Risperidone Prescribing Information
| Initial Dose | Titration (Increments) | Target Dose | Effective Dose Range | |
|---|---|---|---|---|
Schizophrenia: adults | 2 mg | 1 to 2 mg | 4 to 8 mg | 4 to 16 mg |
Schizophrenia: adolescents | 0.5 mg | 0.5 to 1 mg | 3 mg | 1 to 6 mg |
Bipolar mania: adults | 2 to 3 mg | 1 mg | 1 to 6 mg | 1 to 6 mg |
Bipolar mania: children and adolescents | 0.5 mg | 0.5 to 1 mg | 1 to 2.5 mg | 1 to 6 mg |
Irritability in autistic disorder | 0.25 mg Can increase to 0.5 mg by Day 4: (body weight less than 20 kg) 0.5 mg Can increase to 1 mg by Day 4: (body weight greater than or equal to 20 kg) | After Day 4, at intervals of > 2 weeks: 0.25 mg (body weight less than 20 kg) 0.5 mg (body weight greater than or equal to 20 kg) | 0.5 mg: (body weight less than 20 kg) 1 mg: (body weight greater than or equal to 20 kg) | 0.5 to 3 mg |
Severe Renal and Hepatic Impairment in Adults: use a lower starting dose of 0.5 mg twice daily. May increase to dosages above 1.5 mg twice daily at intervals of one week or longer.
Risperidone oral solution is available in a 1 mg/mL strength.
Risperidone oral solution is contraindicated in patients with a known hypersensitivity to either risperidone or paliperidone, or to any of the excipients in the risperidone formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.
The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [seeBoxed Warningand]Warnings and Precautions(5.1)
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see]Warnings and Precautions(5.2)
- Neuroleptic malignant syndrome [see]Warnings and Precautions(5.3)
- Tardive dyskinesia [see]Warnings and Precautions(5.4)
- Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see]Warnings and Precautions(5.5)
- Hyperprolactinemia [see]Warnings and Precautions(5.6)
- Orthostatic hypotension [see]Warnings and Precautions(5.7)
- Falls []seeWarnings and Precautions(5.8)
- Leukopenia, neutropenia, and agranulocytosis [see]Warnings and Precautions(5.9)
- Potential for cognitive and motor impairment [see]Warnings and Precautions(5.10)
- Seizures [see]Warnings and Precautions(5.11)
- Dysphagia [see]Warnings and Precautions(5.12)
- Priapism [see]Warnings and Precautions(5.13)
- Disruption of body temperature regulation [see]Warnings and Precautions(5.14)
The most common adverse reactions in clinical trials (>5% and twice 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.
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 following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [seeBoxed Warningand]Warnings and Precautions(5.1)
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see]Warnings and Precautions(5.2)
- Neuroleptic malignant syndrome [see]Warnings and Precautions(5.3)
- Tardive dyskinesia [see]Warnings and Precautions(5.4)
- Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see]Warnings and Precautions(5.5)
- Hyperprolactinemia [see]Warnings and Precautions(5.6)
- Orthostatic hypotension [see]Warnings and Precautions(5.7)
- Falls []seeWarnings and Precautions(5.8)
- Leukopenia, neutropenia, and agranulocytosis [see]Warnings and Precautions(5.9)
- Potential for cognitive and motor impairment [see]Warnings and Precautions(5.10)
- Seizures [see]Warnings and Precautions(5.11)
- Dysphagia [see]Warnings and Precautions(5.12)
- Priapism [see]Warnings and Precautions(5.13)
- Disruption of body temperature regulation [see]Warnings and Precautions(5.14)
The most common adverse reactions in clinical trials (>5% and twice 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.
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 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone 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.
The most common adverse reactions in clinical trials (≥ 5% and twice 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.
