Risperidone, a benzisoxazole-derivative, is an atypical antipsychotic agent.1, 103, 115, 138, 139, 140, 141
Risperidone is used orally, IM, and subcutaneously for the treatment of schizophrenia; long-acting injectable formulations are labeled only for use in adults, while oral formulations are labeled for use in adults and adolescents ≥13 years of age.1, 103, 115, 138, 139, 140, 141
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 Diagnostic and Statistical Manual of Mental Disorders (DSM)-III-R criteria for schizophrenia and who were hospitalized for psychotic symptoms.1 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) and certain atypical (e.g., olanzapine) antipsychotics in the treatment of schizophrenia.1, 3, 5, 25, 28, 29 Data from limited clinical studies indicate that risperidone improves both positive and negative manifestations of schizophrenia,3 but that such improvements may not be substantially greater than those achieved by haloperidol, a conventional antipsychotic.157 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); 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.1, 3, 5, 12
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.1, 23 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.1, 23 Patients receiving risperidone experienced a substantially longer time to relapse than those who received haloperidol.1, 23 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.23
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.1, 118, 119 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.1, 118 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.1, 119 The primary efficacy measure in both studies was the change in total PANSS score from baseline.1, 118, 119 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.1, 118, 119
Efficacy of extended-release IM risperidone (Risperdal® Consta®) in the treatment of schizophrenia in adults was established, in part, based on extrapolation of efficacy data from oral risperidone.103 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.103, 120 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).103, 120 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.103, 120 Patients receiving extended-release IM injections of risperidone were also given oral risperidone (2 mg daily in the 25-mg group, 4 mg daily in the 50-mg group, and 6 mg daily 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.103, 120 The primary efficacy measure in this study was the change in total PANSS score from baseline to end point.103, 120 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.103, 120 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.103, 120 Subgroup analyses did not reveal any differences in treatment outcomes based on age, race, or gender.103
Studies comparing extended-release IM risperidone (Risperdal® Consta®) to oral antipsychotics for the treatment of schizophrenia have not consistently found an efficacy benefit with extended-release IM risperidone.146 One study comparing extended-release IM risperidone to oral quetiapine found a longer time to relapse and lower relapse rates among patients treated with extended-release IM risperidone;145 however, another study comparing extended-release IM risperidone to psychiatrist's choice of oral antipsychotic did not find a benefit with extended-release IM risperidone in terms of psychiatric hospitalizations.146 One study comparing extended-release IM risperidone to extended-release IM paliperidone concluded that efficacy was similar between treatments.144
Efficacy of extended-release IM risperidone (Rykindo®) in the treatment of schizophrenia in adults was established based on the extrapolation of efficacy data for Risperdal®Consta®.139
Efficacy of extended-release risperidone subcutaneous injection (Uzedy®) in the treatment of schizophrenia in adults was established, in part, based on extrapolation of efficacy data from oral risperidone.140 In addition, the efficacy of this product was established in a randomized withdrawal study (RISE) in adults who met the DSM-V criteria for schizophrenia and had a PANSS score <100 at baseline.140, 142 In this study, all patients received 12 weeks of open-label oral risperidone (2-5 mg) during an initial stabilization phase; then, patients who met specific criteria for at least 4 consecutive weeks (outpatient status, PANSS total score ≤80, minimal psychotic symptoms on PANSS, CGI-Severity [CGI-S] ≤4, and CGI-Severity of Suicidality [CGI-SS] ≤2 on part 1 and ≤5 on part 2) were randomized to receive extended-release risperidone subcutaneous injection (Uzedy®) once monthly, extended-release risperidone subcutaneous injection (Uzedy®) once every 2 months, or placebo injections once monthly.140, 142 The dose of extended-release risperidone subcutaneous injection (Uzedy®) (subcutaneous dosage range: 50-250 mg) was individualized based on the dosage of oral risperidone the patient received during the stabilization phase (oral dosage range: 2-5 mg).140, 142 The primary endpoint was time to relapse.140, 142 Relapse was defined as any one of the following: CGI-Improvement (CGI-I) ≥5 plus an increase in at least 1 individual PANSS item (conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content) to a score of >4 with an absolute increase of ≥2; CGI-I ≥5 plus an increase in at least 1 individual PANSS item (conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content) to a score of >4 with an absolute increase of ≥4 in the combined score of these 4 PANSS items; hospitalization due to worsening psychotic symptoms; CGI-SS of 4 or 5 on part 1 and/or 6 or 7 on part 2; or violent behavior resulting in clinically significant self-injury, injury to another person, or property damage.140, 142 Time to relapse was substantially longer among patients receiving extended-release risperidone subcutaneous injection (Uzedy®) once monthly or once every 2 months compared to placebo.140, 142 Subgroup analyses did not reveal any differences in treatment outcomes based on age, race, or gender.140
Efficacy of extended-release risperidone for subcutaneous injection (Perseris®) in the treatment of schizophrenia in adults was established based on an 8-week, randomized, double-blind, placebo-controlled trial.141, 143 The trial enrolled adults experiencing acute exacerbations of schizophrenia (PANSS total score 80-120 at screening without improvement in PANSS total score ≥20% between screening and the first dosing day).141, 143 At the screening visit, patients received 2 doses of oral risperidone 0.25 mg 24 hours apart to establish tolerability; patients were then hospitalized (if not already inpatient) and tapered off of any current oral antipsychotics over 3-8 days.141, 143 Patients were randomized to receive extended-release risperidone for subcutaneous injection (Perseris®) 90 mg on day 1 and day 29; extended-release risperidone for subcutaneous injection (Perseris®) 120 mg on day 1 and day 29; or placebo.141, 143 The primary endpoint was change in PANSS total score from baseline to day 57.141, 143 Both dosages of extended-release risperidone for subcutaneous injection (Perseris®) improved PANSS score to a greater extent than placebo at day 57.141, 143 Subgroup analyses did not reveal any differences in treatment outcomes based on gender, age, or race.141
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic medication.147 The APA states that, with the possible exception of clozapine, 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.147 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).147 Patients whose symptoms improve on an antipsychotic medication should continue treatment with an antipsychotic medication long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another antipsychotic medication for maintenance therapy.147 Use of a long-acting injectable antipsychotic is suggested for patients who prefer such treatment or who have a history of poor or uncertain adherence.147
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.148 Choice of antipsychotic medication should be based on patient-specific factors and the side effect profiles of the different antipsychotic medications.148 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.148 A long-acting injectable antipsychotic may be offered to help improve medication adherence.148
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.1, 115, 138 Extended-release risperidone (Risperdal® Consta® or Rykindo®) is also used IM as monotherapy or adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults.103, 139
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.1, 99, 149 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).1, 99, 149 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.1, 99 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.1, 149 Risperidone was found to be superior to placebo in the reduction of the Y-MRS total score in both studies.1, 99, 149 Patients who completed these trials were eligible to enroll in a 9-week extension study; all patients in the extension study received open-label oral risperidone 1-6 mg daily (mean modal dosage: 4.6 mg daily).150 Patients continued to improve during the 9-week extension study, and patients who switched from placebo to risperidone had marked improvement in symptoms.150
An additional randomized controlled trial compared risperidone (flexible dosages of 1-6 mg daily) to haloperidol (flexible dosages of 2-12 mg daily) and placebo in adults with bipolar disorder and a current manic episode according to DSM-IV criteria.151 In this study, risperidone improved Y-MRS total scores compared to placebo; improvements in Y-MRS total scores were not substantially different for risperidone and haloperidol.151
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.1, 121 The pediatric patients were randomized to receive 1 of 2 dosage ranges of risperidone or placebo.1, 121 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.121 The principal rating instrument used for assessing manic symptoms in this trial was the Y-MRS.1, 121 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).1, 121
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).1, 100 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.1, 100 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.1, 100 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.1, 100 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.1, 100
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.1, 101 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.1, 101 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.1, 101 A possible explanation for the failure of this trial was enzymatic induction of clearance of risperidone and its principal active metabolite, 9-hydroxyrisperidone (paliperidone), by carbamazepine in the subgroup of patients receiving combined therapy with these drugs, resulting in subtherapeutic plasma concentrations of risperidone and 9-hydroxyrisperidone.1, 101
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.103, 122 All patients in this study were treated with open-label extended-release IM risperidone therapy for 26 weeks.103, 122 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.103, 122 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.103, 122 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.103, 122
