risperidone 0.5 mg tablet

Uses

Psychotic Disorders

Risperidone is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Schizophrenia

Risperidone is used orally for the treatment of schizophrenia in adults and adolescents 13-17 years of age and IM as an extended-release injection for the treatment of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

Short-term efficacy of oral risperidone for the treatment of schizophrenia in adults was established in 4 controlled studies of 4-8 weeks' duration in patients who met DSM-III-R criteria for schizophrenia and who were hospitalized for psychotic symptoms. In these and other clinical studies conducted principally in patients with schizophrenia, oral risperidone was more effective than placebo and at least as effective as conventional (e.g., haloperidol, perphenazine) and certain atypical (e.g., olanzapine) antipsychotics in the treatment of schizophrenia. Data from limited clinical studies indicate that risperidone improves both positive and negative manifestations of schizophrenia, but that such improvements may not be substantially greater than those achieved by haloperidol, a conventional antipsychotic. In these studies, improvement in manifestations of schizophrenia was based on the results of various psychiatric rating scales, including the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbances, activation, hostility/suspiciousness, and anxiety/depression; the BPRS psychosis cluster that assesses factors such as conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content in actively psychotic schizophrenic patients; the Scale for the Assessment of Negative Symptoms (SANS); the Positive and Negative Syndrome Scale (PANSS); and the Clinical Global Impression (CGI) scale.

Long-term efficacy of oral risperidone for the treatment of schizophrenia was established in a randomized, double-blind study in 365 adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Patients were randomized to receive either flexible dosages of risperidone (2-8 mg daily) or haloperidol (5-20 mg daily) for 1-2 years and observed for relapse. Patients receiving risperidone experienced a substantially longer time to relapse than those who received haloperidol. In this study, approximately 25% of patients who received usual dosages of risperidone had relapsed by the end of the study compared with approximately 40% of those receiving usual dosages of haloperidol.

Efficacy of oral risperidone for the treatment of schizophrenia in adolescents was demonstrated in 2 short-term, double-blind clinical trials of 6-8 weeks' duration in adolescent patients 13-17 years of age who met DSM-IV criteria for schizophrenia and were experiencing an acute episode of schizophrenia at the time of enrollment. In the first study, patients were randomized to receive flexible dosages of risperidone of 1-3 mg daily or 4-6 mg daily or placebo. In the second study, patients were randomized to receive either risperidone target dosages of 0.15-0.6 mg daily or 1.5-6 mg daily. The primary efficacy measure in both studies was the change in total PANSS score from baseline. In these studies, risperidone in the target dosage groups from 1-6 mg daily was found to be more effective than placebo in substantially reducing the total PANSS score; however, dosages higher than 3 mg daily did not demonstrate additional efficacy.

Efficacy of the extended-release IM formulation of risperidone (Risperdal Consta) in the treatment of schizophrenia in adults was established, in part, based on extrapolation of efficacy data from oral risperidone. In addition, efficacy of extended-release IM risperidone was established in a multicenter, placebo-controlled study of 12 weeks' duration in adult inpatients and outpatients who met DSM-IV criteria for schizophrenia. During the 1-week run-in period of this study, other oral antipsychotic agents were discontinued and all patients received oral risperidone therapy (initially, 2 mg daily and titrated up to 4 mg daily for at least 3 days). During the 12-week, double-blind phase, patients were randomized to receive IM injections of 25, 50, or 75 mg of extended-release risperidone or placebo every 2 weeks. Patients receiving extended-release IM injections of risperidone were also given oral risperidone (2 mg daily in the 25-mg group, 4 mg in the 50-mg group, and 6 mg in the 75-mg group) for 3 weeks following the first injection to provide therapeutic plasma concentrations of the drug until the main release phase of risperidone from the IM injection site had begun; patients who received placebo injections were given placebo tablets. The primary efficacy measure in this study was the change in total PANSS score from baseline to end point. Total PANSS scores demonstrated substantially greater improvement in the patients treated with each of the 3 IM dosages of extended-release risperidone (25, 50, and 75 mg every 2 weeks) compared with patients receiving placebo. Although there were no significant differences in treatment effects between the 3 dosage groups, the effect size for the 75-mg group was numerically less than that of the 50-mg group. Subgroup analyses did not reveal any differences in treatment outcomes based on age, race, or gender.

Efficacy of extended-release IM risperidone in the treatment of schizophrenia has not been evaluated in controlled clinical trials for longer than 12 weeks; however, oral risperidone has been shown to be effective in delaying time to relapse with longer-term use. If the extended-release IM injection of risperidone is used for extended periods, the long-term risks and benefits of the drug should be reassessed periodically on an individualized basis.

Parenteral antipsychotic therapy with a long-acting IM preparation may be particularly useful in patients with schizophrenia and a history of poor compliance. In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug. The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur.

The manufacturer of extended-release IM risperidone recommends that patients should first receive oral risperidone therapy to establish tolerability of the drug before the long-acting IM preparation is used.

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program,

Geriatric Considerations

Although risperidone has been studied for use in the management of psychosis and aggression in institutionalized geriatric patients with moderate to severe dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia), vascular dementia, or a combination of the 2 types of dementia (i.e., mixed dementia), use of the drug in geriatric patients with dementia-related psychosis is associated with an increased risk of adverse cerebrovascular events. In randomized, placebo-controlled studies in nursing home residents with dementia, oral risperidone at a dosage of approximately 1 mg daily was more effective than placebo in decreasing psychotic and behavioral symptoms (e.g., aggression, agitation) of dementia, as assessed by the Behavioral Pathology in Alzheimer's Disease scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). However, evidence from these studies showed a significantly higher incidence of adverse cerebrovascular events such as stroke and transient ischemic attacks (TIAs) associated with risperidone therapy relative to placebo. In addition, geriatric patients with dementia-related psychosis treated with atypical antipsychotic agents are at an increased risk of death compared with that among patients receiving placebo.(See Cautions: Geriatric Precautions.) Risperidone is not approved for the treatment of dementia-related psychosis.

Bipolar Disorder

Risperidone is used orally as monotherapy for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults and adolescents 10-17 years of age, or in conjunction with lithium or valproate for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults. Risperidone as an extended-release injection is also used IM as monotherapy or adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults.

Efficacy of oral risperidone monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 2 placebo-controlled trials of 3 weeks' duration in adults who met the DSM-IV criteria for bipolar I disorder with acute manic or mixed episodes with or without psychotic features. The principal 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 in a range from 0 (no manic features) to 60 (maximum score). In the first 3-week, placebo-controlled trial, which was limited to patients with manic episodes, risperidone monotherapy was given at an initial dosage of 3 mg daily and subsequently in a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 4.1 mg daily. In the second 3-week, placebo-controlled trial, patients also were given an initial dosage of risperidone 3 mg daily and subsequently a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 5.6 mg daily. Risperidone was found to be superior to placebo in the reduction of the Y-MRS total score in both studies.

Efficacy of oral risperidone as monotherapy in the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10-17 years of age was demonstrated in a 3-week, double-blind, placebo-controlled trial. The pediatric patients were randomized to receive 1 of 2 dosage ranges of risperidone or placebo. Risperidone was initiated at 0.25 mg daily and titrated to the maximum tolerated dosage within the target dosage ranges of 0.5-2.5 mg daily or 3-6 mg daily within 10 days. The principal rating instrument used for assessing manic symptoms in this trial was the Y-MRS. Both dosage ranges of risperidone were found to be substantially superior to placebo in reducing the Y-MRS total score; however, dosages exceeding 2.5 mg daily did not demonstrate greater efficacy than lower dosages of the drug (0.5-2.5 mg daily).

Efficacy of oral risperidone when used in conjunction with lithium or valproate in the treatment of acute manic or mixed episodes associated with bipolar I disorder has been demonstrated in one placebo-controlled trial of 3 weeks' duration in adults who met the DSM-IV criteria for bipolar I disorder (with or without a rapid cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). In this study, inpatients and outpatients with bipolar disorder experiencing manic or mixed episodes who had not adequately responded to lithium or valproate monotherapy were randomized to receive risperidone, haloperidol, or placebo in conjunction with their original therapy. Risperidone therapy was given in an initial dosage of 2 mg daily and subsequently given in a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 3.8 mg daily. Lithium and valproate were given in conjunction with risperidone and plasma drug concentrations were maintained within therapeutic ranges of 0.6-1.4 mEq/L for lithium and 50-120 mcg/mL for valproate. Addition of risperidone to lithium or valproate was shown to be superior to continued monotherapy with lithium or valproate as assessed by reduction of Y-MRS total score.

