Risperidone side effects

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Contents

* 1 List of side effects
* 1.1 Overview
* 1.2 Associated with discontinuation of treatment
* 1.2.1 Schizophrenia (discontinuation)
* 1.2.2 Bipolar mania (discontinuation)
* 1.3 Commonly observed in controlled clinical trials
* 1.3.1 Schizophrenia (common)
* 1.3.2 Bipolar mania (common)
* 1.4 Incidence of 1% or more (schizophrenia)
* 1.5 Incidence of 2% or more (bipolar mania)
* 1.5.1 Monotherapy in bipolar mania
* 1.5.2 Adjunctive therapy in bipolar mania
* 1.6 Dose dependency extrapyramidal symptoms
* 1.7 Other adverse events
* 1.8 Vital sign changes
* 1.9 Weight changes
* 1.10 Laboratory changes
* 1.11 ECG changes
* 1.12 Pediatric patients with autistic disorder
* 1.13 Premarketing evaluation
* 1.14 Post-introduction reports

## List of side effects

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Overview

Associated with discontinuation of treatment

* Schizophrenia (discontinuation)
* Bipolar mania (discontinuation)

Commonly observed in controlled clinical trials

* Schizophrenia (common)
* Bipolar mania (common)

Incidence of 1% or more (schizophrenia)

Incidence of 2% or more (bipolar mania)

* Monotherapy in bipolar mania
* Adjunctive therapy in bipolar mania

Dose dependency extrapyramidal symptoms

Other adverse events

Vital sign changes

Weight changes

Laboratory changes

ECG changes

Pediatric patients with autistic disorder

Premarketing evaluation

Post-introduction reports

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### Overview

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The following findings are based on the short-term, placebo-controlled, North American, premarketing trials for schizophrenia and acute bipolar mania, and are followed by a description of adverse events and other safety measures in short-term, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder. In patients with Bipolar I Disorder, treatment-emergent adverse events are presented separately for risperidone as monotherapy and as adjunctive therapy to mood stabilizers.
Certain portions of the discussion below relating to objective or numeric safety parameters, namely dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia. However, this information is also generally applicable to bipolar mania and pediatric patients with autistic disorder. Return to top

### Associated with discontinuation of treatment

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#### Schizophrenia (discontinuation)

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Approximately 9% (244/2607) of Risperdal® (risperidone)-treated patients in Phase 2 and 3 studies discontinued treatment due to an adverse event, compared with about 7% on placebo and 10% on active control drugs. The more common events (≥0.3%) associated with discontinuation and considered to be possibly or probably drug-related included: extrapyramidal symptoms, dizziness, hyperkinesia, somnolence, nausea.
Suicide attempt was associated with discontinuation in 1.2% of Risperdal®-treated patients compared to 0.6% of placebo patients, but, given the almost 40-fold greater exposure time in Risperdal® compared to placebo patients, it is unlikely that suicide attempt is a Risperdal®-related adverse event. Discontinuation for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control patients in the Phase 2 and 3 trials. Return to top

#### Bipolar mania (discontinuation)

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In the US placebo-controlled trial with risperidone as monotherapy, approximately 8% (10/134) of Risperdal®-treated patients discontinued treatment due to an adverse event, compared with approximately 6% (7/125) of placebo-treated patients. The adverse events associated with discontinuation and considered to be possibly, probably, or very likely drug-related included paroniria, somnolence, dizziness, extrapyramidal disorder, and muscle contractions involuntary. Each of these events occurred in one Risperdal®-treated patient (0.7%) and in no placebo-treated patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, there was no overall difference in the incidence of discontinuation due to adverse events (4% for Risperdal® vs. 4% for placebo).Return to top

### Commonly observed in controlled clinical trials

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#### Schizophrenia (common)