6.1 Clinical Trials ExperienceBecause 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.
Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Percentage of Patients Reporting Reaction | |||
R isperidone | |||
System/Organ Class Adverse Reaction | 2 to 8 mg per day (n = 366) | > 8 to 16 mg per day (n = 198) | Placebo (n = 225) |
Cardiac Disorders | |||
Tachycardia | 1 | 3 | 0 |
Eye Disorders | |||
Vision blurred | 3 | 1 | 1 |
Gastrointestinal Disorders | |||
Nausea | 9 | 4 | 4 |
Constipation | 8 | 9 | 6 |
Dyspepsia | 8 | 6 | 5 |
Dry mouth | 4 | 0 | 1 |
Abdominal discomfort | 3 | 1 | 1 |
Salivary hypersecretion | 2 | 1 | <1 |
Diarrhea | 2 | 1 | 1 |
General Disorders | |||
Fatigue | 3 | 1 | 0 |
Chest pain | 2 | 2 | 1 |
Asthenia | 2 | 1 | <1 |
Infections and Infestations | |||
Nasopharyngitis | 3 | 4 | 3 |
Upper respiratory tract infection | 2 | 3 | 1 |
Sinusitis | 1 | 2 | 1 |
Urinary tract infection | 1 | 3 | 0 |
Investigations | |||
Blood creatine phosphokinase increased | 1 | 2 | <1 |
Heart rate increased | <1 | 2 | 0 |
Musculoskeletal and Connective Tissue Disorders | |||
Back pain | 4 | 1 | 1 |
Arthralgia | 2 | 3 | <1 |
Pain in extremity | 2 | 1 | 1 |
Nervous System Disorders | |||
Parkinsonism* | 14 | 17 | 8 |
Akathisia* | 10 | 10 | 3 |
Sedation | 10 | 5 | 2 |
Dizziness | 7 | 4 | 2 |
Dystonia* | 3 | 4 | 2 |
Tremor* | 2 | 3 | 1 |
Dizziness postural | 2 | 0 | 0 |
Psychiatric Disorders | |||
Insomnia | 32 | 25 | 27 |
Anxiety | 16 | 11 | 11 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Nasal congestion | 4 | 6 | 2 |
Dyspnea | 1 | 2 | 0 |
Epistaxis | <1 | 2 | 0 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 1 | 4 | 1 |
Dry skin | 1 | 3 | 0 |
Vascular Disorders | |||
Orthostatic hypotension | 2 | 1 | 0 |
*Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 1 to 3 mg per day (n = 55) | 4 to 6 mg per day (n = 51) | Placebo (n = 54) |
Gastrointestinal Disorders | |||
Salivary hypersecretion | 0 | 10 | 2 |
Nervous System Disorders | |||
Sedation | 24 | 12 | 4 |
Parkinsonism* | 16 | 28 | 11 |
Tremor | 11 | 10 | 6 |
Akathisia* | 9 | 10 | 4 |
Dizziness | 7 | 14 | 2 |
Dystonia* | 2 | 6 | 0 |
Psychiatric Disorders | |||
Anxiety | 7 | 6 | 0 |
* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.
Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 1 to 6 mg per day (n = 448) | Placebo (n = 424) |
Eye Disorders | ||
Vision blurred | 2 | 1 |
Gastrointestinal Disorders | ||
Nausea | 5 | 2 |
Diarrhea | 3 | 2 |
Salivary hypersecretion | 3 | 1 |
Stomach discomfort | 2 | <1 |
General Disorders | ||
Fatigue | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 25 | 9 |
Sedation | 11 | 4 |
Akathisia* | 9 | 3 |
Tremor* | 6 | 3 |
Dizziness | 6 | 5 |
Dystonia* | 5 | 1 |
Lethargy | 2 | 1 |
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.
Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone + Mood Stabilizer (n = 127) | Placebo + Mood Stabilizer (n = 126) |
Cardiac Disorders | ||
Palpitations | 2 | 0 |
Gastrointestinal Disorders | ||
Dyspepsia | 9 | 8 |
Nausea | 6 | 4 |
Diarrhea | 6 | 4 |
Salivary hypersecretion | 2 | 0 |
General Disorders | ||
Chest pain | 2 | 1 |
Infections and Infestations | ||
Urinary tract infection | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 14 | 4 |
Sedation | 9 | 4 |
Akathisia* | 8 | 0 |
Dizziness | 7 | 2 |
Tremor | 6 | 2 |
Lethargy | 2 | 1 |
Psychiatric Disorders | ||
Anxiety | 3 | 2 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Pharyngolaryngeal pain | 5 | 2 |
Cough | 2 | 0 |
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.
Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 0.5 to 2.5 mg per day (n = 50) | 3 to 6 mg per day (n = 61) | Placebo (n = 58) |
Eye Disorders | |||
Vision blurred | 4 | 7 | 0 |
Gastrointestinal Disorders | |||
Abdominal pain upper | 16 | 13 | 5 |
Nausea | 16 | 13 | 7 |
Vomiting | 10 | 10 | 5 |
Diarrhea | 8 | 7 | 2 |
Dyspepsia | 10 | 3 | 2 |
Stomach discomfort | 6 | 0 | 2 |
General Disorders | |||
Fatigue | 18 | 30 | 3 |
Metabolism and Nutrition Disorders | |||
Increased appetite | 4 | 7 | 2 |
Nervous System Disorders | |||
Sedation | 42 | 56 | 19 |
Dizziness | 16 | 13 | 5 |
Parkinsonism* | 6 | 12 | 3 |
Dystonia* | 6 | 5 | 0 |
Akathisia* | 0 | 8 | 2 |
Psychiatric Disorders | |||
Anxiety | 0 | 8 | 3 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Pharyngolaryngeal pain | 10 | 3 | 5 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 0 | 7 | 2 |
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 0.5 to 4 mg/day (n = 107) | Placebo (n = 115) |
Gastrointestinal Disorders | ||
Vomiting | 20 | 17 |
Constipation | 17 | 6 |
Dry mouth | 10 | 4 |
Nausea | 8 | 5 |
Salivary hypersecretion | 7 | 1 |
General Disorders and Administration Site Conditions | ||
Fatigue | 31 | 9 |
Pyrexia | 16 | 13 |
Thirst | 7 | 4 |
Infections and Infestations | ||
Nasopharyngitis | 19 | 9 |
Rhinitis | 9 | 7 |
Upper respiratory tract infection | 8 | 3 |
Investigations | ||
Weight increased | 8 | 2 |
Metabolism and Nutrition Disorders | ||
Increased appetite | 44 | 15 |
Nervous System Disorders | ||
Sedation | 63 | 15 |
Drooling | 12 | 4 |
Headache | 12 | 10 |
Tremor | 8 | 1 |
Dizziness | 8 | 2 |
Parkinsonism* | 8 | 1 |
Renal and Urinary Disorders | ||
Enuresis | 16 | 10 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Cough | 17 | 12 |
Rhinorrhea | 12 | 10 |
Nasal congestion | 10 | 4 |
Skin and Subcutaneous Tissue Disorders | ||
Rash | 8 | 5 |
*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.
The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, 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: ear pain, 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, feeling abnormal
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: decreased appetite, polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint stiffness, 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, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, 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, acne, hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were:
Risperidone | |||
Adverse Reaction | 2 to 8 mg/day (n = 366) | > 8 to 16 mg/day (n = 198) | Placebo (n = 225) |
Dizziness | 1.4% | 1% | 0% |
Nausea | 1.4% | 0% | 0% |
Vomiting | 0.8% | 0% | 0% |
Parkinsonism | 0.8% | 0% | 0% |
Somnolence | 0.8% | 0% | 0% |
Dystonia | 0.5% | 0% | 0% |
Agitation | 0.5% | 0% | 0% |
Abdominal pain | 0.5% | 0% | 0% |
Orthostatic hypotension | 0.3% | 0.5% | 0% |
Akathisia | 0.3% | 2% | 0% |
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.
Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction 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 risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-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 risperidone-treated patients were:
Adverse Reaction | Risperidone 1 to 6 mg/day (n = 448) | Placebo (n = 424) |
Parkinsonism | 0.4% | 0% |
Lethargy | 0.2% | 0% |
Dizziness | 0.2% | 0% |
Alanine aminotransferase increased | 0.2% | 0.2% |
Aspartate aminotransferase increased | 0.2% | 0.2% |
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (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:
Dose Groups | Placebo | Risperidone 2 mg | Risperidone 6 mg | Risperidone 10 mg | Risperidone 16 mg |
Parkinsonism | 1.2 | 0.9 | 1.8 | 2.4 | 2.6 |
EPS Incidence | 13% | 17% | 21% | 21% | 35% |
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups | Risperidone 1 mg | Risperidone 4 mg | Risperidone 8 mg | Risperidone 12 mg | Risperidone 16 mg |
Parkinsonism | 0.6 | 1.7 | 2.4 | 2.9 | 4.1 |
EPS Incidence | 7% | 12% | 17% | 18% | 20% |
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (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.
Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [
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 risperidone 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 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 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 to 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone 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 to 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.
6.2 Postmarketing ExperienceThe 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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.
Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.