In a second 3-week, placebo-controlled trial, inpatients and outpatients with bipolar mania receiving lithium, valproate (as divalproex), or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive oral risperidone or placebo in conjunction with their original therapy. Risperidone was given in a flexible dosage range of 1-6 mg daily, with an initial dosage of 2 mg daily; the mean modal dosage was 3.7 mg daily. Addition of risperidone to lithium, valproate, or carbamazepine therapy (with plasma drug concentrations maintained within therapeutic ranges of 0.6-1.4 mEq/L, 50-125 mcg/mL, or 4-12 mcg/mL, respectively) was not found to be superior to lithium, valproate, or carbamazepine given alone as assessed by reduction of the Y-MRS total score. A possible explanation for the failure of this trial was enzymatic induction of clearance of risperidone and its principal active metabolite, 9-hydroxyrisperidone, by carbamazepine in the subgroup of patients receiving combined therapy with these drugs, resulting in subtherapeutic plasma concentrations of risperidone and 9-hydroxyrisperidone.

Efficacy of the extended-release IM formulation of risperidone (Risperdal Consta) as monotherapy in the maintenance treatment of bipolar I disorder was established in a multicenter, placebo-controlled trial in adults who met the DSM-IV criteria for bipolar I disorder and who were either stable on their drug regimen or experiencing an acute manic or mixed episode. All patients in this study were treated with open-label extended-release IM risperidone therapy for 26 weeks. Patients received an initial risperidone dosage of 25 mg IM every 2 weeks; the dosage was increased to 37.5 or 50 mg or decreased to 12.5 mg every 2 weeks as clinically indicated; patients who maintained response at 26 weeks were randomized to double-blind treatment with either the same IM dosage of risperidone or placebo and then monitored for relapse. Time to relapse to any mood episode (the primary outcome variable) was substantially delayed in patients receiving extended-release IM risperidone therapy compared with placebo. The majority of relapses were caused by manic rather than depressive symptoms; based on patient history, patients enrolled in the study had more manic episodes than depressive episodes.

Efficacy of extended-release IM risperidone as adjunctive therapy with lithium or valproate in the maintenance treatment of bipolar I disorder was established in a multicenter, double-blind, placebo-controlled study in adults with bipolar I disorder treated with mood stabilizers (primarily lithium or valproate), antidepressants, and/or anxiolytics who had experienced at least 4 episodes of mood disorder requiring clinical intervention in the previous 12 months and at least 2 episodes in the previous 6 months. Following a 16-week, open-label treatment phase with extended-release IM risperidone (initial risperidone dosage of 25 mg every 2 weeks and increased to 37.5 or 50 mg or decreased to 12.5 mg, if necessary), patients who remained stable were randomized either to continue IM risperidone at the same dosage or to receive placebo for up to 52 weeks while continuing their usual treatment and were observed for relapse. Continuation of IM risperidone therapy in addition to mood stabilizers delayed time to relapse to any mood episode (depression, mania, hypomania, or mixed) compared with placebo; the relapses were approximately half depressive and half manic or mixed episodes in this study.

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate. For more severe manic or mixed episodes, combined therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy. For further information on the management of bipolar disorder,

The manufacturers state that clinicians who elect to use risperidone for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

Autistic Disorder

Risperidone is used orally for the management 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.

Short-term efficacy of oral risperidone in children and adolescents with autistic disorder was established in 2 placebo-controlled trials of 8 weeks' duration in 156 children and adolescents (aged 5-16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of the patients in these 2 trials were under 12 years of age and the majority weighed over 20 kg (weight range: 16-104.3 kg). The principal rating instruments used for assessing efficacy in these trials were 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), which measures the emotional and behavioral symptoms of autism, including aggression toward others, deliberate self-injuriousness, temper tantrums, and rapidly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.

In the first 8-week, placebo-controlled trial, children and adolescents 5-16 years of age with autistic disorder received twice-daily placebo or risperidone 0.5-3.5 mg daily on a weight-adjusted basis, starting at 0.25 mg daily or 0.5 mg daily if baseline weight was less than 20 kg or 20 kg or greater, respectively; dosage was then titrated according to clinical response. Risperidone (mean modal dosage of 1.9 mg/day; equivalent to 0.06 mg/kg daily) was found to substantially improve scores on the ABC-I subscale and the CGI-C scale compared with placebo in this study.

In the second 8-week, placebo-controlled trial, children and adolescents 5-12 years of age with autistic disorder were given an initial risperidone dosage of 0.01 mg/kg daily, which was then titrated up to 0.02-0.06 mg/kg daily based on clinical response. Risperidone (mean modal dosage of 0.05 mg/kg daily; equivalent to 1.4 mg daily) substantially improved scores on the ABC-I subscale compared with placebo.

A third clinical trial conducted in children and adolescents 5-17 years of age who met DSM-IV criteria for autistic disorder and who had associated irritability and related behavioral symptoms compared 2 weight-based, fixed dosages of oral risperidone (high-dose and low-dose). Over 77% of the enrolled patients were younger than 12 years of age (mean age: 9 years) and 88% of the patients were male. In this 6-week, multicenter, double-blind study, patients were randomized to receive high-dose risperidone (1.25 mg daily for patients weighing from 20 to up to 45 kg and 1.75 mg daily for patients weighing 45 kg or more), low-dose risperidone (0.125 mg daily for those weighing from 20 to up to 45 kg and 0.175 mg daily for those weighing 45 kg or more), or placebo; the doses were administered once daily in the morning or evening (if sedation occurred). The primary outcome measure in this study was the change from baseline to end point in the ABC-I subscale. Treatment with risperidone substantially improved ABC-I scores in the high-dose risperidone group but not in the low-dose group, compared with placebo.

The efficacy of oral risperidone for long-term use (i.e., longer than 8 weeks) in children and adolescents with autistic disorder has been demonstrated in an open-label extension of the first 8-week, placebo-controlled trial in which 63 patients received risperidone for 4 or 6 months (depending on whether they received risperidone or placebo in the double-blind study). During the open-label treatment period, patients were maintained on a mean modal risperidone dosage of 1.8-2.1 mg daily (equivalent to 0.05-0.07 mg/kg daily).

Children and adolescents who maintained their positive response to risperidone (defined as at least a 25% improvement on the ABC-I subscale and a CGI-C rating of much improved or very much improved) during the 4-6 month, open-label treatment period (average duration of therapy was 140 days) were randomized to receive either risperidone or placebo during an 8-week, double-blind withdrawal trial. A substantially lower relapse rate was observed in the risperidone group compared with the placebo group during the pre-planned interim analysis of data from this trial. Based on the interim analysis results, the study was terminated since a statistically significant effect on relapse prevention was demonstrated. Relapse was defined as at least a 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline for the randomized withdrawal phase).

The manufacturers state that clinicians who elect to use risperidone in children and adolescents with autistic disorder for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.

Although not curative, pharmacologic agents, such as risperidone, generally are used in children and adolescents with autistic disorder to reduce behavioral disturbances associated with autism and to help facilitate the child's or adolescent's adjustment and engagement in intensive, targeted educational interventions. In clinical studies, risperidone was not found to improve certain core symptoms of autism (e.g., language deficits, impaired social relatedness). However, the drug was more effective than placebo in improving scores on subscales for sensory motor behaviors, affectual reactions, and sensory responses in a controlled study. The possible risks, including clinically important weight gain, tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions associated with the drug, should be considered.(See Cautions.)

Risperidone also has been used in a limited number of adults for the treatment of autistic disorder and other pervasive developmental disorders.

Dosage and Administration

Administration

Risperidone is administered orally or by IM injection.

Oral Administration

Risperidone is administered orally, either in a once-daily dose or in 2 equally divided doses daily. Since food reportedly does not affect the rate or extent of GI absorption, the drug can be administered without regard to meals. Some experts state that once-daily administration of risperidone may be sufficient in most patients receiving maintenance therapy because of the extended half-life of the drug's principal active metabolite (9-hydroxyrisperidone).

Because risperidone can cause orthostatic hypotension and syncope, twice-daily oral administration of the drug may be preferable in geriatric patients and patients with renal or hepatic impairment to minimize the risk of these adverse effects.

In pediatric patients receiving risperidone for the management of schizophrenia or bipolar mania who experience persistent somnolence, twice-daily administration may be helpful.

In children and adolescents receiving risperidone for the management of irritability associated with autistic disorder who experience persistent somnolence, administering the drug once daily at bedtime, twice-daily administration, or a reduction in dosage may be helpful.

Risperidone oral solution may be administered directly from the calibrated pipette provided by the manufacturer or mixed in a beverage prior to administration. The oral solution is compatible in the following beverages: water, coffee, orange juice, and low-fat milk; risperidone oral solution is not compatible in cola or tea.