An additional randomized controlled trial compared extended-release IM risperidone monotherapy to placebo for up to 18 months in adults with bipolar I disorder according to DSM-IV-TR criteria.152 In this trial, all patients underwent a 12-week open label treatment phase with extended-release IM risperidone (25, 37.5, or 50 mg every 2 weeks); following this phase, patients who responded to treatment were randomized to continue extended-release IM risperidone or switch to placebo.152 The primary endpoint was time to recurrence of any mood episode (defined as a hypomanic, manic, mixed, or depressive episode based on DSM-IV-TR criteria; treatment with a mood stabilizer, antipsychotic, benzodiazepine, or antidepressant; hospitalization for bipolar mood episode; or CGI-S ≥4 with either Y-MRS >12 or Montgomery-Asberg Depression Rating Scale [MADRS] score >12).152 During the trial, time to recurrence of any mood episode was prolonged among patients receiving extended-release IM risperidone compared to placebo.152
Efficacy of extended-release IM risperidone (Risperdal® Consta®) 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.103, 123 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.103, 123 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.103, 123
Efficacy of extended-release IM risperidone (Rykindo®) as monotherapy or in conjunction with lithium or valproate in adults with bipolar I disorder was established based on the extrapolation of efficacy data for Risperdal® Consta®.139
Legacy practice guidelines from APA recommend lithium plus an antipsychotic or valproate plus an antipsychotic for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.153 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to side effect profiles.153 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic.153 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign side effect profile.153 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.153 The guideline states that, for patients treated with an antipsychotic medication during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotics should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.153
Guidelines from the Department of Veterans Affairs and Department of Defense suggest lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.154 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, and risperidone are recommended as alternative treatments.154 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.154 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.154 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.154
Risperidone is used orally for the management of irritability associated with autistic disorder in children and adolescents 5-17 years of age, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.1, 115, 138
Risperidone also has been used in a limited number of adults† for the treatment of autistic disorder and other pervasive developmental disorders.109
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 (5-16 years of age) who met the DSM-IV criteria for autistic disorder.1, 31, 105 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).1, 31, 105 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.1, 31, 105 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.1, 31, 105 The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.1, 31
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.1, 31 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.1, 31
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.1, 105 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.1, 105
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).1, 124 Over 77% of the enrolled patients were younger than 12 years of age (mean age: 9 years) and 88% of the patients were male.1, 124 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).1, 124 The primary outcome measure in this study was the change from baseline to end point in the ABC-I subscale.1, 124 Treatment with risperidone substantially improved ABC-I scores in the high-dose risperidone group but not in the low-dose group, compared with placebo.1, 124 In a flexible dosage open-label extension study, patients continued to demonstrate improvement in irritability and related behaviors over 26 weeks.155
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).1, 31, 106 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).1, 106
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.1, 107 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.1, 107 Based on the interim analysis results, the study was terminated since a statistically significant effect on relapse prevention was demonstrated.1, 107 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).1, 107
The American Academy of Pediatrics (AAP) and the American Academy of Child and Adolescent Psychiatry (AACAP) have developed guidelines for children and adolescents with autism spectrum disorder (ASD).169, 170 While there are no medications that correct core social and communication symptoms in patients with ASD, there are medications that may be used to help manage behavioral and psychiatric symptoms.169 For symptoms of irritability and severe disruptive behavior, the AAP suggests the use of aripiprazole or risperidone.169 These atypical antipsychotics may also improve repetitive behaviors, decrease hyperactivity, and may help with mood dysregulation disorders.169 The AACAP states that pharmacotherapy may be offered to pediatric patients with ASD when there is a specific target symptom or comorbid condition.170 The AACAP also lists risperidone and aripiprazole as options for the treatment of irritability associated with autism.170
Risperidone has been used for the adjunctive treatment of major depressive disorder †, though the magnitude of benefit may be small.156, 165
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.164, 165, 166, 167, 168 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.164, 165, 166, 167, 168 In general, antidepressants have shown similar effectiveness; therefore, initial treatment is guided by specific patient- and drug-related factors.164, 165, 166, 167, 168 For patients who do not respond or have an inadequate response to initial treatment with an antidepressant, approaches to therapy may include changing to a different antidepressant or psychotherapy, or augmentation with psychotherapy or another pharmacological agent.164, 165, 166, 167, 168
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.165 Treatment of major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.165 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), trazodone, vilazodone, or vortioxetine is suggested.165 No evidence is available to suggest superiority of one agent over another.165 The guidelines recommend against using esketamine, ketamine, monoamine oxidase inhibitors (MAOIs), nefazodone, or tricyclic antidepressants (TCAs) as initial therapy.165 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic (e.g., aripiprazole, brexpiprazole, extended-release quetiapine).165
A guideline from the American College of Physicians (ACP) provides recommendations for initial and second-line treatment of the acute phase of major depressive disorder.168 For initial pharmacotherapy, ACP recommends the use of a second-generation antidepressant (e.g., SSRI, SNRI).168 For patients in the acute phase of moderate to severe major depressive disorder who do not respond to initial treatment with an adequate dose of a second-generation antidepressant, ACP suggests switching to or augmenting with cognitive behavioral therapy, switching to a different second-generation antidepressant, or augmenting with a second pharmacologic agent.168 Suggested second-line augmentation agents include mirtazapine, bupropion, or buspirone.168
Risperidone has been used as adjunctive treatment for obsessive-compulsive disorder (OCD)†.158, 177 Legacy practice guidelines from the APA list cognitive behavioral therapy and pharmacotherapy as safe and effective first-line treatments for OCD.176 For pharmacotherapy, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) are first line.176 If a patient does not respond to one SSRI, they may switch to a different SSRI, switch to clomipramine, augment their current SSRI with a second-generation antipsychotic, switch to venlafaxine, or switch to mirtazapine.176 Updated guidelines from international experts state that escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline are first-line treatments for OCD.177 For treatment-resistant patients, augmentation with antipsychotics (e.g., aripiprazole, risperidone) or other drugs (e.g., memantine, ondansetron, lamotrigine) may be considered.177
Risperidone has been used for the treatment of Tourette's syndrome† .159, 160, 172, 178
The American Academy of Neurology guideline on the treatment of tics in people with Tourette's syndrome states that physicians may prescribe antipsychotics (such as risperidone) for the treatment of tics when the benefits of treatment outweigh the risks.178 According to the AACAP practice parameter for children and adolescents with tic disorders, including Tourette's disorder, medications should be considered for patients with chronic tic disorders if they have moderate to severe tics causing severe impairment in quality of life or medication-responsive psychiatric comorbidities.172 Atypical antipsychotics such as aripiprazole and risperidone are listed as options to treat tic disorders.172 Haloperidol, pimozide, clonidine, and guanfacine are also listed as having been used for the treatment of tic disorders.172
Risperidone has been used for the treatment of delusional infestation† .171
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.1, 35, 36, 37, 103 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).35, 36, 37 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.1 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.1, 103 Risperidone is not approved for the treatment of dementia-related psychosis.1, 103
The APA recommends that antipsychotic medication should only be used for the treatment of agitation or psychosis in patients with dementia when symptoms are severe, are dangerous, and/or cause significant distress to the patient.173 Prior to nonemergency treatment with an antipsychotic, review of clinical response to nonpharmacological interventions is recommended; a discussion of the risks and benefits of antipsychotic treatment with the patient, the patient's surrogate decision maker, or family or other caregivers is also recommended.173 In another treatment algorithm, for the diagnosis of urgent behavioral and psychological symptoms associated with dementia (BPSD), first-line pharmacotherapy options include oral aripiprazole and risperidone.174 For emergent BPSD, IM injections of olanzapine and then haloperidol are recommended.174 For non-emergent BPSD, the first initial treatment is decreasing anticholinergic load and optimizing pain control, followed by sleep optimization with consideration of the use of trazodone.174 If there is an inadequate response, donepezil and memantine can be initiated.174 The addition of escitalopram or sertraline can then be considered if there is still an inadequate response.174 Use of second-generation antipsychotics such as aripiprazole or risperidone should be reserved for patients with inadequate response to the maximum doses of escitalopram or sertraline.174 The American Geriatrics Society (AGS) 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults state that antipsychotics should be avoided in patients with cognitive impairment or dementia due to increased risk of stroke and greater rate of cognitive decline and mortality.175 Antipsychotics should be avoided unless documented nonpharmacologic options have failed and/or the patient is threatening substantial harm to self or others; if used, use the lowest effective dosage and consider periodic deprescribing attempts.175
