pms-Risperidone

pms-Risperidone Adverse Reactions

risperidone

Manufacturer:

Pharmascience

Distributor:

T-BOMA
Full Prescribing Info
Adverse Reactions
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Schizophrenia and Related Psychotic Disorders: Adverse Events Associated with Discontinuation of Treatment: An estimated 9% of approximately 1,800 patients who received risperidone in controlled clinical trials discontinued treatment due to adverse reactions. The more common events causing discontinuation included: Psychiatric (4.1%): primarily psychosis, agitation, suicide attempt, somnolence; Neurological (3.2%): primarily extrapyramidal disorder, dizziness; Cardiovascular (1.2%): primarily hypotension. Other events leading to discontinuation included: tachycardia/palpitations (0.6%), nervousness (0.4%), nausea (0.3%) and insomnia (0.3%).
Commonly Observed Adverse Events in Short-term Clinical Trials: The most frequent adverse reactions reported during clinical trials with risperidone were insomnia, agitation, extrapyramidal disorder, anxiety, headache and rhinitis (see Table 8 and Table 9). In some instances, it has been difficult to differentiate adverse events from symptoms of the underlying psychosis.
Serious Adverse Events: The most serious adverse reactions reported were rare cases of syncope, cardiac arrhythmias, first degree AV-block, and seizures.
Extrapyramidal Symptoms: Parkinsonian side effects reported were usually mild, but dose related; they were reversible upon dose reduction and/or administration of antiparkinsonian medication.
Vital Sign Changes: Hypotension (including orthostatic) and tachycardia (including reflex tachycardia) have been observed following the administration of risperidone (see Cardiovascular under Precautions).
ECG Changes: Electrocardiograms were evaluated in patients treated with risperidone (N=380), haloperidol (N=126) and placebo (N=120). In the risperidone group, eight patients had a slight increase in QTc intervals from less than 450 msec at baseline to intervals ranging from 450 to 474 msec during treatment. Changes of this type were not seen in placebo-treated patients but were observed in three haloperidol-treated subjects.
Hyperprolactinemia: Risperidone elevated plasma prolactin levels. Associated manifestations, namely amenorrhea, galactorrhea, and menorrhagia, have occurred.
In controlled clinical trials prolactin levels were higher in patients treated with risperidone than in haloperidol-treated patients; however, the incidence of solicited adverse events considered to be possibly prolactin-related in patients treated with risperidone (≤ 10 mg per day) was low (< 6%), and similar to that in haloperidol-treated patients. (See Table 7.)

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Weight Gain: In a pool of 6- to 8-week placebo-controlled clinical trials, which compared risperidone and placebo in the treatment of schizophrenia, 18% of patients treated with risperidone and 9% of placebo-treated patients met a weight gain criterion of ≥ 7% of baseline body weight. This difference was statistically significant. With continued treatment, weight gain (mean: 2.3 kg in long-term studies) has been seen.
Other Adverse Events: Erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, and rash have also been reported during treatment with risperidone. As with other antipsychotics, cases of water intoxication, either due to polydipsia or to syndrome of inappropriate secretion of antidiuretic hormone (SIADH), have occasionally been reported during treatment with risperidone.
Adverse Events in North American Studies: Table 8 enumerates adverse events that occurred at an incidence of 1% or more, and were at least as frequent among patients treated with risperidone receiving doses of ≤ 10 mg/day as among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials. Patients received risperidone at fixed doses of 2, 6, 10, or 16 mg/day in the dose comparison trial, or up to a maximum dose of 10 mg/day in the flexible dose study. Table 8 shows the percentage of patients in each dose group (≤ 10 mg/day or 16 mg/day) who spontaneously reported at least one episode of an event at some time during their treatment. Patients given doses of 2, 6, or 10 mg did not differ substantially in these rates. Reported adverse events were classified using the World Health Organization preferred terms. (See Table 8.)

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Adverse Events in All International Trials: Table 9 lists the overall incidence of adverse reactions noted for all international controlled clinical trials including the North American trials. Some adverse events were reported at a higher incidence in the North American trials than appear in Table 8, due to differences in reporting practices and/or methodology. (See Table 9.)

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Adverse Reactions During Long-Term Treatment: Long-term clinical trials with risperidone were carried out in 1,235 chronic schizophrenic patients, with 671 patients receiving the drug for at least one year. The pattern of adverse events observed in patients receiving risperidone in long-term clinical trials is consistent with those observed in short-term trials.
Adverse events were collected through spontaneous reporting, open questioning or utilization of the UKU side effect rating scale. Listed (in decreasing order) are those events which developed or showed deterioration during treatment compared to baseline in at least 10% of patients.
Psychic: asthenia/lassitude/increased fatigability, concentration difficulties, sleepiness/sedation, reduced duration of sleep, increased duration of sleep, failing memory, increased dream activity, insomnia.
Autonomic: orthostatic dizziness, constipation, nausea/vomiting, polyuria/polydipsia, palpitations/tachycardia, reduced salivation, accommodation disturbances, increased tendency to sweating, diarrhea, micturition disturbances.
Other: weight gain, weight loss, amenorrhea, ejaculatory dysfunction, erectile dysfunction, diminished sexual desire, tension headache, headache, increased sexual desire, orgastic dysfunction, pruritus.
Elderly Patients with Severe Dementia: Adverse Events Associated with Discontinuation of Treatment: In the fixed-dose, dose-response study, 95/617 patients discontinued treatment due to an adverse event. The most frequently reported adverse events were somnolence, extrapyramidal symptoms (EPS), and agitation, with somnolence and EPS being dose-related. (See Table 10.)