Patients receiving risperidone orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing. The tablet should not be pushed through the foil, since this may damage the tablet. With dry hands, the blister backing should be peeled back to expose the tablet. The tablet should then be gently removed and immediately placed on the tongue, where it rapidly disintegrates (i.e., within seconds) in saliva, and then subsequently swallowed with or without liquid. Risperidone orally disintegrating tablets should not be divided or chewed.

IM Administration

In patients who have never received oral risperidone, the manufacturer recommends that tolerability with oral risperidone therapy should be established prior to initiating IM therapy with extended-release risperidone (Risperdal Consta).

Risperidone extended-release injection is commercially available in a dose pack containing a vial of the drug in extended-release microspheres, a prefilled syringe containing 2 mL of diluent, a vial adapter device, and 2 safety needles for IM injection (one for deltoid and one for gluteal administration). Risperidone extended-release microspheres for injection must be reconstituted prior to administration using only the components of the dose pack supplied by the manufacturer. The dose pack should be allowed to sit at room temperature for at least 30 minutes before reconstitution; the dose pack should not be warmed any other way. Risperidone extended-release microspheres should be reconstituted using only the diluent in the prefilled syringe supplied by the manufacturer. The entire contents of the prefilled syringe should be injected into the vial, and the vial should be shaken vigorously while the plunger rod is held down with the thumb for at least 10 seconds to ensure a homogeneous suspension; the reconstituted suspension should appear uniform, thick, and milky. The manufacturer's prescribing information should be consulted for additional details on use of the components of the dose pack to reconstitute and administer risperidone injection. The manufacturer states that different dosage strengths of IM risperidone should not be combined in a single administration.

Following reconstitution, immediate use is necessary because the suspension will settle over time. Once the reconstituted suspension has been transferred to the syringe and the appropriate needle attached, the syringe should be vigorously shaken again to resuspend the drug just prior to the IM injection.

The entire contents of the vial should be administered by deep IM injection into either the deltoid muscle (using the 1-inch needle supplied by the manufacturer) or the upper outer quadrant of the gluteal area (using the 2-inch needle supplied by the manufacturer) every 2 weeks, alternating between the 2 arms or 2 buttocks, respectively.Each injection should be administered by a health care professional. IM injections at the same dosages into the deltoid and gluteal areas are bioequivalent and are, therefore, interchangeable. The injection should not be administered IV. In addition, care should be taken to avoid inadvertent injection into a blood vessel.

Dispensing and Administration Precautions

The US Food and Drug Administration (FDA) alerted healthcare professionals and patients of medication error reports in which patients were given risperidone (Risperdal) instead of ropinirole hydrochloride (Requip, a nonergot-derivative dopamine receptor agonist) and vice versa. As of June 2011, the FDA had evaluated 226 wrong drug medication errors associated with confusion between these 2 drugs; all of the reports involved tablet formulations of the drugs. Several of these cases resulted in adverse effects (including confusion, lethargy, ataxia, hallucinations, tiredness, dizziness, tingling, numbness, and altered mental status) and some of the patients who took the wrong drug required hospitalization. The FDA has determined that the factors contributing to the confusion between these 2 products include similarities in both the trade (brand) and generic (nonproprietary) names, similarities in the container labels and carton packaging, illegible handwriting on the prescriptions, and overlapping product characteristics (such as drug strengths, dosage forms, and dosing intervals). It is also possible that the 2 products may be stocked close to one another on pharmacy shelves whether they are alphabeticized by brand or generic name. In addition, some generic manufacturers make both products. Healthcare professionals are therefore reminded to clearly print out or spell out the drug name on prescriptions and to make sure their patients know the name of their prescribed drug and the reason they are taking it.

Dosage

Schizophrenia

Oral Dosage

Risperidone has a bell-shaped dose-response curve, with therapeutic efficacy of oral dosages of 12-16 mg daily lower than that of dosages of 4-8 mg daily in adults. Because dosage information contained in the manufacturers' labeling principally is derived from early clinical studies of the drug in patients not typical of the general population of patients treated in the community (i.e., in hospitalized, chronically ill schizophrenic patients accustomed to high-dose antipsychotic therapies), dosage of risperidone should be individualized according to the patient's response and tolerance. Clinicians also may consider consulting published protocols for specific dosage information, particularly in geriatric or younger patients, and in those experiencing their first psychotic episode.

The manufacturers' labeling states that the initial oral dosage of risperidone for the treatment of schizophrenia in adults is 2 mg daily (given as either 2 mg once daily or 1 mg twice daily). The dosage may be increased in increments of 1-2 mg daily at intervals of 24 hours or greater, as tolerated, up to a target dosage of 4-8 mg daily (administered once daily or in 2 equally divided doses). The manufacturers state that slower dosage titration may be appropriate in certain patients.

Evidence from open-labeled studies and clinical experience with the drug indicate that an initial dosage of 1-2 mg daily, with dosage increases in increments of 0.5-1 mg daily titrated over 6-7 days, as tolerated, to a target dosage of 4 mg daily may be appropriate for the management of schizophrenia in most otherwise healthy adult patients. Lower initial dosages (e.g., 1 mg daily) and slower dosage titrations to an initial target dosage of 2 mg daily may be appropriate for younger patients and in those being treated for their first psychotic episode; dosage may then be titrated up to 4 mg daily depending on clinical response at the lower dosage and adverse neurologic effects. Such patients appear to benefit optimally from a risperidone dosage of 1-3 mg daily. A substantial number of patients being treated for their first psychotic episode start to develop extrapyramidal symptoms once dosages are increased above 2 mg daily. Dosage reductions should be considered in any patient who develops extrapyramidal symptoms.

While antipsychotic efficacy has been established in clinical trials at oral risperidone dosages ranging from 4-16 mg daily, the manufacturers and some clinicians state that dosages exceeding 6 mg daily, when given in 2 divided doses, did not result in further improvement but were associated with increases in some adverse effects, including extrapyramidal manifestations. Therefore, the manufacturers state that dosages exceeding 6 mg (in 2 divided doses) daily generally are not recommended and those exceeding 16 mg daily have not been evaluated for safety. In a single study of once-daily dosing, efficacy results generally were stronger for 8 mg than for 4 mg.

For the treatment of schizophrenia in adolescents 13-17 years of age, the manufacturer recommends an initial oral risperidone dosage of 0.5 mg once daily in the morning or evening. Dosage adjustments may be made in increments of 0.5 or 1 mg daily at intervals of 24 hours or greater, as tolerated, up to the recommended dosage of 3 mg daily. While antipsychotic efficacy in adolescents has been demonstrated in clinical trials at oral dosages ranging from 1-6 mg daily, no additional benefit was observed with dosages exceeding 3 mg daily and higher dosages were associated with increased adverse effects. Dosages exceeding 6 mg daily in adolescents have not been evaluated in clinical studies. Pediatric patients who experience persistent somnolence may benefit from twice-daily administration of the drug in 2 equally divided doses.

The manufacturers state that there are no systematically collected data that specifically address switching from other antipsychotic agents to risperidone or concomitant administration with other antipsychotic agents. The first risperidone dose should be administered in place of the next scheduled parenteral antipsychotic dose in schizophrenic patients being switched from long-acting (depot) parenteral antipsychotic therapy to oral risperidone therapy.

The optimum duration of oral risperidone therapy currently is not known, but maintenance therapy with risperidone 2-8 mg daily has been shown to be effective in adults for up to 2 years. The manufacturers state that patients responding to risperidone therapy should generally continue to receive therapy at their effective dosage beyond the acute response. Patients should be reassessed periodically to determine the need for continued therapy with the drug. If risperidone therapy is reinitiated after a drug-free period, the manufacturers recommend that the appropriate recommended schedule of careful dosage titration be employed.

The American Psychiatric Association (APA) states that prudent long-term treatment options in adults with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

IM Dosage

For the management of schizophrenia in adults, the recommended dosage of extended-release risperidone injection is 25 mg administered by deep IM injection into the deltoid or gluteal area every 2 weeks. The manufacturer recommends that patients first receive oral risperidone to establish tolerability of the drug before the extended-release risperidone injection is used. To ensure that adequate plasma antipsychotic concentrations are maintained prior to the main release of risperidone from the injection site, therapy with oral risperidone or another oral antipsychotic agent (e.g., for patients being switched from other oral antipsychotic therapy to IM risperidone) should be given with the first IM injection of risperidone and continued for 3 weeks, then discontinued. The need for continuing any concomitant therapy for managing extrapyramidal manifestations should be periodically reevaluated.