Dispensing and Administration Precautions
Risperidone is administered orally or by subcutaneous or IM injection.1, 103, 115, 138, 139, 140, 141 Risperidone is available as oral tablets, oral solution, and orally disintegrating tablets;1, 115, 138 extended-release IM injection (Risperdal® Consta®; Rykindo®);103, 139 and extended-release subcutaneous injection (Uzedy®; Perseris®).140, 141
Risperidone is administered orally, either in a once-daily dose or in 2 equally divided doses daily.1, 115, 138 Since food reportedly does not affect the rate or extent of GI absorption, the drug can be administered without regard to meals.1, 115, 138
Risperidone oral solution may be administered directly from the calibrated oral dosing syringe provided by the manufacturer or mixed in a beverage prior to administration.1 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.1 Refer to the full prescribing information for additional information regarding administration of the oral solution.1
Patients receiving risperidone orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing.1, 115 The tablet should not be pushed through the foil, since this may damage the tablet.1, 115 With dry hands, the blister backing should be peeled back to expose the tablet.1, 115 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.1, 115 Risperidone orally disintegrating tablets should not be divided or chewed.1, 115 Refer to the full prescribing information for additional information regarding administration of the orally disintegrating tablets.1, 115
Store risperidone tablets and orally disintegrating tablets at room temperature (15—25°C); protect from light and moisture.1, 115, 138 Store risperidone oral solution at controlled room temperature (15—25°C); protect from light and freezing.1
The manufacturers' prescribing information should be consulted for specific details on administration of oral risperidone.1, 138
In patients who have never received oral risperidone, tolerability with oral risperidone therapy should be established prior to initiating IM therapy with extended-release risperidone (Risperdal® Consta®, Rykindo®).103, 139
Reconstitution is necessary prior to administration.103, 139
Administer the entire vial and syringe contents in one dose.103, 139 The manufacturers state that different dosage strengths of IM risperidone should not be combined in a single administration.103, 139
The manufacturer's prescribing information should be consulted for specific details on reconstitution and administration of risperidone IM injection.103, 139
Risperdal® Consta®: Risperidone extended-release injection is commercially available in a single-use 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).103
Risperidone extended-release microspheres for injection are supplied in a powder form that must be reconstituted prior to administration using only the components of the dose pack supplied by the manufacturer.103 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.103
Following reconstitution, immediate use is necessary because the suspension will settle over time.103 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.103
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.103 Each injection should be administered by a health care professional.103 IM injections at the same dosages into the deltoid and gluteal areas are bioequivalent and are, therefore, interchangeable.103 The injection should not be administered IV.103 In addition, care should be taken to avoid inadvertent injection into a blood vessel.103
Store the entire risperidone dose pack in the refrigerator (2—8°C) and protected from light.103 If refrigeration is not possible, the drug may be stored at temperatures not exceeding 25°C for no more than 7 days prior to administration.103 Do not expose unrefrigerated product to temperatures above 25°C.103 Do not store the suspension following reconstitution.103
Risperidone extended-release microspheres should be reconstituted using only the diluent in the prefilled syringe supplied by the manufacturer.103 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.103
Rykindo® : Risperidone extended-release injection is commercially available as a single-dose kit consisting of a vial containing a white to almost white powder of extended-release risperidone in microspheres, a prefilled syringe containing 2 mL of diluent, a vial adapter, and a needle for IM injection.139
Risperidone extended-release microspheres for injection must be reconstituted prior to administration using only the components of the dose pack supplied by the manufacturer.139 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.139
Following reconstitution, immediate use is necessary because the suspension will settle over time.139 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.139
Risperidone extended-release injection should be administered every 2 weeks by IM gluteal injection.139 Each injection should be administered by a health care professional.139 Do not administer by any other route.139 Alternate injections between the 2 buttocks.139
Store the entire risperidone kit in the refrigerator (2—8°C) and protected from light.139 If refrigeration is not possible, the drug may be stored in the unopened original packaging at temperatures not exceeding 25°C for no more than 7 days prior to administration.139 After removal from the refrigerator, use the product within 7 days or discard.139 Do not store the suspension following reconstitution.139
Risperidone extended-release microspheres should be reconstituted using only the diluent in the prefilled syringe supplied by the manufacturer.139 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 30 seconds to ensure a homogeneous suspension; the reconstituted suspension should appear uniform, thick, and milky.139
In patients who have never received oral risperidone, tolerability with oral risperidone therapy should be established prior to initiating subcutaneous therapy with extended-release risperidone (Uzedy®, Perseris®).140, 141
The manufacturer's prescribing information and instructions for use should be consulted for specific details on preparation and administration of risperidone subcutaneous injection.140, 141
Uzedy®: Risperidone extended-release injectable suspension for subcutaneous use (Uzedy®) is commercially available in a single-dose kit containing one prefilled syringe and one needle.140 Do not substitute any components of the kit for administration.140 Uzedy® is for subcutaneous injection by a healthcare professional only; do not inject by any other route.140
Store Uzedy®in the refrigerator at 2—8°C in the original carton to protect from light.140 The drug may be stored in unopened original packaging at room temperature (20—25°C) for up to 90 days.140 If unopened, the drug may be returned to refrigerated storage within 90 days.140 Once the carton is opened, administer the drug or discard.140
Prior to administration, remove the kit from the refrigerator and allow to sit at room temperature (20—25°C) for at least 30 minutes.140 The drug is supplied as a white to off-white opaque viscous, extended-release injectable suspension that is a solid at refrigerated temperatures; it must reach room temperature prior to administration.140 Do not warm any other way and keep protected from light.140
Always wear gloves when preparing the drug.140 To prepare Uzedy®, firmly hold the syringe by the white collar and forcefully flick downwards to move the air bubble to the syringe cap; repeat the whipping motion 3 times until the bubble moves to the syringe cap; the bubble will appear partially opaque with best visibility up to a light or against a dark backdrop.140 Hold the syringe vertically, snap off the cap without touching the syringe tip, and securely attach the safety needle.140 Then, select the injection site (stomach area around the belly button or back and outer area of upper arms); do not inject into other areas or an area that is tender, red, bruised, callused, tattooed, hard, or has scars or stretch marks.140 Do not expel any visible air bubble prior to administration.140 To administer, insert the needle into subcutaneous tissue at an angle appropriate for the chosen location and push the plunger with slow, firm, and steady pressure until the entire dose is administered; inject the entire dose at one time without interruption.140 Wait 2—3 seconds before slowly removing needle from the tissue, and then activate (lock) the safety needle shield as instructed.140
If a dose of Uzedy® is missed, administer the next injection as soon as possible; do not administer more frequently than recommended.140
Perseris® : Risperidone extended-release injectable suspension for subcutaneous use (Perseris®) is commercially available in a single-dose kit containing one prefilled syringe with risperidone powder (i.e., powder syringe), one syringe prefilled with the delivery system (i.e., liquid syringe), the desiccant, and one safety needle.141 Perseris® is for subcutaneous injection by a healthcare professional; do not inject by any other route.141
Store Perseris®in the refrigerator at 2—8°C.141 The drug may be stored in unopened original packaging at room temperature (20—25°C) for up to 30 days prior to administration.141 Once removed from the refrigerator, use the drug within 30 days or discard.141
Prior to administration, remove the kit from the refrigerator and allow to come to room temperature (20—25°C) for at least 15 minutes.141
To prepare Perseris®, tap the barrel of the powder syringe to dislodge the packed powder.141 Place the liquid syringe on top of the powder syringe and connect the syringes by twisting approximately ¾ turn; do not over tighten.141 Then, transfer the contents of the liquid syringe into the powder syringe.141 Gently push the powder syringe plunger until resistance is felt, and repeat this gentle back-and-forth process for 5 cycles.141 Continue mixing the syringes for an additional 55 cycles; this mixing can be more vigorous than when premixing.141 The final product should be a cloudy, viscous suspension that is uniform in color (white to yellow-green).141 For any clear areas in the mixture, continue to mix until the distribution of the color is uniform.141 Next, transfer all contents into the liquid syringe for administration as instructed by the manufacturer.141
Select the injection site (abdomen or back of upper arm) with adequate subcutaneous tissue that is free of skin conditions (e.g., nodules, lesions, excessive pigment).141 Do not inject into other areas or an area that is irritated, red, bruised, callused, infected, or scarred.141 Lift the adipose tissue from the underlying muscle to prevent accidental IM injection.141 Rotate injection sites.141 Do not rub the injection area after the injection.141
If a dose of Perseris® is missed, administer the next injection as soon as possible.141
For patients who have never taken oral risperidone, tolerability should be established with oral risperidone prior to initiating treatment with IM or subcutaneous risperidone.103, 139, 140, 141
Oral
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).1, 115, 138 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).1, 115, 138 The manufacturers state that slower dosage titration may be appropriate in certain patients.1, 115, 138