The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [seeBoxed Warningand]Warnings and Precautions(5.1)
- Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see]Warnings and Precautions(5.2)
- Neuroleptic malignant syndrome [see]Warnings and Precautions(5.3)
- Tardive dyskinesia [see]Warnings and Precautions(5.4)
- Metabolic Changes (Hyperglycemia and diabetes mellitus, Dyslipidemia, and Weight Gain) [see]Warnings and Precautions(5.5)
- Hyperprolactinemia [see]Warnings and Precautions(5.6)
- Orthostatic hypotension [see]Warnings and Precautions(5.7)
- Falls []seeWarnings and Precautions(5.8)
- Leukopenia, neutropenia, and agranulocytosis [see]Warnings and Precautions(5.9)
- Potential for cognitive and motor impairment [see]Warnings and Precautions(5.10)
- Seizures [see]Warnings and Precautions(5.11)
- Dysphagia [see]Warnings and Precautions(5.12)
- Priapism [see]Warnings and Precautions(5.13)
- Disruption of body temperature regulation [see]Warnings and Precautions(5.14)
The most common adverse reactions in clinical trials (>5% and twice 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.
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 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone 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.
The most common adverse reactions in clinical trials (≥ 5% and twice 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.
6.1 Clinical Trials ExperienceBecause 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.
Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Percentage of Patients Reporting Reaction | |||
R isperidone | |||
System/Organ Class Adverse Reaction | 2 to 8 mg per day (n = 366) | > 8 to 16 mg per day (n = 198) | Placebo (n = 225) |
Cardiac Disorders | |||
Tachycardia | 1 | 3 | 0 |
Eye Disorders | |||
Vision blurred | 3 | 1 | 1 |
Gastrointestinal Disorders | |||
Nausea | 9 | 4 | 4 |
Constipation | 8 | 9 | 6 |
Dyspepsia | 8 | 6 | 5 |
Dry mouth | 4 | 0 | 1 |
Abdominal discomfort | 3 | 1 | 1 |
Salivary hypersecretion | 2 | 1 | <1 |
Diarrhea | 2 | 1 | 1 |
General Disorders | |||
Fatigue | 3 | 1 | 0 |
Chest pain | 2 | 2 | 1 |
Asthenia | 2 | 1 | <1 |
Infections and Infestations | |||
Nasopharyngitis | 3 | 4 | 3 |
Upper respiratory tract infection | 2 | 3 | 1 |
Sinusitis | 1 | 2 | 1 |
Urinary tract infection | 1 | 3 | 0 |
Investigations | |||
Blood creatine phosphokinase increased | 1 | 2 | <1 |
Heart rate increased | <1 | 2 | 0 |
Musculoskeletal and Connective Tissue Disorders | |||
Back pain | 4 | 1 | 1 |
Arthralgia | 2 | 3 | <1 |
Pain in extremity | 2 | 1 | 1 |
Nervous System Disorders | |||
Parkinsonism* | 14 | 17 | 8 |
Akathisia* | 10 | 10 | 3 |
Sedation | 10 | 5 | 2 |
Dizziness | 7 | 4 | 2 |
Dystonia* | 3 | 4 | 2 |
Tremor* | 2 | 3 | 1 |
Dizziness postural | 2 | 0 | 0 |
Psychiatric Disorders | |||
Insomnia | 32 | 25 | 27 |
Anxiety | 16 | 11 | 11 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Nasal congestion | 4 | 6 | 2 |
Dyspnea | 1 | 2 | 0 |
Epistaxis | <1 | 2 | 0 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 1 | 4 | 1 |
Dry skin | 1 | 3 | 0 |
Vascular Disorders | |||
Orthostatic hypotension | 2 | 1 | 0 |
*Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 1 to 3 mg per day (n = 55) | 4 to 6 mg per day (n = 51) | Placebo (n = 54) |
Gastrointestinal Disorders | |||
Salivary hypersecretion | 0 | 10 | 2 |
Nervous System Disorders | |||
Sedation | 24 | 12 | 4 |
Parkinsonism* | 16 | 28 | 11 |
Tremor | 11 | 10 | 6 |
Akathisia* | 9 | 10 | 4 |
Dizziness | 7 | 14 | 2 |
Dystonia* | 2 | 6 | 0 |
Psychiatric Disorders | |||
Anxiety | 7 | 6 | 0 |
* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.
Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 1 to 6 mg per day (n = 448) | Placebo (n = 424) |
Eye Disorders | ||
Vision blurred | 2 | 1 |
Gastrointestinal Disorders | ||
Nausea | 5 | 2 |
Diarrhea | 3 | 2 |
Salivary hypersecretion | 3 | 1 |
Stomach discomfort | 2 | <1 |
General Disorders | ||
Fatigue | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 25 | 9 |
Sedation | 11 | 4 |
Akathisia* | 9 | 3 |
Tremor* | 6 | 3 |
Dizziness | 6 | 5 |
Dystonia* | 5 | 1 |
Lethargy | 2 | 1 |
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.
Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone + Mood Stabilizer (n = 127) | Placebo + Mood Stabilizer (n = 126) |
Cardiac Disorders | ||
Palpitations | 2 | 0 |
Gastrointestinal Disorders | ||
Dyspepsia | 9 | 8 |
Nausea | 6 | 4 |
Diarrhea | 6 | 4 |
Salivary hypersecretion | 2 | 0 |
General Disorders | ||
Chest pain | 2 | 1 |
Infections and Infestations | ||
Urinary tract infection | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 14 | 4 |
Sedation | 9 | 4 |
Akathisia* | 8 | 0 |
Dizziness | 7 | 2 |
Tremor | 6 | 2 |
Lethargy | 2 | 1 |
Psychiatric Disorders | ||
Anxiety | 3 | 2 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Pharyngolaryngeal pain | 5 | 2 |
Cough | 2 | 0 |
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.
Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 0.5 to 2.5 mg per day (n = 50) | 3 to 6 mg per day (n = 61) | Placebo (n = 58) |
Eye Disorders | |||
Vision blurred | 4 | 7 | 0 |
Gastrointestinal Disorders | |||
Abdominal pain upper | 16 | 13 | 5 |
Nausea | 16 | 13 | 7 |
Vomiting | 10 | 10 | 5 |
Diarrhea | 8 | 7 | 2 |
Dyspepsia | 10 | 3 | 2 |
Stomach discomfort | 6 | 0 | 2 |
General Disorders | |||
Fatigue | 18 | 30 | 3 |
Metabolism and Nutrition Disorders | |||
Increased appetite | 4 | 7 | 2 |
Nervous System Disorders | |||
Sedation | 42 | 56 | 19 |
Dizziness | 16 | 13 | 5 |
Parkinsonism* | 6 | 12 | 3 |
Dystonia* | 6 | 5 | 0 |
Akathisia* | 0 | 8 | 2 |
Psychiatric Disorders | |||
Anxiety | 0 | 8 | 3 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Pharyngolaryngeal pain | 10 | 3 | 5 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 0 | 7 | 2 |
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 0.5 to 4 mg/day (n = 107) | Placebo (n = 115) |
Gastrointestinal Disorders | ||
Vomiting | 20 | 17 |
Constipation | 17 | 6 |
Dry mouth | 10 | 4 |
Nausea | 8 | 5 |
Salivary hypersecretion | 7 | 1 |
General Disorders and Administration Site Conditions | ||
Fatigue | 31 | 9 |
Pyrexia | 16 | 13 |
Thirst | 7 | 4 |
Infections and Infestations | ||
Nasopharyngitis | 19 | 9 |
Rhinitis | 9 | 7 |
Upper respiratory tract infection | 8 | 3 |
Investigations | ||
Weight increased | 8 | 2 |
Metabolism and Nutrition Disorders | ||
Increased appetite | 44 | 15 |
Nervous System Disorders | ||
Sedation | 63 | 15 |
Drooling | 12 | 4 |
Headache | 12 | 10 |
Tremor | 8 | 1 |
Dizziness | 8 | 2 |
Parkinsonism* | 8 | 1 |
Renal and Urinary Disorders | ||
Enuresis | 16 | 10 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Cough | 17 | 12 |
Rhinorrhea | 12 | 10 |
Nasal congestion | 10 | 4 |
Skin and Subcutaneous Tissue Disorders | ||
Rash | 8 | 5 |
*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.