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In two 6- to 8-week placebo-controlled trials, spontaneously-reported, treatment-emergent adverse events with an incidence of 5% or greater in at least one of the Risperdal® groups and at least twice that of placebo were anxiety, somnolence, extrapyramidal symptoms, dizziness, constipation, nausea, dyspepsia, rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials (i.e., in the fixed-dose trial comparing Risperdal® at doses of 2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for detecting adverse events, a method that is more sensitive than spontaneous reporting. By this method, the following additional common and drug-related adverse events occurred at an incidence of at least 5% and twice the rate of placebo: increased dream activity, increased duration of sleep, accommodation disturbances, reduced salivation, micturition disturbances, diarrhea, weight gain, menorrhagia, diminished sexual desire, erectile dysfunction, ejaculatory dysfunction, and orgastic dysfunction. Return to top

#### Bipolar mania (common)

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In the US placebo-controlled trial with risperidone as monotherapy, the most commonly observed adverse events associated with the use of Risperdal® (incidence of 5% or greater and at least twice that of placebo) were somnolence, dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva increased. In the US placebo-controlled trial with risperidone as adjunctive therapy to mood stabilizers, the most commonly observed adverse events associated with the use of Risperdal® were somnolence, dizziness, parkinsonism, saliva increased, akathisia, abdominal pain, and urinary incontinence. Return to top

### Incidence of 1% or more (schizophrenia)

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The list that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent among Risperdal®-treated patients treated at doses of ≤10 mg/day than among placebo-treated patients in the pooled results of two 6- to 8-week controlled trials. Patients received Risperdal® 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 titration study. This table 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 materially in these rates. Reported adverse events were classified using the World Health Organization preferred terms.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in this clinical trial. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.

* Psychiatric: insomnia, agitation, anxiety, somnolence, aggrassive reaction
* Central/peripheral nervous system: extrapyramidal symptoms, headache, dizziness
* Gastrointestinal: constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva increased, toothache
* Respiratory system: rhinitis, coughing, sinusitis, pharyngitis, dyspnea
* Body as a whole: back pain, chest pain, fever
* Dermatological: rash, dry skin, seborrhea
* Infections: upper respiratory
* Visual: abnormal vision
* Musculo-skeletal: arthralgia
* Cardiovascular: tachycardia

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### Incidence of 2% or more (bipolar mania)

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The following lists display adverse events that occurred at an incidence of 2% or more, and were more frequent among patients treated with flexible doses of Risperdal® (1–6 mg daily as monotherapy and as adjunctive therapy to mood stabilizers, respectively) than among patients treated with placebo. Reported adverse events were classified using the World Health Organization preferred terms. Return to top

#### Monotherapy in bipolar mania

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* Central/peripheral nervous system: dystonia, akathisia, dizziness, parkinsonism, hypoaesthesia
* Psychiatric: somnolence, agitation, manic reaction, anxiety, concentration impaired
* Gastrointestinal system: dyspepsia, nausea, saliva increased, dry mouth
* Body as a whole: pain, fatiuge, injury
* Respiratory system: sinusitis, rhinitis, coughing
* Skin/appendages: acne, pruritus
* Visual disorders: vision abnormal
* Cardiovascular (general): hypertension, hypotension
* Heart rate/rhythm: tachycardia

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#### Adjunctive therapy in bipolar mania

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* Gastrointestinal system: saliva increased, diarrhea, abdominal pain, constipation, dry mouth, toothache, tooth disorder
* Psychiatric: somnolence, anxiety, confusion
* Respiratory system: rhinitis, pharyngitis, coughing
* Body as a whole: asthenia
* Urinary system: urinary incontinence
* Heart rate/rhythm: tachycardia
* Metabolic/nutritional: weight increase
* Skin/appendages: rash

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### Dose dependency extrapyramidal symptoms

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Data from two fixed-dose trials 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  | Ris 2  | Ris 6  | Ris 10  | Ris 16

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Parkinsonism  | 1.2  | 0.9  | 1.8  | 2.4  | 2.6
EPS incidence  | 13%  | 13%  | 16%  | 20%  | 31%

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  | Ris 1  | Ris 4  | Ris 8  | Ris 12  | Ris 16

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Parkinsonism  | 0.6  | 1.7  | 2.4  | 2.9  | 4.1
EPS incidence  | 7%  | 12%  | 18%  | 18%  | 21%

