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The following are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [seeBOXED WARNINGS and WARNINGS AND PRECAUTIONS]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS AND PRECAUTIONS]
• Hyperglycemia and diabetes mellitus [see WARNINGS AND PRECAUTIONS]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS]
• Orthostatic hypotension [see WARNINGS AND PRECAUTIONS]
• Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Dysphagia [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Thrombotic Thrombocytopenic Purpura (TTP) [see WARNINGS AND PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS]
• Antiemetic effect [see WARNINGS AND PRECAUTIONS]
• Suicide [see WARNINGS AND PRECAUTIONS]
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see WARNINGS AND PRECAUTIONS]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in clinical trials ( ≥ 10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in > 1% of adults and/or > 2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia.

The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of RISPERDAL® for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received RISPERDAL® while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with RISPERDAL® varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of RISPERDAL® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for RISPERDAL® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The majority of all adverse reactions were mild to moderate in severity.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia

Adult Patients with Schizophrenia

Table 1 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.

Table 1. Adverse Reactions in ≥ 1 % of RISPERDAL®-Treated Adult Patients with Schizoohrenia in Double-Blind. Placebo-Controlled Trials

Pediatric Patients with Schizophrenia

Table 2 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.

Table 2. Adverse Reactions in ≥ 5% of RISPERDAL®-Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Bipolar Mania

Adult Patients with Bipolar Mania

Table 3 lists the adverse reactions reported in 1% or more of RISPERDAL®-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.

Table 3. Adverse Reactions in ≥ 1 % of RISPERDAL®-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials

Table 4 lists the adverse reactions reported in 2% or more of RISPERDAL®-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.

Table 4. Adverse Reactions in ≥ 2% of RISPERDAL®-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials

Pediatric Patients with Bipolar Mania

Table 5 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.

Table 5. Adverse Reactions in ≥ 5% of RISPERDALR-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Autistic Disorder

Table 6 lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials.

Table 6. Adverse Reactions in ≥ 5% of RISPERDAL®-Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials

In another study with patients treated for irritability associated with autistic disorder, headache (6%), epistaxis (6%) and pyrexia (6%) were also observed in RISPERDAL®-treated pediatric subjects.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone

The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with RISPERDAL® in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in RISPERDAL®-treated patients who participated in other studies, including double-blind, active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia.

Blood and Lymphatic System Disorders: granulocytopenia, neutropenia

Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block

Ear and Labyrinth Disorders: tinnitus

Endocrine Disorders: hyperprolactinemia

Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced

Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism

General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness

Immune System Disorders: drug hypersensitivity

Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic

Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased

Metabolism and Nutrition Disorders: polydipsia, anorexia

Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, rhabdomyolysis

Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation

Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep disorder, listlessness, libido decreased, anorgasmia

Renal and Urinary Disorders: enuresis, dysuria, pollakiuria

Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement

Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema

Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular

Vascular Disorders: flushing

Additional Adverse Reactions Reported with RISPERDAL® CONSTA®

The following is a list of additional adverse reactions that have been reported during the premarketing evaluation of RISPERDAL® CONSTA®, regardless of frequency of occurrence:

Cardiac Disorders: bradycardia

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blepharospasm

Gastrointestinal Disorders: toothache, tongue spasm

General Disorders and Administration Site Conditions: pain

Infections and Infestations: lower respiratory tract infection, infection, gastroenteritis, subcutaneous abscess

Injury and Poisoning: fall

Investigations: weight decreased, gamma-glutamyltransferase increased, hepatic enzyme increased

Musculoskeletal, Connective Tissue, and Bone Disorders: buttock pain

Nervous System Disorders: convulsion, paresthesia

Psychiatric Disorders: depression

Skin and Subcutaneous Tissue Disorders: eczema

Vascular Disorders: hypertension

Discontinuations Due to Adverse Reactions

Schizophrenia - Adults

Approximately 7% (39/564) of RISPERDAL®-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more RISPERDAL®-treated patients were:

Table 7. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated Adult Patients in Schizophrenia Trials

Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4% in active control-treated patients in a double-blind, placebo- and active-controlled trial.

Schizophrenia - Pediatrics

Approximately 7% (7/106), of RISPERDAL®-treated patients discontinued treatment due to an adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one RISPERDAL®-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).