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Incidence of Adverse Events: Table 11 enumerates adverse events from the fixed-dose, dose-response study that were more frequent in the risperidone groups than in the placebo group and/or were dose-related. (See Table 11.)

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Other adverse events which occurred in this study with a high incidence but with similar frequencies in the patients treated with risperidone and placebo included injury (28 to 38%), falls (13 to 25%), urinary tract infection (13 to 21%), and purpura (10 to 17%).
In addition, the following adverse drug reactions were reported in six 4- to 12-week, double-blind, placebo-controlled trials in elderly patients with dementia at a frequency ≥ 5% and at least twice the frequency seen in other adult populations: urinary tract infection, peripheral edema, lethargy, and cough.
Cerebrovascular Adverse Events (CVAEs) in Elderly Patients with Dementia: In 6 placebo-controlled dementia trials for elderly patients taking risperidone for 4 to 12 weeks within the approved dosage range, the pooled incidence rate of CVAEs was 3%, compared to 1% for age-matched patients taking placebo. Five patients died in the risperidone group (5/1,009) versus 1 patient in the placebo group (1/712) (see Adults: Severe Dementia of the Alzheimer type - Symptomatic management of aggression and psychotic symptoms under Indications/Uses; Recommended Dose and Dosage Adjustment: Adults: Severe Dementia of the Alzheimer Type under Dosage & Administration; Use in Elderly: Use in Geriatric Patients with Dementia under Precautions).
Bipolar Disorder - Mania: Adverse Events Associated with Discontinuation of Treatment: In the 3-week placebo-controlled trials, a total of 4.2% of patients discontinued from the studies because of an adverse event: 4.1% for placebo, 4.8% for risperidone and 2.8% for haloperidol. The most common adverse event leading to discontinuation was manic reaction: 1.0% for placebo and 1.6% for risperidone.
Incidence of Adverse Events: In the 3-week placebo-controlled trials, in which patients received dosages of 1 - 6 mg/day risperidone, the most commonly observed adverse events associated with the use of risperidone (incidence of ≥ 5% and at least twice placebo) included extrapyramidal disorder, hyperkinesia, dystonia and somnolence. Adverse events that occurred in these trials with an incidence of ≥ 1% and more frequently in patients treated with risperidone than placebo are shown in Table 12. (See Table 12.)