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### Other adverse events

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Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of Risperdal® (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse events: sleepiness, increased duration of sleep, accommodation disturbances, orthostatic dizziness, palpitations, weight gain, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, asthenia/lassitude/increased fatigability, and increased pigmentation. Return to top

### Vital sign changes

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Risperdal® is associated with orthostatic hypotension and tachycardia. Return to top

### Weight changes

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The proportions of Risperdal® and placebo-treated patients meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for Risperdal® (18%) compared to placebo (9%). Return to top

### Laboratory changes

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A between-group comparison for 6- to 8-week placebo-controlled trials revealed no statistically significant Risperdal®/placebo differences in the proportions of patients experiencing potentially important changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no Risperdal®/placebo differences in the incidence of discontinuations for changes in serum chemistry, hematology, or urinalysis. However, Risperdal® administration was associated with increases in serum prolactin. Return to top

### ECG changes

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

### Pediatric patients with autistic disorder

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In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n=156), two patients (one treated with Risperdal® and one treated with placebo) discontinued treatment due to an adverse event.
In addition to spontaneous reporting, in one of the studies, adverse events were also elicited from a checklist for detecting selected events, a method that is more sensitive than spontaneous reporting.
The most common adverse events with Risperdal® that occurred at an incidence equal to or greater than 5% and at a rate of at least twice that of placebo are as follows:

* Psychiatric: somnolence, appetite increased, confusion
* Gastrointestinal: saliva increased, constipation, dry mouth
* Body as a whole: fatigue
* Central/peripheral nervous system: tremor, dystonia, dizziness, autumatism, dyskinesia, parkisonism
* Respiratory: upper respiratory tract infection
* Metabolic/nutritional: weight increase
* Heart rate/rhythm: tachycardia

Weight increase was reported more frequently with Risperdal® than with placebo. The average weight increase over 8 weeks was 2.6 kg in patients treated with Risperdal® compared with 0.9 kg in patients treated with placebo.
There was a higher incidence of adverse events reflecting extrapyramidal symptoms (EPS) in the Risperdal® group (27.6%) compared with the placebo group (10.0%). In addition, between-group comparison of the severity of EPS were assessed objectively by the following rating instruments: the Simpson-Angus Rating Scale (SARS) and the Abnormal Involuntary Movement Scale (AIMS) in one study, and the Extrapyramidal Symptom Rating Scale (ESRS) in the other study. The mean changes between baseline and endpoint in the total ESRS score were –0.3 in the Risperdal® group and –0.4 in the placebo group. The median change from baseline to endpoint was 0 in both treatment groups for each EPS rating scale.
Somnolence was the most frequent adverse event, and was reported at a higher incidence in the Risperdal® group compared with the placebo group. The vast majority of cases (96%) were either mild or moderate in severity. These events were most often of early onset with peak incidence occurring during the first 2 weeks of treatment, and median duration was 16 days. Patients experiencing persistent somnolence may benefit from a change in dosing regimen. Return to top

### Premarketing evaluation

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During its premarketing assessment, multiple doses of Risperdal® were administered to 2607 adult patients with schizophrenia and 1923 pediatric patients in Phase 2 and 3 studies. The conditions and duration of exposure to Risperdal® varied greatly, and included (in overlapping categories) open-label and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and short-term or longer-term exposure. In most studies, untoward events associated with this exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In two large studies, adverse events were also elicited utilizing the UKU (direct questioning) side effect rating scale, and these events were not further categorized using standard terminology. (Note: These events are marked with an asterisk in the listings that follow.)
In the listings that follow, spontaneously reported adverse events were classified using World Health Organization (WHO) preferred terms. The frequencies presented, therefore, represent the proportion of the 2607 adult or 1923 pediatric patients exposed to multiple doses of Risperdal® who experienced an event of the type cited on at least one occasion while receiving Risperdal®. All reported events are included, except those already listed in Incidence of 1% or more (schizophrenia), those events for which a drug cause was remote, and those event terms which were so general as to be uninformative. It is important to emphasize that, although the events reported occurred during treatment with Risperdal®, they were not necessarily caused by it. Serious adverse reactions experienced by the pediatric population were similar to those seen in the adult population.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Return to top
Psychiatric