Some patients not responding to the 25-mg dosage may benefit from increasing the IM dosage to 37.5 or 50 mg every 2 weeks. However, the dosage should not be increased more frequently than every 4 weeks, and clinical effects of the increased dosage should not be expected earlier than 3 weeks after the first injection of the higher dosage. The maximum IM dosage should not exceed 50 mg every 2 weeks since higher dosages were associated with an increased incidence of adverse effects, but no additional clinical benefit was observed.

In some patients, an initial risperidone dosage of 12.5 mg IM every 2 weeks and maintenance dosages as low as 12.5 mg every 2 weeks may be appropriate (e.g., patients with hepatic or renal impairment, patients who are receiving concurrent therapy with other drugs that increase plasma risperidone concentrations, patients with a history of poor tolerability to psychotropic drugs); however, efficacy of the 12.5 mg every 2 weeks dosage has not been evaluated in clinical trials.

Although no controlled studies have been conducted to establish the optimum duration of IM risperidone therapy in patients with schizophrenia, oral risperidone has been shown to be effective in delaying time to relapse with longer-term use. It is recommended that responding patients be continued on treatment with IM risperidone at the lowest dosage needed. Patients should periodically be reassessed to determine the need for continued treatment.

If therapy with IM risperidone is reinitiated after a drug-free period, oral risperidone (or another oral antipsychotic agent) should again be administered initially for supplementation.

Bipolar Disorder

Oral Dosage

For the management of acute manic or mixed episodes associated with bipolar I disorder in adults, either as monotherapy or as adjunctive therapy with lithium or valproate, the recommended initial oral dosage of risperidone is 2-3 mg given once daily. Dosage may be increased or decreased by 1 mg daily at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. In these trials, the short-term (i.e., 3-week) antimanic efficacy of risperidone was demonstrated in a flexible dosage ranging from 1 to 6 mg daily. Safety of dosages exceeding 6 mg daily has not been established.

For the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10-17 years of age, the recommended initial oral dosage of risperidone is 0.5 mg given once daily in the morning or evening. Dosage adjustments may be made in increments of 0.5-1 mg at intervals of not less than 24 hours, as tolerated, up to a target dosage of 1-2.5 mg daily. While efficacy in pediatric patients with bipolar mania has been demonstrated in clinical trials at oral dosages ranging from 0.5-6 mg daily, no additional benefit was observed with dosages exceeding 2.5 mg daily and higher dosages were associated with increased adverse effects. Safety and efficacy of oral dosages exceeding 6 mg daily in children and adolescents have not been evaluated in clinical studies. Pediatric patients who experience persistent somnolence may benefit from twice-daily administration of the drug in 2 equally divided doses.

The optimum duration of risperidone therapy for bipolar disorder currently is not known. While it is generally agreed that pharmacologic 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 support the use of oral risperidone beyond 3 weeks. Therefore, the manufacturers state that clinicians who elect to use risperidone for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

IM Dosage

For the maintenance treatment of bipolar I disorder in adults, either as monotherapy or as adjunctive therapy with lithium or valproate, the recommended dosage of extended-release risperidone injection is 25 mg administered by deep IM injection in the deltoid or gluteal area every 2 weeks. The manufacturer recommends that patients first receive oral risperidone to establish tolerability of the drug before the extended-release risperidone injection is used. To ensure that adequate therapeutic plasma concentrations are maintained prior to the main release of risperidone from the injection site, therapy with oral risperidone or another oral antipsychotic agent (e.g., for patients being switched from other oral antipsychotic therapy to IM risperidone) should be given with the first IM injection of risperidone and continued for 3 weeks, then discontinued. The need for continuing any concomitant therapy for managing extrapyramidal manifestations should be periodically reevaluated.

Some patients not responding to an initial IM risperidone dosage of 25 mg every 2 weeks may benefit from increasing the dosage to 37.5 or 50 mg every 2 weeks. However, the dosage should not be increased more frequently than every 4 weeks, and clinical effects of the increased dosage should not be expected earlier than 3 weeks after the first injection of the higher dosage. Safety and efficacy of IM dosages exceeding 50 mg every 2 weeks have not been evaluated in clinical trials of risperidone in the maintenance treatment of bipolar disorder.

In some patients, an initial dosage of 12.5 mg IM every 2 weeks may be appropriate (e.g., patients with hepatic or renal impairment, patients concurrently receiving drugs that increase plasma concentrations of risperidone, or patients with a history of poor tolerability to psychotropic drugs); however, efficacy of the 12.5-mg IM dosage has not been evaluated in clinical trials.

If therapy with IM risperidone is reinitiated after a drug-free period, oral risperidone (or another oral antipsychotic agent) should again be administered initially for supplementation.

The manufacturer states that clinicians who elect to use extended-release IM risperidone for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

Autistic Disorder

For the management of irritability associated with autistic disorder in children 5 years of age and older and adolescents, the recommended initial oral dosage of risperidone is 0.25 mg daily for patients weighing less than 20 kg and 0.5 mg daily for patients weighing 20 kg or more. The drug may be administered either once or twice daily. Patients experiencing persistent somnolence may benefit from a once-daily dosage administered at bedtime, administering half the daily dosage twice daily, or a reduction in dosage.

Dosage should be individualized according to clinical response and tolerability of the patient. After a minimum of 4 days following initiation of therapy, the dosage may be increased to the recommended dosage of 0.5 mg daily for patients weighing less than 20 kg and 1 mg daily for patients weighing 20 kg or more; this dosage should then be maintained for a minimum of 14 days. In patients not responding adequately, increases in dosage may be considered at intervals of 2 weeks or longer in increments of 0.25 mg daily for patients weighing less than 20 kg or 0.5 mg daily for patients weighing 20 kg or more. Dosages ranging from 0.5-3 mg daily were effective in clinical studies. Dosage data for children weighing less than 15 kg currently are lacking. In addition, safety and efficacy in pediatric patients younger than 5 years of age have not been established.

In the pivotal clinical trials, 90% of patients who responded to risperidone therapy (based on at least 25% improvement in the Irritability subscale of the Aberrant Behavior Checklist [ABC-I]) received dosages ranging from 0.5-2.5 mg daily. The maximum daily dosage in one of the trials, when the therapeutic effect reached a plateau, was 1 mg in patients weighing less than 20 kg, 2.5 mg in patients weighing 20 kg or more, and 3 mg in patients weighing more than 45 kg.

Once adequate clinical response has been achieved and maintained, a gradual reduction in dosage to achieve an optimal balance of efficacy and safety should be considered.

The manufacturers state that clinicians who elect to use risperidone in children and adolescents with autistic disorder for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

Geriatric Patients and Others at Risk of Orthostatic Hypotension

Like other α-adrenergic blocking agents, risperidone can induce orthostatic hypotension (e.g., manifested as dizziness, tachycardia, and occasionally syncope), particularly during initiation of oral therapy with the drug. The manufacturers and some clinicians state that the risk of this effect can be minimized by limiting the initial oral dosage of risperidone to 2 mg daily, given as a single daily dose or 1 mg twice daily, in otherwise healthy adults and to 0.5 mg twice daily in geriatric patients or patients with renal or hepatic impairment. However, other clinicians recommend initiating risperidone therapy at a dosage of 0.25 mg daily in geriatric patients and gradually increasing the dosage as tolerated.(See Cautions: Geriatric Precautions.) Most geriatric patients should not be maintained at an oral dosage exceeding 3 mg daily.

For geriatric patients with schizophrenia or bipolar disorder, the recommended IM risperidone dosage of the extended-release injection is 25 mg every 2 weeks. Oral risperidone (or another oral antipsychotic agent) should be given with the first risperidone extended-release injection and should be continued for 3 weeks to ensure that adequate therapeutic plasma concentrations are maintained prior to the main release phase of risperidone from the injection site.

Geriatric patients and patients with a predisposition to hypotensive reactions or for whom such reactions would pose a particular risk should be instructed in nonpharmacologic interventions that help reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning, slowly rising from a seated position). These patients should avoid sodium depletion or dehydration and circumstances that accentuate hypotension (e.g., alcohol intake, high ambient temperature). Monitoring of orthostatic vital signs also should be considered.

Particular caution also is warranted in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, or conditions that would predispose to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in those for whom such reactions would pose a risk, and cautious dosage titration and careful monitoring are necessary in such patients. Dosage reduction should be considered in any patient in whom hypotension develops.