The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, 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: ear pain, 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, feeling abnormal
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: decreased appetite, polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint stiffness, 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, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, 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, acne, hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were:
Risperidone | |||
Adverse Reaction | 2 to 8 mg/day (n = 366) | > 8 to 16 mg/day (n = 198) | Placebo (n = 225) |
Dizziness | 1.4% | 1% | 0% |
Nausea | 1.4% | 0% | 0% |
Vomiting | 0.8% | 0% | 0% |
Parkinsonism | 0.8% | 0% | 0% |
Somnolence | 0.8% | 0% | 0% |
Dystonia | 0.5% | 0% | 0% |
Agitation | 0.5% | 0% | 0% |
Abdominal pain | 0.5% | 0% | 0% |
Orthostatic hypotension | 0.3% | 0.5% | 0% |
Akathisia | 0.3% | 2% | 0% |
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.
Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction 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 risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-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 risperidone-treated patients were:
Adverse Reaction | Risperidone 1 to 6 mg/day (n = 448) | Placebo (n = 424) |
Parkinsonism | 0.4% | 0% |
Lethargy | 0.2% | 0% |
Dizziness | 0.2% | 0% |
Alanine aminotransferase increased | 0.2% | 0.2% |
Aspartate aminotransferase increased | 0.2% | 0.2% |
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (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:
Dose Groups | Placebo | Risperidone 2 mg | Risperidone 6 mg | Risperidone 10 mg | Risperidone 16 mg |
Parkinsonism | 1.2 | 0.9 | 1.8 | 2.4 | 2.6 |
EPS Incidence | 13% | 17% | 21% | 21% | 35% |
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups | Risperidone 1 mg | Risperidone 4 mg | Risperidone 8 mg | Risperidone 12 mg | Risperidone 16 mg |
Parkinsonism | 0.6 | 1.7 | 2.4 | 2.9 | 4.1 |
EPS Incidence | 7% | 12% | 17% | 18% | 20% |
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (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.
Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [
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 risperidone 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 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 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 to 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone 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 to 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.
6.2 Postmarketing ExperienceThe 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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication.
Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.
6.1 Clinical Trials ExperienceBecause 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.
Table 8 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Percentage of Patients Reporting Reaction | |||
R isperidone | |||
System/Organ Class Adverse Reaction | 2 to 8 mg per day (n = 366) | > 8 to 16 mg per day (n = 198) | Placebo (n = 225) |
Cardiac Disorders | |||
Tachycardia | 1 | 3 | 0 |
Eye Disorders | |||
Vision blurred | 3 | 1 | 1 |
Gastrointestinal Disorders | |||
Nausea | 9 | 4 | 4 |
Constipation | 8 | 9 | 6 |
Dyspepsia | 8 | 6 | 5 |
Dry mouth | 4 | 0 | 1 |
Abdominal discomfort | 3 | 1 | 1 |
Salivary hypersecretion | 2 | 1 | <1 |
Diarrhea | 2 | 1 | 1 |
General Disorders | |||
Fatigue | 3 | 1 | 0 |
Chest pain | 2 | 2 | 1 |
Asthenia | 2 | 1 | <1 |
Infections and Infestations | |||
Nasopharyngitis | 3 | 4 | 3 |
Upper respiratory tract infection | 2 | 3 | 1 |
Sinusitis | 1 | 2 | 1 |
Urinary tract infection | 1 | 3 | 0 |
Investigations | |||
Blood creatine phosphokinase increased | 1 | 2 | <1 |
Heart rate increased | <1 | 2 | 0 |
Musculoskeletal and Connective Tissue Disorders | |||
Back pain | 4 | 1 | 1 |
Arthralgia | 2 | 3 | <1 |
Pain in extremity | 2 | 1 | 1 |
Nervous System Disorders | |||
Parkinsonism* | 14 | 17 | 8 |
Akathisia* | 10 | 10 | 3 |
Sedation | 10 | 5 | 2 |
Dizziness | 7 | 4 | 2 |
Dystonia* | 3 | 4 | 2 |
Tremor* | 2 | 3 | 1 |
Dizziness postural | 2 | 0 | 0 |
Psychiatric Disorders | |||
Insomnia | 32 | 25 | 27 |
Anxiety | 16 | 11 | 11 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Nasal congestion | 4 | 6 | 2 |
Dyspnea | 1 | 2 | 0 |
Epistaxis | <1 | 2 | 0 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 1 | 4 | 1 |
Dry skin | 1 | 3 | 0 |
Vascular Disorders | |||
Orthostatic hypotension | 2 | 1 | 0 |
*Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tremor.