While antipsychotic efficacy has been established in clinical trials at oral risperidone dosages ranging from 4-16 mg daily, the manufacturers 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.1, 115, 138 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.1, 115, 138
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.1, 115, 138
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 at delaying relapse in adults for up to 2 years.1, 115, 138 The manufacturers state that patients responding to risperidone therapy should generally continue to receive therapy at their effective dosage beyond the acute response.1, 115, 138 Patients should be reassessed periodically to determine the need for continued therapy with the drug.1, 115, 138 If risperidone therapy is reinitiated after a drug-free period, the manufacturers recommend that the appropriate recommended schedule of careful dosage titration be employed.1, 115, 138
IM
Risperdal® Consta® : 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.103 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.103 The need for continuing any concomitant therapy for managing extrapyramidal manifestations should be periodically reevaluated.103
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.103 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.103 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.103
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.103
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.103 It is recommended that responding patients be continued on treatment with IM risperidone at the lowest dosage needed.103 Patients should periodically be reassessed to determine the need for continued treatment.103
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.103
Rykindo® : For the management of schizophrenia in adults, the recommended dosage of extended-release risperidone injection is 25 mg administered by IM injection into the gluteal area every 2 weeks.139 Administer the first dose of Rykindo® along with 7 days of oral risperidone.139 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.139 However, the dosage should not be increased more frequently than every 4 weeks.139 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.139 The Rykindo® dosage for patients currently receiving a risperidone long-acting, every-2-week IM formulation (e.g., Risperdal® Consta®) should be the same as that of the previous treatment.139 The first injection of Rykindo® should be administered 4 weeks (no later than 5 weeks) after the last injection of the previous treatment.139 Supplementation with oral risperidone is not recommended.139 The dosage should not be increased more frequently than every 4 weeks.139 There is no information to specifically address reinitiation of IM risperidone treatment.139 When restarting patients who have had an interval off treatment with Rykindo®, the previously established dosage should be reinitiated if there has been no change in the general medical condition of the patient.139 Supplementation with oral risperidone is also necessary.139
Subcutaneous
Uzedy® : For the management of schizophrenia in adults, initiate Uzedy® extended-release risperidone subcutaneous injection as either a once monthly injection or a once every-2-month subcutaneous injection the day after the last dose of oral therapy.140 See Table 1 to determine how to switch from oral risperidone to Uzedy® once monthly (50 mg, 75 mg, 100 mg, or 125 mg) or once every 2 months (100 mg, 150 mg, 200 mg, or 250 mg).140 Neither a loading dose nor supplemental oral risperidone doses are recommended when switching.140 Patients can switch between doses of Uzedy® once monthly and once every 2 months by administering the first dose of the new dosing regimen on the next scheduled date of administration in the original dosing regimen.140 Revise the dosage administration schedule to reflect the change.140
Prior Therapy | Uzedy® Dosage Once Monthly | Uzedy® Dosage Once Every 2 Months |
|---|---|---|
2 mg of oral risperidone daily | 50 mg | 100 mg |
3 mg of oral risperidone daily | 75 mg | 150 mg |
4 mg of oral risperidone daily | 100 mg | 200 mg |
5 mg of oral risperidone daily | 125 mg | 250 mg |
Perseris® : For the management of schizophrenia in adults, initiate Perseris® extended-release risperidone subcutaneous injection at a dosage of 90 mg or 120 mg once monthly by subcutaneous injection.141 Do not administer more than one dose (90 mg or 120 mg total) per month.141 For patients switching from 3 mg of oral risperidone per day, administer a 90 mg dose of Perseris® one day after the last oral risperidone dose.141 For patients switching from 4 mg of oral risperidone per day, administer a 120 mg dose of Perseris® one day after the last oral risperidone dose.141 Patients who are on stable oral risperidone doses lower than 3 mg per day or higher than 4 mg per day may not be candidates for Perseris®.141 Neither a loading dose nor any supplemental oral risperidone is recommended.141
Oral
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.1, 115, 138 Dosage may be increased or decreased by 1 mg daily at intervals of not less than 24 hours.1, 115, 138 In placebo-controlled trials, the short-term (i.e., 3-week) antimanic efficacy of risperidone was demonstrated in a flexible dosage ranging from 1—6 mg daily.1, 115, 138 Safety of dosages exceeding 6 mg daily has not been established.1, 115, 138
The optimum duration of risperidone therapy for bipolar disorder currently is not known.1, 115, 138 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.1, 115, 138 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.1, 115, 138
IM
Risperdal® Consta® : 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.103 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.103 The need for continuing any concomitant therapy for managing extrapyramidal manifestations should be periodically reevaluated.103
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.103 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.103 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.103
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.103
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.103
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.103
Rykindo® : For monotherapy or adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder in adults, the recommended dosage of extended-release risperidone injection is 25 mg administered by IM injection into the gluteal area every 2 weeks.139 Administer the first dose of Rykindo® along with 7 days of oral risperidone.139 Some patients may benefit from increasing the IM dosage to 37.5 or 50 mg every 2 weeks.139 However, the dosage should not be increased more frequently than every 4 weeks.139 Dosages above 50 mg every 2 weeks have not been studied in this population.139 The Rykindo® dosage for patients currently receiving a risperidone long-acting, every-2-week IM formulation (e.g., Risperdal® Consta®) should be the same as that of the previous treatment.139 The first injection of Rykindo® should be administered 4 weeks (no later than 5 weeks) after the last injection of the previous treatment.139 Supplementation with oral risperidone is not recommended.139 The dosage should not be increased more frequently than every 4 weeks.139 There is no information to specifically address reinitiation of IM risperidone treatment.139 When restarting patients who have had an interval off treatment with Rykindo®, the previously established dosage should be reinitiated if there has been no change in the general medical condition of the patient.139 Supplementation with oral risperidone is also necessary.139
Oral
For the treatment of schizophrenia in adolescents 13 to 17 years of age, the manufacturers recommend an initial oral risperidone dosage of 0.5 mg once daily in the morning or evening.1, 115, 138 Dosage adjustments may be made in increments of 0.5-1 mg daily at intervals of 24 hours or greater, as tolerated, up to the recommended dosage of 3 mg daily.1, 115, 138 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.1, 115, 138 Dosages exceeding 6 mg daily in adolescents have not been evaluated in clinical studies.1, 115, 138 Pediatric patients who experience persistent somnolence may benefit from twice-daily administration of the drug in 2 equally divided doses.1, 115, 138
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.1, 115, 138
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.1, 115, 138 The manufacturers state that patients responding to risperidone therapy should generally continue to receive therapy at their effective dosage beyond the acute response.1, 115, 138 Patients should be reassessed periodically to determine the need for continued therapy with the drug.1, 115, 138 If risperidone therapy is reinitiated after a drug-free period, the manufacturers recommend that the appropriate recommended schedule of careful dosage titration be employed.1, 115, 138
Oral
For the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10 to 17 years of age, the recommended initial oral dosage of risperidone is 0.5 mg given once daily in the morning or evening.1, 115, 138 Dosage adjustments may be made in increments of 0.5-1 mg daily at intervals of not less than 24 hours, as tolerated, up to a target dosage of 1-2.5 mg daily.1, 115, 138 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.1, 115, 138 Safety and efficacy of oral dosages exceeding 6 mg daily in children and adolescents have not been evaluated in clinical studies.1, 115, 138 Pediatric patients who experience persistent somnolence may benefit from twice-daily administration of the drug in 2 equally divided doses.1, 115, 138
The optimum duration of risperidone therapy for bipolar disorder currently is not known.1, 115, 138 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.1, 115, 138 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.1, 115, 138
Oral
For the management of irritability associated with autistic disorder in children and adolescents 5 to 17 years of age, 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.1, 115, 138 The drug may be administered either once or twice daily.1, 115, 138 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.1, 115, 138
Dosage should be individualized according to clinical response and tolerability of the patient.1, 115, 138 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.1, 115, 138 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.1, 115, 138 The effective dosage range is 0.5-3 mg daily.1, 115, 138 Dosage data for children weighing less than 15 kg currently are lacking.1, 115, 138 In addition, safety and efficacy in pediatric patients younger than 5 years of age have not been established.1, 115, 138
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.1, 115, 138 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.1, 115, 138
Oral risperidone: A reduced 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.1, 115, 138 Oral risperidone therapy should be initiated at a reduced dosage of 0.5 mg twice daily 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.1, 115, 138