Dosage in Renal and Hepatic Impairment

Because elimination of risperidone may be reduced and the risk of adverse effects, particularly hypotension, increased in patients with renal impairment, oral risperidone therapy should be initiated at a reduced dosage of 0.5 mg twice daily in adults with severe renal impairment (creatinine clearance less than 30 mL/minute) and increased as necessary and tolerated in increments of 0.5 mg or less, administered twice daily; increases beyond a dosage level of 1.5 mg twice daily should be made at intervals of at least 7 days. Likewise, this reduced oral dosage should be employed in patients with severe hepatic impairment (Child-Pugh score 10-15) because of the risk of an increased free fraction of risperidone in such patients.

If IM risperidone is used for management of schizophrenia or bipolar disorder in adults with renal or hepatic impairment, the patient should be treated with titrated doses of oral risperidone prior to initiating treatment with the extended-release injection. The recommended starting oral risperidone dosage is 0.5 mg twice daily during the first week, which can be increased to 1 mg twice daily or 2 mg once daily during the second week. If a dosage of at least 2 mg daily of oral risperidone is well tolerated, an IM dosage of 25 mg of the extended-release injection can be administered every 2 weeks. Alternatively, such patients may receive an initial dosage of 12.5 mg IM every 2 weeks; however, efficacy of the 12.5-mg dosage has not been evaluated in clinical trials. Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun. In some patients, slower titration may be medically appropriate.

Dosage Adjustments for Specific Drug Interactions

Adjustment of risperidone dosage may be necessary in patients receiving concomitant therapy with cytochrome P-450 (CYP) enzyme inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) or CYP2D6 inhibitors (e.g., fluoxetine, paroxetine). When risperidone is used concomitantly with a CYP enzyme inducer (e.g., carbamazepine), the manufacturers recommend that the dosage of oral risperidone be increased, up to double the patient's usual dosage.

In patients receiving IM risperidone, an increase in the IM dosage or addition of oral risperidone may be considered when used concomitantly with a CYP enzyme inducer.

A decrease in the dosage of oral or IM risperidone may be necessary when the CYP enzyme inducer is discontinued.

When oral risperidone is used concomitantly with fluoxetine or paroxetine (CYP2D6 inhibitors), the manufacturers recommend decreasing the dosage of risperidone and not exceeding 8 mg daily in adults. If oral risperidone is initiated in patients receiving fluoxetine or paroxetine, risperidone should be titrated slowly. When fluoxetine or paroxetine is discontinued, an increase in the dosage of risperidone may be necessary.

If fluoxetine or paroxetine is initiated in patients receiving IM risperidone, a dosage reduction may be considered; dosage of IM risperidone may be reduced 2-4 weeks before initiating fluoxetine or paroxetine. If fluoxetine or paroxetine is initiated in patients receiving IM risperidone 25 mg every 2 weeks, the manufacturer recommends continuing 25 mg every 2 weeks; dosage reduction to 12.5 mg every 2 weeks or interruption of therapy may be necessary based on clinical judgment. In patients already receiving fluoxetine or paroxetine, IM risperidone may be initiated at a dosage of 12.5 mg every 2 weeks; however, efficacy of the 12.5-mg dosage has not been evaluated in clinical trials.

Cautions

Risperidone shares many of the toxic potentials of other antipsychotic agents (e.g., other atypical antipsychotic agents, phenothiazines), and the usual precautions associated with therapy with these agents should be observed.

The most frequent adverse effects of oral risperidone reported in over 5% of patients who received the drug in clinical trials and with an incidence of at least twice that of those receiving placebo were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, weight gain, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. Adverse effects associated with discontinuance of oral risperidone therapy in more than 1% of adults and/or more than 2% of pediatric patients were nausea, somnolence, sedation, vomiting, dizziness, and akathisia.

The most frequent adverse effects of oral risperidone reported in at least 5% of adult patients with schizophrenia who received the drug in 3 short-term (4-8 week) clinical studies and with an incidence of at least twice that of those who received placebo were nausea, parkinsonism, akathisia, sedation, and dizziness. Approximately 7% of adult patients receiving oral risperidone in placebo-controlled studies discontinued treatment because of adverse effects compared with 4% of those receiving placebo. Adverse effects associated with discontinuance of therapy in at least 2 risperidone-treated patients were dizziness, nausea, vomiting, parkinsonism, somnolence, dystonia, agitation, abdominal pain, orthostatic hypotension, and akathisia.

Adverse effects occurring in 5% or more of pediatric patients with schizophrenia receiving oral risperidone in a 6-week clinical study and with an incidence of at least twice that of those receiving placebo included salivary hypersecretion, sedation, parkinsonism, akathisia, dizziness, dystonia, and anxiety. Approximately 7% of pediatric patients receiving oral risperidone in the study discontinued treatment because of adverse effects compared with 4% of those receiving placebo. Adverse effects associated with discontinuance of therapy in more than one risperidone-treated patient included dizziness, somnolence, sedation, lethargy, anxiety, balance disorder, hypotension, and palpitation.

The most frequent adverse effects of oral risperidone reported in at least 5% of adult patients with bipolar mania who received the drug as monotherapy in placebo-controlled trials and with an incidence of at least twice that of those receiving placebo were nausea, parkinsonism, sedation, akathisia, tremor, and dystonia. In placebo-controlled trials of oral risperidone in conjunction with mood stabilizers, adverse effects reported in at least 5% of patients and with an incidence of at least twice that of those receiving placebo were parkinsonism, sedation, akathisia, dizziness, tremor, and pharyngolaryngeal pain. In placebo-controlled trials of risperidone monotherapy in adults, approximately 6% of patients receiving the drug discontinued therapy because of adverse effects compared with about 5% of those receiving placebo. Adverse effects associated with discontinuance of therapy in these studies included parkinsonism, lethargy, and dizziness.

Adverse effects reported in 5% or more of pediatric patients with bipolar mania receiving oral risperidone in a 3-week, placebo-controlled trial and with an incidence of at least twice that of those receiving placebo included blurred vision, upper abdominal pain, nausea, vomiting, diarrhea, dyspepsia, stomach discomfort, fatigue, increased appetite, sedation, dizziness, parkinsonism, dystonia, akathisia, anxiety, pharyngolaryngeal pain, and rash. In this study, 12% of pediatric patients receiving risperidone for bipolar mania discontinued treatment because of adverse effects compared with 7% of those receiving placebo. Adverse effects associated with discontinuance of therapy in at least one risperidone-treated patient were nausea, somnolence, sedation, and vomiting.

The most frequent adverse effects of oral risperidone reported in at least 5% of pediatric patients with irritability associated with autistic disorder who received the drug in 3 placebo-controlled trials and with an incidence of at least twice that of those receiving placebo were constipation, dry mouth, salivary hypersecretion, fatigue, nasopharyngitis, upper respiratory tract infection, weight gain, increased appetite, sedation, drooling, tremor, dizziness, parkinsonism, and nasal congestion. Sedation was the most frequent adverse effect in these trials, occurring in 63% of the risperidone-treated patients and in 15% of patients receiving placebo. (See Dosage and Administration: Administration and also see Cautions: Pediatric Precautions.)

The most frequent adverse effects associated with use of risperidone extended-release IM injection reported in at least 5% of adult patients with schizophrenia in clinical trials were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight gain, pain in extremity, and dry mouth. The most frequent adverse effects associated with the use of risperidone extended-release IM injection in adult patients with bipolar disorder were weight gain in the monotherapy study and tremor and parkinsonism in the adjunctive therapy study.

Nervous System Effects

Tardive Dyskinesia

Use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements. In one open-label study, an annual incidence of tardive dyskinesia of 0.3% was reported in patients with schizophrenia who received approximately 8-9 mg of oral risperidone daily for at least 1 year. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of therapy and cumulative dose of antipsychotic agents administered; however, the syndrome may occur, although much less frequently, after relatively short periods of treatment with low dosages. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic therapy is discontinued. However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.

Risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a risperidone-treated patient, risperidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome. For additional information on tardive dyskinesia, .

Extrapyramidal Reactions

Extrapyramidal reactions occurred in 12-17% of adults with schizophrenia receiving oral risperidone dosages of 2-4 mg daily and in 20-35% of patients receiving dosages of 16 mg daily in clinical studies; these reactions appear to be dose related. At recommended therapeutic dosages of risperidone (4-8 mg daily) for schizophrenia, the severity of extrapyramidal reactions appears to be comparable to placebo and clozapine 400 mg daily, and substantially less than that associated with haloperidol 10 or 20 mg daily. Similarly, the severity of parkinsonian symptoms, as assessed on the parkinsonism subscale of the Extrapyramidal Symptom Rating Scale (ESRS), is also linearly related to risperidone dosages of 2-16 mg daily, with the incidence of parkinsonian symptoms at risperidone dosages of 6 mg daily or less comparable to that of placebo and substantially less than that seen with haloperidol dosages of 20 mg daily.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of therapy and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including risperidone. For additional information on NMS, .