Table 9 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 1 to 3 mg per day (n = 55) | 4 to 6 mg per day (n = 51) | Placebo (n = 54) |
Gastrointestinal Disorders | |||
Salivary hypersecretion | 0 | 10 | 2 |
Nervous System Disorders | |||
Sedation | 24 | 12 | 4 |
Parkinsonism* | 16 | 28 | 11 |
Tremor | 11 | 10 | 6 |
Akathisia* | 9 | 10 | 4 |
Dizziness | 7 | 14 | 2 |
Dystonia* | 2 | 6 | 0 |
Psychiatric Disorders | |||
Anxiety | 7 | 6 | 0 |
* Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.
Table 10 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 1 to 6 mg per day (n = 448) | Placebo (n = 424) |
Eye Disorders | ||
Vision blurred | 2 | 1 |
Gastrointestinal Disorders | ||
Nausea | 5 | 2 |
Diarrhea | 3 | 2 |
Salivary hypersecretion | 3 | 1 |
Stomach discomfort | 2 | <1 |
General Disorders | ||
Fatigue | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 25 | 9 |
Sedation | 11 | 4 |
Akathisia* | 9 | 3 |
Tremor* | 6 | 3 |
Dizziness | 6 | 5 |
Dystonia* | 5 | 1 |
Lethargy | 2 | 1 |
* Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis.
Table 11 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone + Mood Stabilizer (n = 127) | Placebo + Mood Stabilizer (n = 126) |
Cardiac Disorders | ||
Palpitations | 2 | 0 |
Gastrointestinal Disorders | ||
Dyspepsia | 9 | 8 |
Nausea | 6 | 4 |
Diarrhea | 6 | 4 |
Salivary hypersecretion | 2 | 0 |
General Disorders | ||
Chest pain | 2 | 1 |
Infections and Infestations | ||
Urinary tract infection | 2 | 1 |
Nervous System Disorders | ||
Parkinsonism* | 14 | 4 |
Sedation | 9 | 4 |
Akathisia* | 8 | 0 |
Dizziness | 7 | 2 |
Tremor | 6 | 2 |
Lethargy | 2 | 1 |
Psychiatric Disorders | ||
Anxiety | 3 | 2 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Pharyngolaryngeal pain | 5 | 2 |
Cough | 2 | 0 |
* Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia.
Table 12 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial.
Percentage of Patients Reporting Reaction | |||
Risperidone | |||
System/Organ Class Adverse Reaction | 0.5 to 2.5 mg per day (n = 50) | 3 to 6 mg per day (n = 61) | Placebo (n = 58) |
Eye Disorders | |||
Vision blurred | 4 | 7 | 0 |
Gastrointestinal Disorders | |||
Abdominal pain upper | 16 | 13 | 5 |
Nausea | 16 | 13 | 7 |
Vomiting | 10 | 10 | 5 |
Diarrhea | 8 | 7 | 2 |
Dyspepsia | 10 | 3 | 2 |
Stomach discomfort | 6 | 0 | 2 |
General Disorders | |||
Fatigue | 18 | 30 | 3 |
Metabolism and Nutrition Disorders | |||
Increased appetite | 4 | 7 | 2 |
Nervous System Disorders | |||
Sedation | 42 | 56 | 19 |
Dizziness | 16 | 13 | 5 |
Parkinsonism* | 6 | 12 | 3 |
Dystonia* | 6 | 5 | 0 |
Akathisia* | 0 | 8 | 2 |
Psychiatric Disorders | |||
Anxiety | 0 | 8 | 3 |
Respiratory, Thoracic and Mediastinal Disorders | |||
Pharyngolaryngeal pain | 10 | 3 | 5 |
Skin and Subcutaneous Tissue Disorders | |||
Rash | 0 | 7 | 2 |
* Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia.
Table 13 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials and one 6-week double-blind, placebo-controlled study.