Risperdal® Consta®: If IM risperidone (Risperdal® Consta®) is used for management of schizophrenia or bipolar disorder in adults with hepatic impairment, the patient should be treated with titrated doses of oral risperidone prior to initiating treatment with the extended-release injection.103 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.103 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.103 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.103 Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun.103 In some patients, slower titration may be medically appropriate.103
Rykindo®: If IM risperidone (Rykindo®) is used for management of schizophrenia or bipolar disorder in adults with hepatic impairment, the patient should be treated with titrated doses of oral risperidone prior to initiating treatment with the extended-release injection.139 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.139 If a total daily dosage of at least 2 mg oral risperidone is well tolerated, an IM dosage of 25 mg of the extended-release injection can be administered every 2 weeks with oral supplementation for 7 days following the first injection.139 In some patients, slower titration may be medically appropriate.139 Alternatively, a starting dosage of Rykindo® 12.5 mg may be appropriate; however, the efficacy of the 12.5 mg dosage has not been evaluated in clinical trials.139
Uzedy®: Prior to initiating treatment with Uzedy® extended-release risperidone subcutaneous injection in patients with hepatic impairment, titrate with oral risperidone up to a dosage of at least 2 mg daily.140 Following oral titration, and based on clinical response and tolerability, the recommended dosage of Uzedy® is 50 mg once monthly in patients with hepatic impairment.140
Perseris®: Prior to initiating treatment with Perseris® extended-release risperidone subcutaneous injection in patients with hepatic impairment, titrate with oral risperidone up to a dosage of at least 3 mg daily.141 Following oral titration, and based on clinical response and tolerability, the recommended dosage of Perseris® is 90 mg once monthly in patients with hepatic impairment.141
Oral risperidone: 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.1, 115, 138
Risperdal® Consta®: If IM risperidone (Risperdal® Consta®) is used for management of schizophrenia or bipolar disorder in adults with renal impairment, the patient should be treated with titrated doses of oral risperidone prior to initiating treatment with the extended-release injection.103 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.103 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.103 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.103 Oral supplementation should be continued for 3 weeks after the first injection until the main release of risperidone from the injection site has begun.103 In some patients, slower titration may be medically appropriate.103
Rykindo®: If IM risperidone (Rykindo®) is used for management of schizophrenia or bipolar disorder in adults with renal impairment, the patient should be treated with titrated doses of oral risperidone prior to initiating treatment with the extended-release injection.139 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.139 If a total daily dosage of at least 2 mg oral risperidone is well tolerated, an IM dosage of 25 mg of the extended-release injection can be administered every 2 weeks with oral supplementation for 7 days following the first injection.139 In some patients, slower titration may be appropriate.139 Alternatively, a starting dosage of Rykindo® 12.5 mg may be appropriate; however, the efficacy of the 12.5 mg dosage has not been studied in clinical trials.139
Uzedy®: Prior to initiating treatment with Uzedy® extended-release risperidone subcutaneous injection in patients with renal impairment, titrate with oral risperidone up to at least 2 mg daily.140 Following oral titration, and based on clinical response and tolerability, the recommended dosage of Uzedy® is 50 mg once monthly in patients with renal impairment.140
Perseris®: Prior to initiating treatment with Perseris® extended-release risperidone subcutaneous injection in patients with renal impairment, titrate with oral risperidone up to at least 3 mg daily.141 Following oral titration, and based on clinical response and tolerability, the recommended dosage of Perseris® is 90 mg once monthly in patients with renal impairment.141
Oral risperidone: Like other α-adrenergic blocking agents, risperidone can induce orthostatic hypotension; the manufacturers state that the risk of this effect can be minimized by limiting the initial oral dosage of risperidone to 0.5 mg twice daily in geriatric patients followed by careful titration.1, 115, 138
Risperdal® Consta®: For otherwise healthy geriatric patients, the recommended IM risperidone dosage of the extended-release injection is 25 mg every 2 weeks.103 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.103
Rykindo®: The manufacturer makes no specific dosage recommendations for this extended-release IM injection for geriatric patients.139
Uzedy®, Perseris®: Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, dosage selection for extended-release subcutaneous injections of risperidone should be cautious, usually initiated at lower dosages in such patients.140, 141
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
A boxed warning concerning the increased risk of death in geriatric patients with dementia-related psychosis treated with antipsychotic drugs is included in the prescribing information for risperidone.1, 103, 115, 138, 139, 140, 141 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 compared with that observed in patients receiving placebo.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141 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.1, 115, 138, 140 The pathologic mechanism for this finding remains to be established and no consistent pattern for the cause of death was observed.1, 115, 138, 140 Risperidone is not approved for the treatment of dementia-related psychosis.1, 103, 115, 138, 139, 140, 141
Other Warnings and Precautions
Cerebrovascular Adverse Reactions, Including Stroke, in Geriatric Patients with Dementia-related Psychosis
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.1, 103, 115, 138, 139, 140, 141
In placebo-controlled trials in geriatric patients with dementia, patients randomized to risperidone had a higher incidence of cerebrovascular events compared to those who received placebo.1, 103, 115, 138, 139, 140, 141
Risperidone is not approved for the treatment of patients with dementia-related psychosis.1, 103, 115, 138, 139, 140, 141
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving antipsychotic agents.1, 103, 115, 138, 139, 140, 141
Clinical manifestations of NMS may include hyperpyrexia, muscle rigidity, altered mental status (including delirium), autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia), elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.1, 103, 115, 138, 139, 140, 141
If NMS is suspected, immediately discontinue risperidone, and provide symptomatic treatment and monitoring.1, 103, 115, 138, 139, 140, 141
Use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1, 103, 115, 138, 139, 140, 141 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 after relatively short periods of treatment with low dosages, or even after discontinuation of treatment.1, 103, 115, 138, 139, 140, 141
Tardive dyskinesia may remit, partially or completely, if antipsychotic therapy is discontinued.1, 103, 115, 138, 139, 140, 141 However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.1, 103, 115, 138, 139, 140, 141 The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.1, 103, 115, 138, 139, 140, 141
Risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141 In patients who do require chronic treatment, the lowest 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.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141
Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).1, 103, 115, 138, 139, 140, 141 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141 Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141 Any patient treated with atypical antipsychotics should be monitored for manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment, and patients who develop these manifestations should undergo fasting blood glucose testing.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141
Undesirable changes in lipid parameters have been observed in patients treated with atypical antipsychotics.1, 103, 115, 138, 139, 140, 141 Before or soon after initiation of antipsychotic therapy, obtain a fasting lipid profile at baseline and monitor periodically during treatment.139, 140, 141
Weight gain has been observed with atypical antipsychotic therapy.1, 103, 115, 138, 139, 140, 141 The manufacturers recommend clinical monitoring of weight in patients receiving risperidone.1, 103, 115, 138, 139, 140, 141 Monitor weight at baseline and frequently thereafter.139
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.1, 103, 115, 138, 139, 140, 141 Risperidone appears to be associated with a higher level of prolactin elevation than other antipsychotic agents.1, 103, 115, 138, 139, 140, 141 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1, 103, 115, 138, 139, 140, 141 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140
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), and in geriatric patients and patients with renal or hepatic impairment.1, 103, 115, 138, 139, 140, 141 Clinically important hypotension has been observed with concomitant use of oral risperidone and antihypertensive drug therapy.1, 103, 115, 138, 139, 140, 141
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.1, 115, 138
Patients 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).103, 139
Monitoring of orthostatic vital signs should be considered in patients for whom orthostatic hypotension is of concern.1, 103, 115, 138, 139, 140, 141 Monitoring of orthostatic vital signs and dosage reduction of risperidone should be considered if hypotension occurs.1, 103, 115, 138, 139, 140, 141
Antipsychotic agents including risperidone may cause somnolence, postural hypotension, and motor and sensory instability, which could lead to falls and, consequently, fractures or other injuries.1, 103, 115, 138, 139, 140, 141
Complete fall risk assessments when initiating risperidone and during long-term antipsychotic therapy in patients (especially geriatric patients) with concomitant diseases, conditions, or medications that could exacerbate the risk of falls.1, 103, 115, 138, 139, 140, 141
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents, including risperidone, have been reported.1, 103, 115, 138, 139, 140, 141 Agranulocytosis also has been reported.1, 103, 115, 138, 139, 140, 141
Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1, 103, 115, 138, 139, 140, 141 Therefore, patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their CBC monitored frequently during the first few months of risperidone therapy.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141
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.1, 103, 115, 138, 139, 140, 141 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), risperidone should be discontinued and the leukocyte count monitored until recovery occurs.1, 103, 115, 138, 139, 140, 141
Cognitive and Motor Impairment
Somnolence (dose-related) has been reported in risperidone-treated patients.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141
Seizures have been reported in adult patients receiving risperidone during premarketing testing.1, 103, 115, 138, 139, 140, 141