Other Nervous System Effects

Dose-related somnolence is a commonly reported adverse effect associated with risperidone treatment. Approximately 41% of patients receiving 16 mg of oral risperidone daily and 16% of patients receiving placebo reported somnolence in a study utilizing a checklist to detect adverse events. Somnolence was reported in 5% of patients receiving extended-release IM risperidone in multiple-dose studies.(See Cautions: Pediatric Precautions.)

Insomnia and anxiety have been reported in 25-32 and 11-16%, respectively, of adult patients with schizophrenia receiving oral risperidone.

Cardiovascular Effects

Orthostatic Hypotension

Orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, has been reported in patients receiving risperidone, probably reflecting the drug's α-adrenergic antagonistic properties. Syncope was reported in 0.2% of patients receiving oral risperidone in phase 2 and 3 studies in adults with schizophrenia and in 0.8% of patients receiving extended-release IM risperidone in multiple-dose studies.

Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose to hypotension (e.g., dehydration, hypovolemia). Clinically important hypotension has been observed with concomitant use of oral risperidone and antihypertensive drug therapy.

The risk of orthostatic hypotension and syncope may be minimized by limiting initial oral risperidone dosages to 2 mg daily (given as 2 mg once daily or as 1 mg twice daily) in otherwise healthy adults and to 0.5 mg twice daily in geriatric patients and patients with renal or hepatic impairment.(See Dosage and Administration.) Monitoring of orthostatic vital signs should be considered in patients for whom orthostatic hypotension is of concern. Dosage reduction of risperidone should be considered if hypotension occurs.

Other Cardiovascular Effects

Pooled analysis of results of placebo-controlled studies indicates that oral risperidone therapy generally is not associated with statistically significant changes in ECG parameters (e.g., PR, QT, or QT_c intervals) and heart rate. However, in short-term studies in adults with schizophrenia, higher oral dosages of risperidone (8-16 mg daily) were associated with a higher mean increase in heart rate of 4-6 beats per minute compared with placebo. In addition, sinus bradycardia, sinus tachycardia, atrioventricular (AV) block, and bundle branch block have been reported in patients receiving risperidone during clinical trials. Atrial fibrillation, cardiopulmonary arrest, QT interval prolongation, and sudden death also have been reported during postmarketing surveillance; however, a causal relationship to the drug has not been established.

Endocrine and Metabolic Effects

Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain. While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving certain atypical antipsychotic agents, including risperidone. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., risperidone, clozapine, olanzapine, quetiapine).

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., risperidone, quetiapine) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics.(See Cautions: Precautions and Contraindications.)

In a pooled analysis of short-term, placebo-controlled studies of 3-8 weeks' duration in adults with schizophrenia or bipolar disorder, risperidone was associated with a mean increase in random serum glucose concentrations of 0.6-0.8 mg/dL compared with a decrease of 1.4 mg/dL for placebo. During longer-term studies in adults, risperidone was associated with a mean increase in serum glucose of 2.8 mg/dL at week 24 and 4.1 mg/dL at week 48.

In children and adolescents receiving risperidone 0.5-6 mg daily for schizophrenia, bipolar disorder, or autistic disorder in short-term studies, the proportion of patients experiencing an increase in fasting serum glucose from below 100 mg/dL to 126 mg/dL or higher was 0.8% for risperidone-treated patients compared with 0% for placebo recipients. During longer-term studies in children and adolescents, risperidone was associated with a mean increase in fasting glucose of 5.2 mg/dL at week 24.

Diabetic coma and diabetic ketoacidosis (in patients with impaired glucose metabolism) have been reported in risperidone-treated patients.

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with atypical antipsychotics. In a pooled analysis of 7 short-term, placebo-controlled studies of 3-8 weeks' duration in adults receiving oral risperidone for schizophrenia or bipolar mania, random cholesterol concentrations increased from baseline by a mean of 6.9 and 1.8 mg/dL in patients receiving risperidone 1-8 mg and more than 8-16 mg daily, respectively, compared with 0.6 mg/dL in those receiving placebo. The proportion of patients with an increase in random cholesterol concentrations from below 200 mg/dL to 240 mg/dL or higher was 4.3% for those receiving risperidone 1-8 mg daily and 6.3% for those receiving more than 8-16 mg of risperidone daily compared with 2.7% for placebo recipients, and the proportion of risperidone-treated patients with an increase in triglyceride concentrations from below 500 mg/dL to 500 mg/dL or higher was 2.5-2.7% compared with 1.1% for placebo recipients. During longer-term studies of oral risperidone, therapy with the drug was associated with a mean increase in nonfasting cholesterol concentrations of 4.4 and 5.5 mg/dL at weeks 24 and 48, respectively, and a mean increase in nonfasting triglycerides of 19.9 mg/dL at week 24.

In children and adolescents receiving oral risperidone 0.5-6 mg daily for schizophrenia, bipolar mania, or autistic disorder in short-term studies, the proportion of risperidone-treated patients with an increase in fasting cholesterol concentrations from below 170 mg/dL to 200 mg/dL or higher was 3.8% compared with 2.4% for placebo recipients and the proportion of risperidone-treated patients with an increase in fasting triglyceride concentrations from below 150 mg/dL to 200 mg/dL or higher was 7.1% compared with 1.5% for placebo recipients. During longer-term studies in children and adolescents, oral risperidone was associated with a mean increase in fasting cholesterol and triglyceride concentrations of 2.1 and 6.8 mg/dL, respectively, at week 24.

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy. The manufacturers recommend clinical monitoring of weight in patients receiving risperidone.

In short-term clinical studies in adults with schizophrenia or bipolar mania, a mean weight gain from baseline of 0.7 and 2.2 kg was reported in patients receiving oral risperidone 1-8 mg and more than 8-16 mg daily, respectively, compared with a weight loss of 0.3 kg in those receiving placebo. The proportion of patients experiencing a weight gain of 7% or more of their baseline body weight was 8.7% for those receiving risperidone 1-8 mg daily and 20.9% for those receiving more than 8-16 mg of risperidone daily compared with 2.9% for placebo recipients. During longer-term studies of risperidone in adults, risperidone was associated with a mean weight gain of 4.3 kg at week 24 and 5.3 kg at week 48.

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, risperidone can elevate serum prolactin concentrations, and the elevation may persist during chronic administration of the drug. Risperidone appears to be associated with a higher level of prolactin elevation than other antipsychotic agents. Elevated prolactin concentrations occur in children and adolescents as well as in adults receiving the drug.(See Cautions: Pediatric Precautions.) Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs. In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.

If risperidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.

Other Endocrine and Metabolic Effects

Increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, decreased appetite, polydipsia, and anorexia have been reported during clinical trials in patients receiving risperidone. Although a causal relationship has not been established, inappropriate antidiuretic hormone secretion and water intoxication have been reported in patients receiving risperidone during postmarketing surveillance. Precocious puberty and pituitary adenomas also have been reported during postmarketing surveillance; however, a causal relationship remains to be established.

GI Effects

Adverse GI effects that have been reported in 5% or more of patients receiving oral or IM risperidone in clinical studies include nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, and increased appetite. In addition, abdominal discomfort has been reported in 1% or more of patients receiving oral risperidone in clinical studies.

Other adverse GI effects reported during clinical trials with oral risperidone include dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, and aptyalism. Toothache and tongue spasm have been reported in patients treated with extended-release IM risperidone. Although a causal relationship to risperidone has not been established, dysgeusia, ileus, pancreatitis, and intestinal obstruction have been reported during postmarketing surveillance.

Respiratory Effects

Nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain were the most common adverse respiratory effects reported in more than 5% of patients receiving oral risperidone during clinical studies. In addition, cough and dyspnea have been reported in up to 2% of patients receiving risperidone in clinical studies. Wheezing, aspiration pneumonia, sinus congestion, dysphonia, productive cough, pulmonary congestion, rales, hyperventilation, and nasal edema also have been reported in patients receiving risperidone in clinical studies. Although a causal relationship to the drug has not been established, sleep apnea and pulmonary embolism have been reported during postmarketing surveillance.

Dermatologic Effects and Sensitivity Reactions

Rash and dry skin have been reported in at least 2% of patients with schizophrenia receiving oral risperidone in clinical studies. In addition, erythema, skin discoloration, skin lesion, pruritus, acne, hyperkeratosis, and seborrheic dermatitis have been reported in clinical trials.

Although a causal relationship has not been established, hypersensitivity reactions, including anaphylaxis and anaphylactic reactions, angioedema, and alopecia, have been reported in patients receiving risperidone during postmarketing surveillance.(See Cautions: Precautions and Contraindications.)

