The following are discussed in more detail in other sections of the labeling:
- Increased mortality in elderly patients with dementia-related psychosis [see
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)]
- Hyperglycemia and diabetes mellitus [see
Warnings and Precautions (5.5)]
- Hyperprolactinemia [see
Warnings and Precautions (5.6)]
- Orthostatic hypotension [see
Warnings and Precautions (5.7)]
- Potential for cognitive and motor impairment [see
Warnings and Precautions (5.8)]
- Seizures [see
Warnings and Precautions (5.9)]
- Dysphagia [see
Warnings and Precautions (5.10)]
- Priapism [see
Warnings and Precautions (5.11)]
- Thrombotic Thrombocytopenic Purpura (TTP) [see
Warnings and Precautions (5.12)]
- Disruption of body temperature regulation [see
Warnings and Precautions (5.13)]
- Antiemetic effect [see
Warnings and Precautions (5.14)]
- Suicide [see
Warnings and Precautions (5.15)]
- Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see
Warnings and Precautions (5.16)]
- Diseases or conditions that could affect metabolism or hemodynamic responses [see
Warnings and Precautions (5.16)]
The most common adverse reactions in clinical trials (less then 10%) were somnolence, appetite increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain, anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in less then 1% of adults and/or less then 2% of pediatrics) were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia [see
Adverse Reactions (6.5)
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 risperidone for the treatment of schizophrenia, bipolar mania, or autistic disorder and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 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.
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 WHOART terminology.
Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of risperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for risperidone 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.
6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical TrialsSchizophreniaAdult Patients with Schizophrenia
Table 1 lists the adverse reactions reported in 1% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials.
Table 1. Adverse Reactions in less then 1% of Risperidone-Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials
Percentage of Patients Reporting Event RisperidoneBody System2-8 mg per day>8-16mg per day PlaceboAdverse Reaction(N=366)(N=198)(N=225)Body as a whole - general disordersBack pain32greater then 1Fatigue310Chest pain312Fever211Asthenia11greater then 1SyncopeLess then 11greater then 1Edemaless then 110Cardiovascular disorders, generalHypotension postural2greater then 10Hypotensiongreater then 110Central and peripheral nervous system disordersParkinsonism*12176Dizziness1042Dystonia*552Akathisia*552Dyskinesia11greater then 1Gastrointestinal system disordersDyspepsia1076Nausea944Constipation897Abdominal pain430Mouth dry4less then 1greater then 1Saliva increased31greater then 1Diarrhea2less then 11Hearing and vestibular disordersEarache110Heart rate and rhythm disordersTachycardia250Arrhythmia010Metabolic and nutritional disordersWeight increase1less then 10Creatine phosphokinase increasedgreater then 12greater then 1Musculoskeletal system disordersArthralgia23greater then 1Myalgia100Platelet, bleeding and clotting disordersEpistaxisgreater then 120Psychiatric disordersAnxiety161211Somnolence1454Anorexia20greater then 1Red blood cell disordersAnemiagreater then 110Reproductive disorders, maleEjaculation failuregreater then 110Respiratory system disordersRhinitis7116Coughing333Upper respiratory tract infection23greater then 1Dyspnea220Skin and appendages disordersRash242Seborrheagreater then 120Urinary system disordersUrinary tract infectiongreater then 130Vision disordersVision abnormal31greater then 1* Parkinsonism includes extrapyramidal disorder, hypokinesia, and bradycardia. Dystonia includes dystonia, hypertonia, oculogyric crisis, muscle contractions involuntary, tetany, laryngismus, tongue paralysis, and torticollis. Akathisia includes hyperkinesia and akathisia.
Pediatric Patients with Schizophrenia
6.4 Other Adverse Reactions Observed During the Premarketing Evaluation of Risperidone
The following adverse reactions occurred in greater then 1% of the adult patients and in greater then 5% of the pediatric patients treated with risperidone in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in risperidone-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.
Body as a Whole, General Disorders: edema peripheral, pain, influenza-like symptoms, leg pain, malaise, allergy, crying abnormal, allergic reaction, rigors, allergy aggravated, anaphylactoid reaction, hypothermia
Central Nervous System Disorders: gait abnormal, speech disorder, coma, ataxia, dysphonia, stupor, cramps legs, vertigo, hypoesthesia, tardive dyskinesia, neuroleptic malignant syndrome
Endocrine Disorders: hyperprolactinemia, gynecomastia
Gastrointestinal System Disorders: dysphagia, flatulence
Heart Rate and Rhythm Disorders: AV block, bundle branch block
Liver and Biliary Disorders: SGPT increased, hepatic enzymes increased
Metabolic and Nutritional Disorders: thirst, hyperglycemia, xerophthalmia, generalized edema, diabetes mellitus aggravated, diabetic coma
Musculoskeletal Disorders: muscle weakness, rhabdomyolysis
Platelet, Bleeding, and Clotting Disorders: purpura
Psychiatric Disorders: insomnia, agitation, emotional lability, apathy, nervousness, concentration impaired, impotence, decreased libido
Reproductive Disorders, Female: amenorrhea, menstrual disorder, leukorrhea
Reproductive Disorders, Male: ejaculation disorder, abnormal sexual function, priapism
Resistance Mechanism Disorders: otitis media, viral infection
Respiratory Disorders: respiratory disorder
Skin and Appendages Disorders: skin ulceration, skin discoloration, rash erythematous, skinexfoliation, rash maculopapular, erythema multiforme
Urinary Disorders: micturition frequency
Vascular Disorders: cerebrovascular disorder
Vision Disorders: conjunctivitis
White Cell Disorders: leucopenia, granulocytopenia
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 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 (pless then 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.
6.7 Changes in Body Weight
The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of less then 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 risperidone (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 less then 7% at endpoint was comparable in the risperidone (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 (8.4)
6.8 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 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 (8-16 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.
Due to Janssen Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled for use in pediatric patients with schizophrenia, bipolar mania or autistic disorder. Information regarding changes in ECG during the treatment of pediatric patients with schizophrenia, 13 to 17 years of age, the treatment of pediatric patients with bipolar mania, 10 to 17 years of age, and the treatment of pediatric patients with irritability associated with autistic disorder, 5 to 16 years of age, is approved for Janssen Pharmaceuticals Corporation's risperidone drug products
6.9 Postmarketing Experience
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.