Risperidone should be administered with caution to patients with a history of seizures or with conditions that may lower the seizure threshold.1, 103, 115, 138, 139, 140, 141 Conditions that lower the seizure threshold may be more prevalent in geriatric patients.139
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1, 103, 115, 138, 139, 140, 141 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.1, 103, 115, 138, 139, 140, 141
Rare cases of priapism have been reported in risperidone-treated patients during postmarketing surveillance.1, 103, 115, 138, 139, 140, 141 Severe priapism may require surgical intervention.1, 103, 115, 138, 139, 140, 141
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 risperidone therapy, the drug should be administered with caution in patients who will be exposed to temperature extremes.1, 103, 115, 138, 139, 140, 141 Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic drugs may contribute to an elevation in core body temperature; use risperidone with caution in patients who may experience these conditions.139, 140, 141
Individuals with phenylketonuria and other individuals who must restrict their intake of phenylalanine should be warned that risperidone orally disintegrating tablets contain phenylalanine, which is a component of aspartame; the respective manufacturer's labeling should be consulted for specific information regarding phenylalanine content of individual preparations and dosage strengths.1, 115
Risperdal® Consta® should be administered by deep IM injection into either the deltoid muscle or the upper outer quadrant of the gluteal area.103 In addition, care should be taken to avoid inadvertent injection into a blood vessel.103
Osteodystrophy and Tumors in Animals
Osteodystrophy, renal tubular tumors, and adrenomedullary pheochromocytomas have been observed in rats following IM administration of extended-release risperidone injections; these findings were not observed with oral risperidone.103, 139 The clinical relevance of these findings to humans is not known.103, 139
A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including risperidone, during pregnancy.1 Clinicians are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at [Web].1, 103, 115, 138, 139, 140, 141
Currently available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse outcomes in the mother or fetus.1, 103, 115, 138, 139, 140, 141 However, there are risks to the mother (e.g., risk of relapse, hospitalization, suicide) associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including risperidone, during pregnancy.1, 103, 115, 138, 139, 140, 141 Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.1, 103, 115, 138, 139, 140, 141
In animals, administration of oral risperidone to pregnant mice caused cleft palate at doses 3—4 times the maximum recommended human dose (MRHD), with maternal toxicity observed at 4 times the MRHD based on body surface area.1, 103, 115, 138, 139, 140, 141 Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the MRHD based on body surface area.1, 103, 115, 138, 139, 140, 141 Oral risperidone administration to pregnant rats at 1.5 times the MRHD (based on body surface area) resulted in increased stillbirths and decreased birth weight.1, 103, 115, 138, 139, 140, 141 Impaired learning was observed in offspring of rats when the dams were dosed at 0.6 times the MRHD and offspring mortality increased at doses 0.1—3 times the MRHD based on body surface area.1, 103, 115, 138, 139, 140, 141 Subcutaneous administration of the risperidone delivery system to pregnant rats and rabbits during organogenesis caused developmental toxicity (e.g., post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on body surface area.141
Neonates exposed to antipsychotic agents, including risperidone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1, 103, 115, 138, 139, 140, 141 There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.1, 103, 115, 138, 139, 140, 141 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.1, 103, 115, 138, 139, 140, 141 Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.1, 103, 115, 138, 139, 140, 141
Risperidone and its principal active metabolite, 9-hydroxyrisperidone (paliperidone), are distributed into milk.1, 103, 115, 138, 139, 140, 141 Sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) have been reported in breast-fed infants exposed to risperidone.1, 103, 115, 138, 139, 140, 141 There are no data on the effects of risperidone on milk production.1, 103, 115, 138, 139, 140, 141
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for risperidone and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.1, 103, 115, 138, 139, 140, 141
Monitor infants exposed to risperidone through breastmilk for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).1, 103, 115, 138, 139, 140, 141
Females and Males of Reproductive Potential
Based on the D2 antagonistic activity of risperidone, treatment with the drug may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.1, 103, 115, 138, 139, 140, 141
Safety and efficacy of risperidone for IM or subcutaneous administration have not been established in pediatric patients.103, 139, 140, 141
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.1, 115, 138 Efficacy and safety of oral 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.1, 115, 138 The safety and efficacy of oral 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.1, 115, 138
Efficacy and safety of oral risperidone in the treatment of irritability associated with autistic disorder have been evaluated in 3 placebo-controlled trials in pediatric patients 5 to 17 years of age.1, 115, 138
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.1, 115, 138
Weight gain has been observed in children and adolescents during treatment with oral risperidone; clinical monitoring of weight is recommended during treatment.1, 115, 138
Somnolence frequently occurred in placebo-controlled trials of oral risperidone in pediatric patients with autistic disorder.1, 115, 138 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).1, 115, 138 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.1, 115, 138 Pediatric patients experiencing persistent somnolence may benefit from a change in dosage regimen.1, 115, 138
Oral risperidone has been shown to elevate prolactin concentrations in children and adolescents as well as adults.1, 115, 138 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.1, 115, 138 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.1, 115, 138 Increases in prolactin concentrations were dose dependent and generally greater in female than male patients across indications.1, 115, 138 In clinical trials conducted in 1885 children and adolescents, galactorrhea and gynecomastia reportedly occurred in 0.8 and 2.3%, respectively, of oral risperidone-treated patients.1, 115, 138
The manufacturers state that the long-term effects of oral risperidone on growth and sexual maturation have not been fully evaluated in children and adolescents.1, 115, 138
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.1, 115, 138 Other clinical experience with oral risperidone has not identified differences in responses between geriatric and younger patients.1, 115, 138 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.1, 115, 138 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.1, 115, 138
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.103, 139 Therefore, the manufacturer states that extended-release IM risperidone dosage recommendations for otherwise healthy geriatric patients are the same as for younger adults.103, 139
Clinical studies of subcutaneous 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.140, 141 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients, dosage selection for subcutaneous risperidone should be cautious, usually initiated at lower dosages in such patients.140, 141
The free fraction of risperidone in plasma is increased by about 35% in patients with hepatic impairment.1, 115, 138 Therefore, dosages of oral risperidone should be reduced in patients with hepatic impairment.1, 115, 138
In patients with hepatic impairment, carefully titrate with oral risperidone prior to initiating treatment with extended-release IM risperidone (Risperdal® Consta®).103 Patients with impaired hepatic function may have an increase in the free fraction of risperidone, possibly resulting in an enhanced effect.103
In patients with hepatic impairment, carefully titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with extended-release IM risperidone (Rykindo®).139 Patients with hepatic impairment were not studied with extended-release IM risperidone (Rykindo®); however, patients with hepatic impairment may have a clinically important increase in the free fraction of risperidone, possibly resulting in an enhanced effect.139
In patients with hepatic impairment, carefully titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with extended-release subcutaneous injections of risperidone (Uzedy®).140 Patients with hepatic impairment were not studied with subcutaneous risperidone (Uzedy®).140
In patients with hepatic impairment, carefully titrate with oral risperidone (up to at least 3 mg) prior to initiating treatment with extended-release subcutaneous injections of risperidone (Perseris®).141 Patients with hepatic impairment were not studied with subcutaneous risperidone (Perseris®).141
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).1, 115, 138 Therefore, dosages of oral risperidone should be reduced in patients with renal impairment.1, 115, 138
In patients with renal impairment, carefully titrate with oral risperidone prior to initiating treatment with extended-release IM risperidone (Risperdal® Consta®).103 Patients with renal impairment may have less ability to eliminate risperidone than patients with normal renal function.103
In patients with renal impairment, carefully titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with extended-release IM risperidone (Rykindo®).139 Patients with renal impairment were not studied with IM risperidone (Rykindo®); however, patients with renal impairment may have less ability to eliminate risperidone than patients with normal renal function.139
In patients with renal impairment, carefully titrate with oral risperidone (up to at least 2 mg) prior to initiating treatment with extended-release subcutaneous risperidone (Uzedy®).140 Patients with renal impairment were not studied with subcutaneous risperidone (Uzedy®).140
In patients with renal impairment, carefully titrate with oral risperidone (up to at least 3 mg) prior to initiating treatment with extended-release subcutaneous risperidone (Perseris®).141
Patients with renal impairment were not studied with subcutaneous risperidone (Perseris®).141
Patients with Parkinson Disease or Dementia with Lewy Bodies
Patients with Parkinson's disease or dementia with Lewy bodies may have an increased sensitivity to risperidone.1, 103, 115, 138, 139, 140, 141 Clinical manifestations of this increased sensitivity can include confusion, obtundation, postural instability with more frequent falls, extrapyramidal adverse effects, and clinical features consistent with neuroleptic malignant syndrome.1, 103, 115, 138, 139, 140, 141
The most frequent adverse effects of oral risperidone reported in ≥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, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.1, 115, 138