Genitourinary Effects

Urinary tract infection has been reported in 1% or more of adult patients with schizophrenia receiving oral risperidone in clinical trials. Adverse genitourinary effects reported in adult and pediatric patients receiving oral risperidone in clinical trials include enuresis, dysuria, pollakiuria, urinary incontinence, cystitis, irregular menstruation, amenorrhea, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, and breast enlargement. Although a causal relationship has not been established, urinary retention has been reported in patients receiving risperidone during postmarketing surveillance.

Rare cases of priapism have been reported in risperidone-treated patients during postmarketing surveillance. Severe priapism may require surgical intervention.

Musculoskeletal Effects

Back or chest pain, arthralgia, and pain in extremities have been reported in 1-4% of patients with schizophrenia receiving oral risperidone in clinical studies. In addition, joint stiffness, joint swelling, musculoskeletal chest pain, abnormal posture, myalgia, neck pain, muscular weakness, and rhabdomyolysis have been reported in patients receiving oral risperidone in clinical trials.

Hematologic Effects

In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents, including risperidone, have been reported. Agranulocytosis also has been reported.

Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia. Therefore, patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of risperidone therapy. Discontinuance of risperidone should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.

Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm), risperidone should be discontinued and the leukocyte count monitored until recovery occurs.(See Cautions: Precautions and Contraindications.)

Lithium reportedly has been used successfully in the treatment of several cases of leukopenia and neutropenia associated with aripiprazole, clozapine, olanzapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.

Anemia, granulocytopenia, eosinophilia, and epistaxis have been reported in patients receiving risperidone in clinical studies.

Thrombotic thrombocytopenic purpura occurred in at least one patient (a 28 year-old female patient) receiving risperidone in a large, open-labeled study. This patient experienced jaundice, fever, and bruising but eventually recovered after receiving plasmapheresis. The relationship of this adverse event to risperidone therapy is unknown.

Hepatic Effects

Elevated ALT or aminotransferase concentrations have been reported in patients receiving oral risperidone in clinical studies. Although a causal relationship to the drug has not been established, jaundice also has been reported during postmarketing surveillance.

Ocular and Otic Effects

Blurred vision has been reported in 1-3% of adults with schizophrenia or bipolar mania and in 4-7% of pediatric patients with bipolar disorder receiving oral risperidone in clinical studies. Ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, increased lacrimation, photophobia, glaucoma, and reduced visual acuity have been reported in patients receiving risperidone in clinical studies. Ear pain and tinnitus also have been reported in clinical studies with the drug.

Retinal artery occlusion has been reported in a patient treated with extended-release IM risperidone during postmarketing surveillance. This case occurred in the presence of abnormal arteriovenous anastomosis.

Precautions and Contraindications

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain). While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.

Because hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving certain atypical antipsychotic agents, including risperidone, the manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be closely monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.(See Cautions: Endocrine and Metabolic Effects.) Any patient who develops manifestations of hyperglycemia during treatment with an atypical antipsychotic should undergo fasting blood glucose testing. In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the antipsychotic; in other cases, hyperglycemia resolved with discontinuance of the suspect drug. For further information on the management of diabetes risks in patients receiving atypical antipsychotics, .

Because of the possibility of orthostatic hypotension, caution should be observed in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease (see Cautions: Geriatric Precautions), conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia), and patients receiving antihypertensive agents. Since patients with a recent history of myocardial infarction or unstable heart disease were excluded from premarketing clinical studies, clinicians should be aware that risperidone has not been evaluated or used to any appreciable extent in such patients. Patients receiving risperidone should be advised of the risk of orthostatic hypotension, especially during the period of initial dosage titration.(See Geriatric Patients and Others at Risk of Orthostatic Hypotension under Dosage and Administration: Dosage and Cautions: Cardiovascular Effects.)

Clinical experience with IM risperidone therapy in patients with certain concomitant diseases is limited. The manufacturer of extended-release IM risperidone advises using the drug with caution in patients with altered metabolism or hemodynamics.

Patients with parkinsonian syndrome or dementia with Lewy bodies reportedly have an increased sensitivity to antipsychotic agents, including risperidone. Clinical manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with more frequent falls, extrapyramidal adverse effects, and clinical features consistent with neuroleptic malignant syndrome. For additional information on extrapyramidal adverse effects and neuroleptic malignant syndrome, .

Clearance of risperidone and its principal active metabolite, 9-hydroxyrisperidone, are decreased by 60% in patients with moderate to severe renal impairment (creatinine clearance 15-59 mL/minute), and free fraction of risperidone is increased by about 35% in patients with hepatic impairment. Therefore, lower initial dosages of oral risperidone should be used in patients with severe renal or hepatic impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of risperidone therapy. Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.(See Cautions: Hematologic Effects.)

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that risperidone orally disintegrating tablets contain aspartame (e.g., NutraSweet), which is metabolized in the GI tract to provide phenylalanine following oral administration; the respective manufacturer's labeling should be consulted for specific information regarding phenylalanine content of individual preparations and dosage strengths.

Because seizures have occurred in 0.3% of patients receiving risperidone orally or IM in clinical studies, the drug should be administered with caution to patients with a history of seizures.

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents, including risperidone. Because aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced dementia of the Alzheimer's type, risperidone and other antipsychotic drugs should be used with caution in patients at risk for aspiration pneumonia.

Because disruption of the body's ability to regulate body temperature has been associated with the use of antipsychotic agents and because both hypothermia and hyperthermia have been associated with oral and extended-release IM risperidone therapy, the drug should be administered with caution in patients who will be exposed to temperature extremes.

Because risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including driving automobiles, until they are reasonably certain that risperidone therapy does not adversely affect them.

Risperidone has an antiemetic effect in animals; this effect also may occur in humans, and may mask manifestations of overdosage with certain drugs or may obscure the cause of vomiting in various disorders such as intestinal obstruction, Reye's syndrome, or brain tumor.

Osteodystrophy, renal tubular tumors, and adrenomedullary pheochromocytomas have been observed in rats following IM administration of extended-release risperidone; these findings were not observed previously with oral risperidone. The clinical relevance of these findings to humans is not known.

Because the possibility of a suicide attempt is inherent in patients with schizophrenia or bipolar disorder, close supervision of high-risk patients is recommended during risperidone therapy. Because extended-release IM risperidone is administered by a health care professional, suicide due to an overdose is unlikely.

Patients should be advised to inform their clinician if they are taking, or plan to take, any prescription or nonprescription drugs, or have any concomitant illnesses (e.g., diabetes mellitus). Patients also should be advised to avoid alcohol while taking risperidone.

Risperidone is contraindicated in patients with known hypersensitivity to the drug.(See Cautions: Dermatologic Effects and Sensitivity Reactions.)

Pediatric Precautions

The safety and efficacy of risperidone in children younger than 13 years of age with schizophrenia or younger than 10 years of age with bipolar I disorder have not been established. Safety and efficacy of oral risperidone for the treatment of schizophrenia in adolescents 13-17 years of age were demonstrated in 2 short-term clinical trials in 417 patients.(See Schizophrenia under Uses: Psychotic Disorders.)

Efficacy and safety of risperidone for the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10-17 years of age were demonstrated in a 3-week, placebo-controlled study in 169 patients.(See Uses: Bipolar Disorder.)

Efficacy and safety of the drug in the treatment of irritability associated with autistic disorder have been evaluated in 3 placebo-controlled trials of 6-8 weeks' duration in 252 children and adolescents 5-17 years of age.(See Uses: Autistic Disorder.) Additional safety information also was assessed from long-term studies in patients with schizophrenia or autistic disorder and from short- and long-term studies in more than 1200 pediatric patients with other psychiatric disorders who were of similar age and weight and who received similar risperidone dosages as patients treated for irritability associated with autistic disorder.

In clinical trials in 1885 children and adolescents treated with risperidone, 2 patients (0.1%) reportedly developed tardive dyskinesia, which resolved upon discontinuance of therapy. In addition, approximately 15% of children and adolescents receiving 0.5-2.5 mg daily dosages of risperidone developed withdrawal dyskinesia during the discontinuance phase of one long-term (6 month), open-label study.

In children and adolescents receiving oral risperidone 0.5-6 mg daily for schizophrenia, bipolar mania, autistic disorder, or other psychiatric disorders in short-term studies, approximately 33% of the risperidone-treated patients gained 7% or more of their baseline body weight compared with 7% of those receiving placebo; mean weight gain was 2 and 0.6 kg in the risperidone and placebo groups, respectively. During longer-term, open-label studies of risperidone in children and adolescents, risperidone was associated with a mean weight gain of 5.5 kg at week 24 and 8 kg at week 48.