* Frequent: increased dream activity, diminished sexual desire, nervousness
* Infrequent: impaired concentration, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia
* Rare: emotional lability, nightmares, delirium, withdrawal syndrome, yawning

Central/peripheral nervous system

* Frequent: increased sleep duration
* Infrequent: dysarthria, vertigo, stupor, paraesthesia, confusion
* Rare: aphasia, cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migraine, hyperreflexia, choreoathetosis

Gastrointestinal

* Frequent: anorexia, reduced salivation
* Infrequent: flatulence, diarrhea, increased appetite, stomatitis, melena, dysphagia, hemorrhoids, gastritis
* Rare: fecal incontinence, eructation, gastroesophageal reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis

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Body as whole

* Frequent: fatigue
* Infrequent: edema, rigors, malaise, influenza-like symptoms
* Rare: pallor, enlarged abdomen, allergic reaction, ascites, sarcoidosis, flushing

Respiratory system

* Infrequent: hyperventilation, bronchospasm, pneumonia, stridor
* Rare : asthma, increased sputum, aspiration

Skin/appendage

* Frequent: increased pigmentation, photosensitivity
* Infrequent: increased sweating, acne, decreased sweating, alopecia, hyperkeratosis, pruritus, skin exfoliation
* Rare: bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria

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Cardiovascular

* Infrequent: palpitation, hypertension, hypotension, AV block, myocardial infarction
* Rare: ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles, ST depression, myocarditis

Vision

* Infrequent: abnormal accommodation, xerophthalmia
* Rare: diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation

Metabolic/nutritional

* Infrequent: hyponatremia, weight increase, creatine phosphokinase increase, thirst, weight decrease, diabetes mellitus
* Rare: decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia

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Urinary system

* Frequent: polyuria/polydipsia
* Infrequent: urinary incontinence, hematuria, dysuria
* Rare: urinary retention, cystitis, renal insufficiency

Musculo-skeletal system

* Infrequent: myalgia. Rare: arthrosis, synostosis, bursitis, arthritis, skeletal pain

Reproductive (female)

* Frequent: menorrhagia, orgastic dysfunction, dry vagina
* Infrequent: nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage

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Liver/biliary system

* Infrequent: increased SGOT, increased SGPT
* Rare: hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis, hepatocellular damage

Platelet/bleeding/clotting

* Infrequent: epistaxis, purpura
* Rare: hemorrhage, superficial phlebitis, thrombophlebitis, thrombocytopenia

Hearing/vestibular

* Rare: tinnitus, hyperacusis, decreased hearing

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Red blood cell

* Infrequent: anemia, hypochromic anemia
* Rare: normocytic anemia

Reproductive (male)

* Frequent: erectile dysfunction
* Infrequent: ejaculation failure

White cell/resistance

* Infrequent: granulocytopenia
* Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly

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Endocrine

* Rare: gynecomastia, male breast pain, antidiuretic hormone disorder

Special senses

* Rare: bitter taste

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### Post-introduction reports

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Adverse events reported since market introduction which were temporally (but not necessarily causally) related to Risperdal® therapy, include the following: anaphylactic reaction, angioedema, apnea, atrial fibrillation, cerebrovascular disorder, including cerebrovascular accident, diabetes mellitus aggravated, including diabetic ketoacidosis, hyperglycemia, intestinal obstruction, jaundice, mania, pancreatitis, Parkinson's disease aggravated, pituitary adenomas, pulmonary embolism, precocious puberty, and QT prolongation. There have been rare reports of sudden death and/or cardiopulmonary arrest in patients receiving Risperdal®. A causal relationship with Risperdal® has not been established. It is important to note that sudden and unexpected death may occur in psychotic patients whether they remain untreated or whether they are treated with other antipsychotic drugs. Return to top

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Adapted from the FDA Package Insert.