The most frequent adverse effects of IM risperidone in patients with schizophrenia (≥5%) were headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increase, pain in extremity, and dry mouth.103, 139 The most frequent adverse effects of IM risperidone in patients with bipolar disorder were weight increase (5% in monotherapy trial) and tremor and parkinsonism (≥10% in adjunctive therapy trial).103, 139
The most frequent adverse effects of subcutaneous risperidone (Uzedy®) reported in ≥5% of patients who received the drug in clinical trials and with an incidence greater than 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, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain.140 The most frequent injection site reactions with subcutaneous risperidone (Uzedy®) (≥5% and greater than placebo) were pruritus and nodule.140
The most frequent adverse effects of subcutaneous risperidone (Perseris®) reported in ≥5% of patients who received the drug in clinical trials and with an incidence of at least twice that of those receiving placebo were increased weight, sedation/somnolence, and musculoskeletal pain.141
In vitro studies indicate that risperidone is a relatively weak inhibitor of cytochrome P-450 (CYP) 2D6.1, 103, 115, 138, 139, 140, 141 Risperidone is metabolized by CYP2D6 to 9-hydroxyrisperidone (paliperidone), which has similar pharmacologic activity to risperidone; the clinical effects of risperidone result from the combined concentrations of risperidone and 9-hydroxyrisperidone.1, 103, 115, 138, 139, 140, 141
In vitro, drugs metabolized by CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 only weakly inhibit risperidone metabolism.1, 103, 115, 138
The interactions of IM or subcutaneous risperidone with coadministration of other drugs have not been studied.103, 139, 140, 141 The following drug interaction data are based on studies with oral risperidone.103, 139, 140, 141
Drugs Affecting Hepatic Microsomal Enzymes
CYP2D6 Inhibitors: Fluoxetine, paroxetine, and other CYP2D6 enzyme inhibitors increase plasma concentrations of risperidone.1, 115, 138 Inhibitors of CYP2D6 interfere with conversion of risperidone to 9-hydroxyrisperidone.1, 115, 138
Concomitant use of risperidone with strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) may increase the plasma exposure of risperidone and lower the plasma exposure of 9-hydroxyrisperidone.139, 140, 141
Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) increased the plasma concentration of risperidone by 2.5—2.8-fold and 3—9-fold, respectively.103, 139, 140, 141 Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.103, 139, 140, 141 Paroxetine lowered the concentration of 9-hydroxyrisperidone by approximately 10%.103, 139, 140, 141
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.1, 115, 138 If oral risperidone is initiated in patients receiving fluoxetine or paroxetine, risperidone should be titrated slowly.1, 115, 138 When fluoxetine or paroxetine is discontinued, an increase in the dosage of risperidone may be necessary.1, 115, 138
If fluoxetine, paroxetine, or another CYP2D6 inhibitor is initiated in patients receiving IM risperidone (Risperdal®Consta®), a dosage reduction may be considered; dosage of IM risperidone may be reduced 2-4 weeks before initiating fluoxetine or paroxetine.103 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.103 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.103
When considering initiation of strong CYP2D6 inhibitors in patients receiving IM risperidone (Rykindo®), patients may be placed on a lower dose of Rykindo® between 2—4 weeks before the planned start of the strong CYP2D6 inhibitor.139 When a strong CYP2D6 inhibitor is initiated in patients receiving Rykindo® 25 mg, continue treatment with 25 mg unless clinical judgment necessitates either lowering the Rykindo® dosage to 12.5 mg or interruption of risperidone treatment.139 When Rykindo® is initiated in patients already receiving a CYP2D6 inhibitor, a starting dose of 12.5 mg can be considered.139 The efficacy of the 12.5 mg dosage has not been studied in clinical trials.139
When considering initiation of a strong CYP2D6 inhibitor in patients receiving subcutaneous risperidone (Uzedy®), patients may be placed on the lowest dose of Uzedy® (50 mg once monthly or 100 mg once every 2 months) before the planned start of the strong CYP2D6 inhibitor.140 When a strong CYP2D6 inhibitor is initiated in patients receiving Uzedy® 50 mg once monthly or 100 mg once every 2 months, continue risperidone treatment at the same dosage unless clinical judgment necessitates interruption of risperidone treatment.140
When considering initiation of a strong CYP2D6 inhibitor in patients receiving subcutaneous risperidone (Perseris®), patients may be placed on the lowest dose of Perseris® (90 mg) between 2—4 weeks before the planned start of the strong CYP2D6 inhibitor.141 When a strong CYP2D6 inhibitor is initiated in patients receiving Perseris® 90 mg, continue treatment with 90 mg unless clinical judgment necessitates interruption of risperidone treatment.141
CYP Inducers: CYP inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) may decrease plasma concentrations of risperidone; a decrease in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone may occur.1, 115, 138
Concomitant use of a strong CYP3A4 inducer (e.g., carbamazepine) with risperidone may cause decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, resulting in decreased efficacy of risperidone.139, 140, 141
Carbamazepine decreased plasma risperidone and 9-hydroxyrisperidone concentrations by about 50%; carbamazepine concentrations were not affected.103, 139, 140, 141
When oral 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.1, 115, 138 A decrease in the dosage of oral risperidone may be necessary when the CYP enzyme inducer is discontinued.1, 115, 138
When initiating therapy with a (strong) CYP3A4 inducer in patients receiving IM risperidone (Risperdal® Consta®), closely monitor patients during the first 4—8 weeks because the Risperdal® Consta® dosage may need to be adjusted.103 A dosage increase or additional oral risperidone may need to be considered.103 When discontinuing a CYP3A4 inducer, the dosage of Risperdal® Consta®should be re-evaluated and decreased, if necessary.103 Patients may be placed on a lower dosage of Risperdal® Consta® between 2—4 weeks before the planned discontinuation of CYP3A4 inducers.103 For patients treated with the recommended dosage of 25 mg of Risperdal® Consta® who are discontinuing from carbamazepine or other CYP3A4 inducers, continue treatment with the 25-mg dosage unless clinical judgment necessitates lowering the dosage to 12.5 mg or interruption of risperidone treatment.103 The efficacy of the 12.5 mg dosage has not been studied in clinical trials.103
When initiating therapy with a strong CYP3A4 inducer in patients receiving IM risperidone (Rykindo®), closely monitor patients during the first 4—8 weeks because the Rykindo® dosage may need to be adjusted.139 A dosage increase or additional oral risperidone may need to be considered.139 When discontinuing a strong CYP3A4 inducer, the dosage of Rykindo® should be re-evaluated and decreased, if necessary.139 Patients may be placed on a lower dosage of Rykindo® between 2—4 weeks before the planned discontinuation of CYP3A4 inducers.139 For patients treated with the recommended dosage of 25 mg of Rykindo®who are discontinuing from a CYP3A4 enzyme inducer, continue treatment with the 25 mg dosage unless clinical judgment necessitates either lowering the Rykindo®dosage to 12.5 mg or interruption of risperidone treatment.139 The efficacy of the 12.5 mg dosage has not been studied in clinical trials.139
When initiating a strong CYP3A4 inducer in patients receiving subcutaneous risperidone (Uzedy®), closely monitor patients during the first 4—8 weeks; a dosage increase or additional oral risperidone may be considered.140 In patients receiving Uzedy® at a specific dosage, consider increasing the dosage to the next highest dosage.140 In patients receiving Uzedy® 125 mg once monthly or 250 mg once every 2 months, additional oral risperidone therapy may need to be considered.140 When discontinuing a strong CYP3A4 inducer, the dosage of Uzedy® or any additional oral risperidone should be reevaluated and, if necessary, decreased.140 For patients treated with Uzedy® 50 mg once monthly or 100 mg once every 2 months who are discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the same dosage unless clinical judgment necessitates interruption of risperidone treatment.140 Monitor for changes in efficacy and safety carefully with any dosage adjustment of Uzedy®.140
When initiating a strong CYP3A4 inducer in patients receiving subcutaneous risperidone (Perseris®), closely monitor patients during the first 4—8 weeks; a dosage increase or additional oral risperidone may need to be considered.141 In patients receiving Perseris® 90 mg, consider increasing the dosage to 120 mg.141 In patients receiving Perseris® 120 mg, additional oral risperidone therapy may need to be considered.141 When discontinuing a strong CYP3A4 inducer, the dosage of Perseris® or any additional oral risperidone should be reevaluated and, if necessary, decreased.141 For patients treated with Perseris® 90 mg who are discontinuing from a strong CYP3A4 inducer, it is recommended to continue treatment with the same dosage unless clinical judgment necessitates interruption of risperidone treatment.141 Carefully monitor for changes in efficacy and safety with any dosage adjustment of Perseris®.141
Drugs Metabolized by Hepatic Microsomal Enzymes
Drugs metabolized by CYP2D6: Risperidone is a relatively weak inhibitor of CYP2D6 and is not expected to substantially inhibit the clearance of drugs metabolized by this isoenzyme.1, 103, 115, 138, 139, 140, 141 Risperidone did not substantially affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP2D6.1, 115, 138, 139, 140, 141 No dosage adjustment of CYP2D6 substrates (donepezil and galantamine) is necessary.139, 140, 141
Because of the potential of risperidone to cause orthostatic hypotension, additive hypotensive effects may occur with concomitant use with antihypertensive drugs.1, 103, 115, 138, 139, 140, 141 Use concomitantly with caution.139, 140, 141
Due to potential for additive CNS effects, caution is advised when risperidone is used concomitantly with other CNS agents or alcohol.1, 103, 115, 138, 139, 140, 141
No clinically important effects on the pharmacokinetics of risperidone or the active antipsychotic moiety were observed.1, 103, 115, 138, 139, 140, 141 Risperidone dosage adjustment is not required.1, 115, 138, 139, 140, 141
Cimetidine increased bioavailability of oral risperidone by 64%, but had no effect on the AUC of active antipsychotic moiety.103, 139, 140, 141 Risperidone dosage adjustment is not required.1, 115, 138, 139, 140, 141
Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.1, 103, 115, 138, 139, 140, 141 Risperidone dosage adjustment is not required.140, 141
No clinically important effects on the pharmacokinetics of digoxin were observed when used concomitantly with oral risperidone 0.25 mg twice daily.1, 103, 115, 138, 139, 140, 141 Digoxin dosage adjustment is not required.1, 103, 115, 138, 139, 140, 141
No substantial pharmacokinetic interactions between erythromycin (moderate CYP3A4 inhibitor) and oral risperidone observed.1, 103, 115, 138, 139, 140, 141 Risperidone dosage adjustment is not required.1, 103, 115, 138, 139, 140, 141