In long-term, open-label trials in patients with autistic disorder or other psychiatric disorders, a mean body weight gain of 7.5 kg after 12 months of risperidone therapy was reported, which was higher than the normal expected weight gain (i.e., 3-3.5 kg per year adjusted for age, based on the US Centers for Disease Control and Prevention normative data). The majority of the weight increase occurred within the first 6 months of drug exposure. When treating pediatric patients with risperidone, the manufacturers recommend that weight gain should be assessed against that expected with normal growth.

Somnolence frequently occurred in placebo-controlled trials of oral risperidone in pediatric patients with autistic disorder. Most cases were mild to moderate in severity, occurred early during therapy (peak incidence during the first 2 weeks of therapy), and were transient (median duration of 16 days). Somnolence also was the most common adverse effect in clinical trials in children and adolescents with bipolar disorder as well as in schizophrenia clinical trials in adolescents; as in the autistic disorder trials, somnolence usually occurred early during therapy and was transient. Pediatric patients experiencing persistent somnolence may benefit from a change in dosage regimen.(See Dosage and Administration: Administration.)

Risperidone has been shown to elevate prolactin concentrations in children and adolescents as well as adults. In double-blind, placebo-controlled trials of up to 8 weeks' duration in children and adolescents 5-17 years of age, 49% of oral risperidone-treated patients had elevated prolactin concentrations compared with 2% of those receiving placebo. Similarly, in placebo-controlled trials in children and adolescents 10-17 years of age with bipolar disorder or adolescents 13-17 years of age with schizophrenia, 82-87% of risperidone-treated patients had elevated prolactin concentrations compared with 3-7% of placebo recipients. Increases in prolactin concentrations were dose dependent and generally greater in female than male patients across indications.

In clinical trials conducted in 1885 children and adolescents, galactorrhea and gynecomastia reportedly occurred in 0.8 and 2.3%, respectively, of risperidone-treated patients.

The manufacturers state that the long-term effects of risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.

Geriatric Precautions

Clinical studies of oral risperidone for the management of schizophrenia did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Other clinical experience with oral risperidone has not identified differences in responses between geriatric and younger patients. However, serious adverse effects, including an increased risk of death, have been reported in geriatric patients receiving risperidone or other atypical antipsychotic agents in clinical trials in patients with dementia-related psychosis. Risperidone is not approved for the treatment of dementia-related psychosis.(See Geriatric Considerations in Uses: Psychotic Disorders.)

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., risperidone, aripiprazole, olanzapine, quetiapine) compared with that in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with 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. Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear.

A higher incidence of mortality also was observed in geriatric patients with dementia-related psychosis receiving oral risperidone and furosemide concurrently in 2 out of 4 placebo-controlled trials when compared with that in patients receiving risperidone alone or placebo and furosemide concurrently. The pathologic mechanism for this finding remains to be established and no consistent pattern for the cause of death was observed.

Adverse cerebrovascular events (e.g., stroke, transient ischemic attack), some of which resulted in fatalities, have been reported in clinical studies of risperidone in geriatric patients (mean age 85 years; range: 73-97) with dementia-related psychosis.

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, oral risperidone generally should be initiated at lower dosages in such patients. Although geriatric patients exhibit a greater tendency to orthostatic hypotension, the manufacturers state that its risk may be minimized by limiting the initial oral dosage to 0.5 mg twice daily followed by careful titration and close monitoring of orthostatic vital signs in patients for whom this is of concern. However, there is some evidence that even lower initial dosages and slower dosage titration are better tolerated in these patients. Therefore, some clinicians recommend initiating oral risperidone therapy at 0.25 mg daily, and gradually increasing dosages, as tolerated, to a dosage of 2 mg daily in these patients. Higher oral dosages (e.g., 3 or 4 mg daily) may be required in some patients, but are usually associated with greater incidence of extrapyramidal reactions. Most geriatric patients should not be maintained at an oral risperidone dosage exceeding 3 mg daily.(See Geriatric Patients and Others at Risk of Orthostatic Hypotension under Dosage and Administration: Dosage.)

No differences in the tolerability of extended-release IM risperidone were observed in an open-label study in otherwise healthy geriatric patients and younger patients with schizophrenia or schizoaffective disorder. Therefore, the manufacturer states that extended-release IM risperidone dosage recommendations for otherwise healthy geriatric patients are the same as for younger adults.

Mutagenicity and Carcinogenicity

Risperidone did not exhibit mutagenic or clastogenic potential in the Ames gene mutation test, mouse lymphoma assay, in vitro rat hepatocyte DNA-repair assay, in vivo micronucleus test in mice, the sex-linked recessive lethal test in Drosophila, or the chromosomal aberration studies in human lymphocytes or Chinese hamster ovary cells.

Statistically significant increases in pituitary gland adenomas and mammary gland adenocarcinomas were observed in female mice receiving oral risperidone dosages of 0.63, 2.5, and 10 mg/kg (equivalent to approximately 2, 9, and 38 times the maximum recommended human dosage for schizophrenia on a mg/kg basis or 0.2, 0.75, and 3 times the maximum recommended human dosage on a mg/m basis, respectively) for 18 months. In addition, statistically significant increases were observed in mammary gland adenocarcinomas in both male and female rats, and mammary gland neoplasms and endocrine pancreas adenomas in male rats receiving oral risperidone dosages of 0.63, 2.5, and 10 mg/kg (equivalent to approximately 2, 9, and 38 times the maximum recommended human dosage for schizophrenia on a mg/kg basis or 0.4, 1.5, and 6 times the maximum recommended human dosage on a mg/m basis, respectively) for 25 months.

Although an increase in prolactin-mediated mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents following long-term administration of other antipsychotic agents, no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of antipsychotic drugs and tumorigenesis in humans; current evidence is considered too limited to be conclusive at this time. If risperidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin dependent in vitro.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproductive studies in rats and rabbits using risperidone dosages of 0.4-6 times the maximum recommended human dosage on a mg/m basis have not revealed evidence of fetal malformation. However, risperidone has been shown to cross the placenta in rats, and an increased rate of stillborn rat pups occurred at dosages 1.5 times higher than the maximum recommended human dosage on a mg/m basis. In 3 reproductive studies in rats, there was an increase in pup deaths during the first 4 days of lactation at dosages 0.1-3 times the human dosage on a mg/m basis. It is not known whether these deaths resulted from a direct effect on the fetuses or pups or to effects on the dams. In a separate reproductive study in rats, an increased number of pup deaths (at birth or by the day after birth) and a decrease in birth weight were observed in pups of dams treated with risperidone. Risperidone also appeared to impair maternal behavior, as evidenced by reduced weight gain and decreased survival (from day 1-4 of lactation) in pups born to control dams but reared by risperidone-treated dams.

Although there are no adequate and controlled studies to date in humans, one case of agenesis of the corpus callosum has been reported in an infant exposed to risperidone in utero; however, a causal relationship to risperidone therapy is unknown.

Neonates exposed to antipsychotic agents, including risperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. The majority of cases were also confounded by other factors, including concomitant use of other drugs known to be associated with withdrawal symptoms, prematurity, congenital malformations, and obstetrical and perinatal complications; however, some cases suggested that neonatal extrapyramidal symptoms and withdrawal may occur with exposure to antipsychotic agents alone. Some of the cases described time of symptom onset, which ranged from birth to one month after birth. Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.

Risperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The effect of risperidone on labor and delivery in humans is unknown.

Fertility

Oral risperidone (0.16-5 mg/kg) has been shown to impair mating, but not fertility, in Wistar rats in 3 reproductive studies at dosages 0.1-3 times the maximum recommended human dosage on a mg/m basis. The effect appeared to be in females since impaired mating behavior was not noted in the mating and fertility study in which only males were treated. Sperm motility and concentration were decreased in beagles at dosages 0.6-10 times the maximum recommended human dosage on a mg/m basis; dose-related decreases were also observed in serum testosterone concentrations at the same dosages. Serum testosterone and sperm parameters partially recovered but remained decreased after treatment was discontinued. A no-effect dosage was not found in these studies in either rats or dogs.

Lactation

Risperidone and its principal active metabolite, 9-hydroxyrisperidone, are distributed into milk. Because of the potential for serious adverse reactions to risperidone in nursing infants, the manufacturers of oral risperidone state that a decision should be made whether to discontinue nursing or risperidone, taking into consideration the importance of the drug to the woman. The manufacturer of the long-acting risperidone injection states that women receiving IM risperidone should not breast-feed during treatment and for at least 12 weeks after the last injection.