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Suicide: In the 3-week double-blind phase of controlled clinical trials, suicide-related adverse events occurred at an incidence of 0.45% for patients treated with risperidone (2 patients/448) compared to 0 for patients treated with placebo (0 patients/424). Suicide attempt and completed suicide occurred in one patient each.
The incidence of suicide-related adverse events was 0.67% (3 patients/446) during 9 weeks of open-label risperidone treatment. Suicide attempts were reported for two patients and completed suicide occurred in one patient.
Hyperprolactinemia: In controlled clinical trials, patients treated with risperidone had higher prolactin levels than patients treated with placebo or haloperidol. Associated manifestations that occurred in fewer than 1% of patients treated with risperidone during the bipolar clinical trials, which are not listed in Table 12, included ejaculation failure, abnormal sexual function, decreased libido, and impotence.
Extrapyramidal symptoms in bipolar disorder clinical trials: Adverse events related to extrapyramidal symptoms (EPS) were reported more frequently in all clinical trials for bipolar disorder than schizophrenia, regardless of study population demographics, and this may be consistent with a greater susceptibility to EPS-related adverse reactions in bipolar patients that has been observed in clinical practice. The lower mean body weight and body mass index (BMI) of an Indian study population (RIS-IND-2) and a higher mean risperidone dose may have contributed to a higher incidence of EPS-related AEs in this trial (45%, mean modal dose 5.6 mg/day; mean modal dose is the average of individual subjects' most frequent daily dose) compared to the U.S. (36.6%, mean modal dose 4.0 mg/day) and international (31.2%, mean modal dose 4.2 mg/day) trials. EPS-related adverse events in all studies were usually mild, dose-related and reversible upon dose reduction and/or administration of antiparkinsonian medication.
Abnormal Hematologic and Clinical Chemistry Findings: In one study in which testosterone levels were measured, testosterone decreased below the normal range in 6 out of 85 patients.
Other Clinical Trial Adverse Drug Reactions Reported with Paliperidone and Risperidone: Paliperidone is the active metabolite of risperidone. Therefore, the adverse reaction profiles of both the oral and injectable formulations of paliperidone are relevant to one another and, also, to risperidone. In addition to the previously mentioned adverse reactions, the following adverse reactions, classified using MedDRA terminology, have been noted with the use of paliperidone and/or risperidone products and can be expected to occur with both the oral and injectable formulations of risperidone. The following ADRs were reported with risperidone and/or paliperidone by < 1% of risperidone-treated subjects in the pooled clinical trial database.
Infections and infestations: Acarodermatitis, Bronchitis, Cystitis, Ear infection, Eye infection, Infection, Localized infection, Onychomycosis, Respiratory tract infection, Tonsillitis, Viral infection.
Blood and lymphatic system disorders: Eosinophil count increased, Haematocrit decreased, Neutropenia, White blood cell count decreased.
Endocrine disorders: Glucose urine present, Hyperprolactinemia.
Metabolism and nutrition disorders: Anorexia, Blood cholesterol increased, Blood triglycerides increased, Hyperglycemia, Polydipsia, Weight decreased.
Psychiatric disorders: Blunted affect, Depression, Libido decreased, Nightmare, Sleep disorder.
Nervous system disorders: Cerebrovascular disorder, Convulsion (includes Grand mal convulsion), Coordination abnormal, Diabetic coma, Hypoesthesia, Loss of consciousness, Paresthesia, Psychomotor hyperactivity, Tardive dyskinesia, Unresponsive to stimuli.
Eye disorders: Dry eye, Eye rolling, Eyelid margin crusting, Glaucoma, Lacrimation increased, Ocular hyperaemia.
Ear and labyrinth disorders: Tinnitus, Vertigo.
Cardiac disorders: Atrioventricular block, Bradycardia, Conduction disorder, Electrocardiogram abnormal, Electrocardiogram QT prolonged, Sinus arrhythmia.
Vascular disorders: Flushing.
Respiratory, thoracic and mediastinal disorders: Dysphonia, Hyperventilation, Pneumonia aspiration, Rales, Respiratory disorder, Respiratory tract congestion, Wheezing.
Gastrointestinal disorders: Cheilitis, Fecal incontinence, Flatulence, Gastroenteritis, Swollen tongue.
Hepatobiliary disorders: Gamma-glutamyltransferase increased, Hepatic enzyme increased, Transaminases increased.
Skin and subcutaneous tissue disorders: Eczema, Skin discolouration, Skin disorder, Skin lesion.
Musculoskeletal and connective tissue disorders: Joint stiffness, Muscular weakness, Rhabdomyolysis.
Renal and urinary disorders: Dysuria.
Reproductive system and breast disorders: Amenorrhea, Breast discharge, Ejaculation disorder, Gynecomastia, Menstrual disorder (includes Menstruation irregular, Oligomenorrhea), Sexual dysfunction, Vaginal discharge.
General disorders and administration site conditions: Body temperature decreased, Chills, Discomfort, Drug withdrawal syndrome, Face edema, Malaise, Peripheral coldness, Thirst.
Injury, poisoning and procedural complications: Procedural pain.
Post-Market Adverse Drug Reactions: Adverse events first identified during post-market experience with risperidone are included in Table 13. In Table 13, ADRs are presented by frequency category based on spontaneous reporting rates according to the following convention: Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000, including isolated reports; Not known (cannot be estimated from the available data). (See Table 13.)

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Adverse events reported since market introduction of risperidone, which were temporally (but not necessarily causally) related to risperidone therapy, include the following: angioedema, skin manifestations of allergy including cases of Stevens-Johnson syndrome, systemic manifestations of allergy including a case of anaphylactic shock, neuroleptic malignant syndrome, body temperature dysregulation, apnea, atrial fibrillation, benign pituitary adenomas, intestinal obstruction, Parkinson's disease aggravated, and cerebrovascular adverse events, such as strokes (cerebrovascular accident), and transient ischemic attacks, including some fatalities.
Hyperglycemia and exacerbation of pre-existing diabetes have been reported during risperidone treatment (see Endocrine and Metabolism: Hyperglycemia and Diabetes Mellitus under Precautions).
As with other neuroleptics, sudden death, torsades de pointes, ventricular tachycardia, arrhythmia, cardiopulmonary arrest and QT prolongation have been reported during risperidone treatment. Many of the patients had pre-existing cardiovascular disease, were on concomitant medications known to prolong the QT interval, had risk factors for QT prolongation, took an overdose of risperidone, and/or were morbidly obese. Very rarely, QT prolongation has been reported in the absence of confounding factors.
Significant weight gain has been reported in both clinical trials and post-marketing (see Endocrine and Metabolism: Weight Gain under Precautions).
In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Granulocytopenia and agranulocytosis have also been reported (see Hematologic: Leukopenia, Neutropenia, and Agranulocytosis Class Effect under Precautions).
In post-marketing experience, drug withdrawal syndrome neonatal has been reported very rarely.
Atypical antipsychotic drugs, such as risperidone, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of, or that are at risk of, sleep apnea, pms-RISPERIDONE should be prescribed with caution.
Risks of somnambulism (sleep walking) and sleep-related eating disorder have been associated with the use of atypical antipsychotics including pms-RISPERIDONE.
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