Levodopa and Dopamine Agonists
Risperidone may antagonize the effects of levodopa and dopamine agonists.1, 103, 115, 138, 139, 140, 141 Use concomitantly with caution.139, 140, 141
Concomitant administration of lithium with repeated doses of risperidone (3 mg orally twice daily) did not affect the peak plasma concentrations or AUC of lithium.1, 103, 115, 138, 139, 140, 141 Lithium dosage adjustment is not recommended.1, 103, 115, 138, 139, 140, 141
Concomitant administration of risperidone with methylphenidate, when there is change in dosage of either drug, may increase the risk of extrapyramidal symptoms (EPS).1, 103, 115, 138, 139, 140, 141 Monitor for symptoms of EPS with concomitant use.1, 103, 115, 138, 139, 140, 141
Ranitidine increased bioavailability of oral risperidone by 26% and increased combined risperidone and 9-hydroxyrisperidone AUC by 20%.103, 139, 140, 141 Risperidone dosage adjustment is not required.1, 115, 138, 139, 140, 141
No clinically important pharmacokinetic interactions were observed.103, 139, 140, 141 Topiramate dosage adjustment is not required.139, 140, 141
Oral risperidone increased peak valproate concentration by 20% but had no effect on valproate AUC.1, 103, 115, 138, 139, 140, 141 Valproate dosage adjustment is not recommended.1, 103, 115, 138, 139, 140, 141
Risperidone is a benzisoxazole-derivative antipsychotic agent.1, 103, 115, 138, 139, 140, 141 The drug has been described as an atypical antipsychotic agent.1, 103, 115, 138, 139, 140, 141 The principal active metabolite of risperidone is 9-hydroxyrisperidone (paliperidone); the clinical effects of risperidone result from the combined concentrations of risperidone and 9-hydroxyrisperidone.1, 103, 115, 138, 139, 140, 141
The exact mechanism of antipsychotic action of risperidone has not been fully elucidated but may involve antagonism of both type 2 serotonergic (5-HT2) receptors and dopamine D2 receptors.1, 103, 115, 138, 139, 140, 141 Antagonism at other receptors (e.g., α1- and α2-adrenergic receptors, histamine H1 receptors) may contribute to other effects of risperidone.1, 103, 115, 138, 139, 140, 141
Risperidone is a monoaminergic antagonist which exhibits high affinity for 5-HT2, dopamine D2, α1- and α2-adrenergic, and histamine H1 receptors.1, 103, 115, 138, 139, 140, 141 Risperidone exhibits low to moderate affinity for other serotonin receptor subtypes (e.g., 5HT1C, 5HT1A, 5HT1D), and weak affinity for dopamine D1 receptors and the haloperidol-sensitive sigma site.1, 103, 115, 138, 139, 140, 141 The drug possesses no affinity for cholinergic muscarinic or β1- and β2-adrenergic receptors.1, 103, 115, 138, 139, 140, 141
Risperidone is well absorbed after oral administration, with peak drug plasma concentrations attained in approximately 1 hour.1, 115, 138 The absolute oral bioavailability of risperidone is 70%; the relative oral bioavailability from a tablet is 94% compared with a solution.1, 115, 138 Commercially available risperidone conventional and orally disintegrating tablets and oral solution are bioequivalent.1, 115, 138 The mean peak plasma concentrations of the major active metabolite, 9-hydroxyrisperidone (paliperidone), occur at about 3 and 17 hours in patients who are extensive and poor metabolizers of cytochrome P-450 (CYP) 2D6, respectively.1, 115, 138 Steady state of risperidone is reached in 1 day in extensive metabolizers and expected in 5 days in poor metabolizers; 9-hydroxyrisperidone steady state is reached in 5-6 days in extensive metabolizers.1, 115, 138 Food does not affect the rate or extent of risperidone absorption.1, 115, 138
After IM administration of risperidone (Risperdal® Consta®), there is a small initial release of the drug (<1% of dose) followed by a 3-week lag time; the main drug release starts from 3 weeks onward and is maintained for 4-6 weeks and then subsides by 7 weeks after the injection.103 Therefore, oral antipsychotic supplementation should be administered during the first 3 weeks of treatment with IM risperidone to maintain therapeutic levels until the main release of risperidone from the injection site has started.103 IM risperidone injections (Risperdal® Consta®) into the deltoid and gluteal areas are bioequivalent and therefore interchangeable.103 With IM administration of extended-release risperidone injection every 2 weeks, steady-state plasma concentrations are achieved after 4 doses and are maintained 4-6 weeks after the last injection.103
After a single IM risperidone injection (Rykindo®), the release profile consists of an initial release of the drug followed by a stable release phase of 2—4 weeks.139 The median time to peak concentration of risperidone and 9-hydroxyrisperidone combined are 14 and 17 days following administration of 25 mg and 50 mg of the drug, respectively.139 The combination of the release profile and the dosage regimen (IM injections every 2 weeks) of Rykindo® results in sustained concentrations within the dosing interval (every 2 weeks).139 Steady-state plasma concentrations are reached after 2 injections and can be maintained for 2—3 weeks after the last injection.139
Subcutaneous risperidone (Uzedy®) contains risperidone in a liquid delivery system.140 A depot forms following subcutaneous injection, providing sustained plasma levels of risperidone and 9-hydroxyrisperidone combined over 1 or 2 months.140 After subcutaneous administration, the median time to peak plasma concentrations for risperidone and 9-hydroxyrisperidone combined ranges from 8—14 days.140 Therapeutic concentrations in plasma are achieved within 6—24 hours following the first injection.140 Steady-state levels of risperidone and 9-hydroxyrisperidone are approached within 2 months of Uzedy® initiation.140 Administration in the abdomen and upper arm results in similar pharmacokinetic profiles for all doses, therefore these injection sites can be used interchangeably.140
Similar to Uzedy®, subcutaneous risperidone (Perseris®) contains risperidone in a liquid delivery system.141 A depot forms following subcutaneous injection, providing sustained plasma levels of risperidone over the monthly dosing interval.141 After single subcutaneous injection, there are 2 absorption peaks for risperidone in plasma; the first peak is due to an initial release of the drug during the depot formation process, and the second peak (observed at 10 to 14 days after administration) is associated with the slow release of risperidone from the depot.141 For both 9-hydroxyrisperidone and total active moiety, the median time to peak plasma concentrations of the first and second peak ranges from 4—48 hours and 7—11 days, respectively.141 Plasma concentrations of risperidone, 9-hydroxyrisperidone, and total active moiety approach steady-state levels after the first dose of Perseris®.141
Risperidone is rapidly distributed.1, 103, 115, 138, 140, 141 The drug is approximately 90% protein bound (mainly to albumin and α1-acid glycoprotein); the major active metabolite (9-hydroxyrisperidone) is 77% protein bound.1, 103, 115, 138, 139, 140, 141 Risperidone is extensively metabolized, principally in the liver via CYP2D6, to the active metabolite (9-hydroxyrisperidone) which has similar pharmacologic activity to parent drug.1, 103, 115, 138, 139, 140, 141 N-Dealkylation is a minor metabolic pathway.1, 103, 115, 138, 139, 140, 141 Risperidone is excreted principally in the urine (70%) and to much lesser extent, in the feces (14%).1, 103, 115, 138, 139, 140, 141
After oral administration, overall mean elimination half-life for active moiety (risperidone plus 9-hydroxyrisperidone) is about 20 hours.1, 115, 138 After IM risperidone administration, the apparent half-life of the active moiety is 3-6 days.103, 139 The elimination phase is complete approximately 7-8 and 6 weeks after the last injection of Risperdal® Consta® and Rykindo®, respectively.103, 139 Following administration of Uzedy®, the mean apparent half-life ranges between 14—22 days for risperidone, 9-hydroxyrisperidone, and risperidone and 9-hydroxyrisperidone combined.140 Following a single subcutaneous injection of Perseris®, the mean apparent terminal half-life of risperidone ranges between 9—11 days; the mean apparent terminal half-life ranges between 8—9 days for both 9-hydroxyrisperidone and total active moiety.141
Notably, CYP2D6 is subject to genetic polymorphism; extensive metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, while poor metabolizers convert it much more slowly.1, 103, 115, 138, 139, 140, 141 Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations, the pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) are similar after single and multiple doses in extensive and poor metabolizers.1, 103, 115, 138, 139 Following subcutaneous administration, plasma exposure to risperidone and 9-hydroxyrisperidone combined was similar in CYP2D6 extensive, intermediate, poor and non-poor metabolizers.140, 141
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 1 mg/mL* | ||
Tablets | 0.25 mg* | |||
0.5 mg* | RisperDAL® | Janssen | ||
risperiDONE Tablets | ||||
1 mg* | RisperDAL® | Janssen | ||
risperiDONE Tablets | ||||
2 mg* | RisperDAL® | Janssen | ||
risperiDONE Tablets | ||||
3 mg* | RisperDAL® | Janssen | ||
risperiDONE Tablets | ||||
4 mg* | RisperDAL® | Janssen | ||
risperiDONE Tablets | ||||
Tablets, orally disintegrating | 0.25 mg* | |||
0.5 mg* | RisperDAL® M-TAB® | Janssen | ||
risperiDONE Orally Disintegrating Tablets | ||||
1 mg* | RisperDAL® M-TAB® | Janssen | ||
risperiDONE Orally Disintegrating Tablets | ||||
2 mg* | RisperDAL® M-TAB® | Janssen | ||
risperiDONE Orally Disintegrating Tablets | ||||
3 mg* | RisperDAL® M-TAB® | Janssen | ||
risperiDONE Orally Disintegrating Tablets | ||||
4 mg* | RisperDAL® M-TAB® | Janssen | ||
risperiDONE Orally Disintegrating Tablets | ||||
Parenteral | For injectable suspension, extended-release, for IM use | 12.5 mg | RisperDAL® Consta® (available as dose pack containing a vial adapter device, 2 safety needles, and with 2-mL prefilled syringe diluent) | Janssen |
Rykindo® (available as dose pack containing a vial adapter device, 1 needle, and with 2-mL prefilled syringe diluent) | ||||
25 mg | RisperDAL® Consta® (available as dose pack containing a vial adapter device, 2 safety needles, and with 2-mL prefilled syringe diluent) | Janssen | ||
Rykindo® (available as dose pack containing a vial adapter device, 1 needle, and with 2-mL prefilled syringe diluent) | ||||
37.5 mg | RisperDAL® Consta® (available as dose pack containing a vial adapter device, 2 safety needles, and with 2-mL prefilled syringe diluent) | Janssen | ||
Rykindo® (available as dose pack containing a vial adapter device, 1 needle, and with 2-mL prefilled syringe diluent) | ||||
50 mg | RisperDAL® Consta® (available as dose pack containing a vial adapter device, 2 safety needles, and with 2-mL prefilled syringe diluent) | Janssen | ||
Rykindo® (available as dose pack containing a vial adapter device, 1 needle, and with 2-mL prefilled syringe diluent) | ||||
For injectable suspension, extended-release, for subcutaneous use | 50 mg/0.14 mL | Uzedy® | ||
75 mg/0.21 mL | Uzedy® | |||
100 mg/0.28 mL | Uzedy® | |||
125 mg/0.35 mL | Uzedy® | |||
150 mg/0.42 mL | Uzedy® | |||
200 mg/0.56 mL | Uzedy® | |||
250 mg/0.7 mL | Uzedy® | |||
90 mg | Perseris® | |||
120 mg | Perseris® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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