Bipolar Mania - Adults

In double-blind, placebo-controlled trials with RISPERDAL® as monotherapy, approximately 6% (25/448) of RISPERDAL®-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in RISPERDAL®-treated patients were:

Table 8. Adverse Reactions Associated With Discontinuation in 2 or More RISPERDAL®-Treated Adult Patients in Bipolar Mania Clinical Trials

Bipolar Mania - Pediatrics

In a double-blind, placebo-controlled trial 12% (13/111) of RISPERDAL®-treated patients discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one RISPERDAL®-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).

Autistic Disorder - Pediatrics

In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one RISPERDAL®-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.

Dose Dependency of Adverse Reactions in Clinical Trials

Extrapyramidal Symptoms

Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with RISPERDAL® treatment.

Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of RISPERDAL® (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS:

Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day):

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Other Adverse Reactions

Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of RISPERDAL® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p < 0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration.

Changes in Body Weight

The proportions of RISPERDAL® and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for RISPERDAL® (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint was comparable in the RISPERDAL® (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).

Changes in body weight were also evaluated in pediatric patients [see Use in Specific Populations]

Changes in ECG

Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all RISPERDAL® doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases in mean heart rate, similar among all treatment groups.

In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 -16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the RISPERDAL® groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes.

In a placebo-controlled acute mania trial in children and adolescents (aged 10-17 years), there were no significant changes in ECG parameters, other than the effect of RISPERDAL® to transiently increase pulse rate ( < 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13-17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication.

Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.

Centrally-Acting Drugs and Alcohol

Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® is taken in combination with other centrally-acting drugs and alcohol.

Drugs with Hypotensive Effects

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

Levodopa and Dopamine Agonists

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

Amitriptyline

Amitriptyline did not affect the pharmacokinetics of risperidone or risperidone and 9-hydroxyrisperidone combined.

Cimetidine and Ranitidine

Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of risperidone and 9-hydroxyrisperidone combined, whereas ranitidine increased the AUC of risperidone and 9-hydroxyrisperidone combined by 20%.

Clozapine

Chronic administration of clozapine with RISPERDAL® may decrease the clearance of risperidone.

Lithium

Repeated oral doses of RISPERDAL® (3 mg twice daily) did not affect the exposure (AUC) or peak plasma concentrations (Cmax) of lithium (n=13).

Valproate

Repeated oral doses of RISPERDAL® (4 mg once daily) did not affect the pre-dose or average plasma concentrations and exposure (AUC) of valproate (1000 mg/day in three divided doses) compared to placebo (n=21). However, there was a 20% increase in valproate peak plasma concentration (Cmax) after concomitant administration of RISPERDAL®.

Digoxin

RISPERDAL® (0.25 mg twice daily) did not show a clinically relevant effect on the pharmacokinetics of digoxin.

Drugs That Inhibit CYP 2D6 and Other CYP Isozymes

Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6, an enzyme that is polymorphic in the population and that can be inhibited by a variety of psychotropic and other drugs [see CLINICAL PHARMACOLOGY]. Drug interactions that reduce the metabolism of risperidone to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies involving a modest number of poor metabolizers (n=70) does not suggest that poor and extensive metabolizers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

In vitro studies showed that drugs metabolized by other CYP isozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors of risperidone metabolism.

Fluoxetine and Paroxetine

Fluoxetine (20 mg once daily) and paroxetine (20 mg once daily) have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dosing of RISPERDAL®. The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Erythromycin

There were no significant interactions between RISPERDAL® and erythromycin.

Carbamazepine and Other Enzyme Inducers

Carbamazepine co-administration decreased the steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. The dose of RISPERDAL® may need to be titrated accordingly for patients receiving carbamazepine, particularly during initiation or discontinuation of carbamazepine therapy. Co-administration of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with RISPERDAL® may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® treatment.

Drugs Metabolized by CYP 2D6

In vitro studies indicate that risperidone is a relatively weak inhibitor of CYP 2D6. Therefore, RISPERDAL® is not expected to substantially inhibit the clearance of drugs that are metabolized by this enzymatic pathway. In drug interaction studies, RISPERDAL® did not significantly affect the pharmacokinetics of donepezil and galantamine, which are metabolized by CYP 2D6.

Drug Abuse And Dependence

Controlled Substance

RISPERDAL® (risperidone) is not a controlled substance.

Abuse

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

Dependence

RISPERDAL® has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Last reviewed on RxList: 7/25/2011
This monograph has been modified to include the generic and brand name in many instances.