disorders: Infrequent: abnormal accommodation, xerophthalmia. Rare: diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation.<br/>Metabolic and Nutritional Disorders: Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight decrease, diabetes mellitus. Rare: decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia.<br/>Urinary System Disorders: Frequent: polyuria/polydipsia. Infrequent: urinary incontinence, hematuria, dysuria. Rare: urinary retention, cystitis, renal insufficiency.<br/>Musculo-Skeletal System Disorders: Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain.<br/>Reproductive Disorders, Female: Frequent: menorrhagia, orgastic dysfunction, dry vaginaInfrequent: nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage.<br/>Liver and Biliary System Disorders: Infrequent: increased SGOT, increased SGPT. Rare: hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis, hepatocellular damage.<br/>Platelet, Bleeding, and Clotting Disorders: Infrequent: epistaxis, purpura. Rare: hemorrhage, superficial phlebitis, thrombophlebitis, thrombocytopenia.<br/>Hearing and Vestibular Disorders: Rare: tinnitus, hyperacusis, decreased hearing.<br/>Red Blood Cell Disorders: Infrequent: anemia, hypochromic anemia. Rare: normocytic anemia.<br/>Reproductive Disorders, Male: Frequent: erectile dysfunctionInfrequent: ejaculation failure.<br/>White Cell and Resistance Disorders: Infrequent: granulocytopenia Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly.<br/>Endocrine Disorders: Rare: gynecomastia, male breast pain, antidiuretic hormone disorder.<br/>Special Senses: Rare: bitter taste.<br/>Postintroduction Reports: 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, cerebrovascular disorder, including cerebrovascular accident, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary adenomas, pulmonary embolism, precocious puberty, and QT prolongation. 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.

Schizophrenia: 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 .<br/>Bipolar Mania:<br/>Monotherapy: RISPERDAL is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder. The efficacy of RISPERDAL was established in two placebo-controlled trials (3-week) with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features .<br/>Combination Therapy: The combination of RISPERDAL with lithium or valproate is indicated for the short-term treatment of acute manic or mixed episodes associated with Bipolar I Disorder. The efficacy of RISPERDAL in combination with lithium or valproate was established in one placebo-controlled (3-week) trial with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features (see CLINICAL PHARMACOLOGY). The effectiveness of RISPERDAL for longer-term use, that is, for more than 3 weeks of treatment of an acute episode, and for prophylactic use in mania, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).<br/>Irritability Associated with Autistic Disorder: RISPERDAL is indicated for the treatment of irritability associated with autistic disorder in children and adolescents, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. The efficacy of RISPERDAL 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. The benefit of maintaining patients with irritability associated with autistic disorder on therapy with RISPERDAL after achieving a responder status for an average duration of about 140 days was demonstrated in acontrolled trial (see CLINICAL PHARMACOLOGY - Clinical Trials.) Physicians who elect to use RISPERDAL for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

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