Percentage of Patients Reporting Reaction | ||
System/Organ Class Adverse Reaction | Risperidone 0.5 to 4 mg/day (n = 107) | Placebo (n = 115) |
Gastrointestinal Disorders | ||
Vomiting | 20 | 17 |
Constipation | 17 | 6 |
Dry mouth | 10 | 4 |
Nausea | 8 | 5 |
Salivary hypersecretion | 7 | 1 |
General Disorders and Administration Site Conditions | ||
Fatigue | 31 | 9 |
Pyrexia | 16 | 13 |
Thirst | 7 | 4 |
Infections and Infestations | ||
Nasopharyngitis | 19 | 9 |
Rhinitis | 9 | 7 |
Upper respiratory tract infection | 8 | 3 |
Investigations | ||
Weight increased | 8 | 2 |
Metabolism and Nutrition Disorders | ||
Increased appetite | 44 | 15 |
Nervous System Disorders | ||
Sedation | 63 | 15 |
Drooling | 12 | 4 |
Headache | 12 | 10 |
Tremor | 8 | 1 |
Dizziness | 8 | 2 |
Parkinsonism* | 8 | 1 |
Renal and Urinary Disorders | ||
Enuresis | 16 | 10 |
Respiratory, Thoracic and Mediastinal Disorders | ||
Cough | 17 | 12 |
Rhinorrhea | 12 | 10 |
Nasal congestion | 10 | 4 |
Skin and Subcutaneous Tissue Disorders | ||
Rash | 8 | 5 |
*Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness.
The following additional adverse reactions occurred across all placebo-controlled, active-controlled, and open-label studies of risperidone in adults and pediatric patients.
Blood and Lymphatic System Disorders: anemia, 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: ear pain, 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, feeling abnormal
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: decreased appetite, polydipsia, anorexia
Musculoskeletal and Connective Tissue Disorders: joint stiffness, 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, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation
Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, and anorgasmia
Renal and Urinary Disorders: enuresis, dysuria, pollakiuria, urinary incontinence
Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, galactorrhea, 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, acne, hyperkeratosis, seborrheic dermatitis
Vascular Disorders: hypotension, flushing
Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were:
Risperidone | |||
Adverse Reaction | 2 to 8 mg/day (n = 366) | > 8 to 16 mg/day (n = 198) | Placebo (n = 225) |
Dizziness | 1.4% | 1% | 0% |
Nausea | 1.4% | 0% | 0% |
Vomiting | 0.8% | 0% | 0% |
Parkinsonism | 0.8% | 0% | 0% |
Somnolence | 0.8% | 0% | 0% |
Dystonia | 0.5% | 0% | 0% |
Agitation | 0.5% | 0% | 0% |
Abdominal pain | 0.5% | 0% | 0% |
Orthostatic hypotension | 0.3% | 0.5% | 0% |
Akathisia | 0.3% | 2% | 0% |
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.
Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse reaction 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 risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%).
In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-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 risperidone-treated patients were:
Adverse Reaction | Risperidone 1 to 6 mg/day (n = 448) | Placebo (n = 424) |
Parkinsonism | 0.4% | 0% |
Lethargy | 0.2% | 0% |
Dizziness | 0.2% | 0% |
Alanine aminotransferase increased | 0.2% | 0.2% |
Aspartate aminotransferase increased | 0.2% | 0.2% |
In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse reaction, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%).
In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event.
Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment.
Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (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:
Dose Groups | Placebo | Risperidone 2 mg | Risperidone 6 mg | Risperidone 10 mg | Risperidone 16 mg |
Parkinsonism | 1.2 | 0.9 | 1.8 | 2.4 | 2.6 |
EPS Incidence | 13% | 17% | 21% | 21% | 35% |
Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day):
Dose Groups | Risperidone 1 mg | Risperidone 4 mg | Risperidone 8 mg | Risperidone 12 mg | Risperidone 16 mg |
Parkinsonism | 0.6 | 1.7 | 2.4 | 2.9 | 4.1 |
EPS Incidence | 7% | 12% | 17% | 18% | 20% |
Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (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.
Weight gain was observed in short-term, controlled trials and longer-term uncontrolled studies in adult and pediatric patients [
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 risperidone 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 to 16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4 to 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 to 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone 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 to 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 to 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.
The data described in this section are derived from a clinical trial database consisting of 9803 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9803 patients, 2687 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone 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.
Risperidone oral solution contains risperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- 1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C23H27FN4O2 and its molecular weight is 410.49. The structural formula is:
Risperidone is a white to slightly beige powder. It is practically insoluble in water, freely soluble in methylene chloride, and soluble in methanol and 0.1
Risperidone is also available as a 1 mg/mL oral solution. Risperidone Oral Solution contains the following inactive ingredients: benzoic acid, sodium hydroxide, sorbitol solution, tartaric acid, and purified water.