Adverse findings were assessed by spontaneous reports of adverse events, laboratory tests, vital signs, body weight, and ECGs. Adverse events were classified using the World Health Organization preferred terms. Treatment-emergent adverse events were defined as those events with an onset between the first dose and 49 days after the last dose.

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 nondrug factors to the side effect incidence rate in the population studied.

Associated with Discontinuation of Treatment

In the 12-week, placebo-controlled trial, the incidence of schizophrenic patients who discontinued treatment due to an adverse event was lower with RISPERDAL® CONSTA® (11%; 22/202 patients) than with placebo (13%; 13/98 patients).

Incidence in Controlled Trials

The incidence of adverse reactions in the placebo-controlled trial was based on 202 schizophrenic patients treated with 25 or 50 mg RISPERDAL® CONSTA® and 98 schizophrenic patients treated with placebo for up to 12 weeks.

Commonly Observed Adverse Events in Controlled Clinical Trials

Spontaneously reported, treatment-emergent adverse events with an incidence of 5% or greater in at least one of the RISPERDAL® CONSTA® groups (25 mg or 50 mg) and at least twice that of placebo were: somnolence, akathisia, parkinsonism, dyspepsia, constipation, dry mouth, fatigue, weight increase.

Adverse Events Occurring at an Incidence of 2% or More in Patients Treated with RISPERDAL® CONSTA®:

Table 1 enumerates adverse events that occurred at an incidence of 2% or more, and were at least as frequent among patients treated with 25 mg or 50 mg RISPERDAL® CONSTA as patients treated with placebo in the 12-week, placebo-controlled trial. This table shows the percentage of patients in each dose group who spontaneously reported at least one episode of an event at some time during double-blind treatment. All patients were titrated to a dose of 4 mg oral RISPERDAL® during a 1-week run-in period. Patients who received RISPERDAL® CONSTA® were given doses of oral RISPERDAL® (2 mg for patients in the 25-mg group, and 4 mg for patients in the 50-mg group) during the 3 weeks after the first injection to provide therapeutic levels until the main release phase of risperidone from the injection site had begun. Patients who received placebo injections were given placebo tablets.

Table 1. Incidence (% of Patients) of Treatment-Emergent Adverse Events in a 12-Week, Placebo-Controlled Clinical Trial

Dose Dependency of Adverse Events

Extrapyramidal Symptoms

Two methods were used to measure extrapyramidal symptoms (EPS) in the 12-week, placebo-controlled trial comparing three doses of RISPERDAL® CONSTA® (25 mg, 50 mg, and 75 mg) with placebo, including: (1) the incidence of spontaneous reports of EPS symptoms; and (2) the change from baseline to endpoint on the total score (sum of the subscale scores for parkinsonism, dystonia, and dyskinesia) of the Extrapyramidal Symptom Rating Scale (ESRS).

As shown in Table 1, the overall incidence of EPS-related adverse events (akathisia, dystonia, parkinsonism, and tremor) in patients treated with 25 mg RISPERDAL® CONSTA® was comparable to that of patients treated with placebo; the incidence of EPS-related adverse events was higher in patients treated with 50 mg RISPERDAL® CONSTA®.

The median change from baseline to endpoint in total ESRS score showed no worsening in patients treated with RISPERDAL® CONSTA® compared with patients treated with placebo: 0 (placebo group); -1 (25-mg group, significantly less than the placebo group); and 0 (50-mg group).

Vital Sign Changes

RISPERDAL® is associated with orthostatic hypotension and tachycardia (see PRECAUTIONS). In the placebo-controlled trial, orthostatic hypotension was observed in 2% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® (see PRECAUTIONS).

Weight Changes

In the 12-week, placebo-controlled trial, 9% of patients treated with RISPERDAL® CONSTA®, compared with 6% of patients treated with placebo, experienced a weight gain of >7% of body weight at endpoint.

Laboratory Changes

The percentage of patients treated with RISPERDAL® CONSTA® who experienced potentially important changes in routine serum chemistry, hematology, or urinalysis parameters was similar to or less than that of placebo patients. Additionally, no patients discontinued treatment due to changes in serum chemistry, hematology, or urinalysis parameters.

ECG Changes

The electrocardiograms of 202 schizophrenic patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® and 98 schizophrenic patients treated with placebo in a 12-week, double-blind, placebo-controlled trial were evaluated. Compared with placebo, there were no statistically significant differences in QTc intervals (using Fridericia's and linear correction factors) during treatment with RISPERDAL® CONSTA®.

Between-group comparisons for pooled placebo-controlled trials with oral RISPERDAL® 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 oral 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 oral risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute).

Pain Assessment and Local Injection Site Reactions

The mean intensity of injection pain reported by patients using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 16.7 to 12.6; 25 mg: 12.0 to 9.0; 50 mg: 18.2 to 11.8). After the sixth injection (Week 10), investigator ratings indicated that 1% of patients treated with 25 mg or 50 mg RISPERDAL® CONSTA® experienced redness, swelling, or induration at the injection site.

Other Events Observed During the Premarketing Evaluation of RISPERDAL® CONSTA®

During its premarketing assessment, RISPERDAL® CONSTA® was administered to 1499 patients in multiple-dose studies. The conditions and duration of exposure to RISPERDAL® CONSTA® 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 and long-term exposure studies. In all studies, untoward events associated with this exposure were obtained by spontaneous report and were 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 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 1499 patients exposed to multiple doses of RISPERDAL® CONSTA® who experienced an event of the type cited on at least one occasion while receiving RISPERDAL® CONSTA®. All reported events are included except those already listed in Table 1, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. It is important to emphasize that, although the reported events occurred during treatment with RISPERDAL® CONSTA®, they were not necessarily caused by it.

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 the placebo-controlled trial appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients.

Psychiatric Disorders

Frequent: anxiety, psychosis, depression, agitation, nervousness, paranoid reaction, delusion, apathy. Infrequent: anorexia, impaired concentration, impotence, emotional lability, manic reaction, decreased libido, increased appetite, amnesia, confusion, euphoria, depersonalization, paroniria, delirium, psychotic depression.

Central and Peripheral Nervous System Disorders

Frequent: hypertonia, dystonia. Infrequent: dyskinesia, vertigo, leg cramps, tardive dyskinesia^a, involuntary muscle contractions, paraesthesia, abnormal gait, bradykinesia, convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis, tetany, apraxia, dementia, migraine. Rare: neuroleptic malignant syndrome.

Body as a Whole/General Disorders

Frequent: back pain, chest pain, asthenia. Infrequent: malaise, choking.

Gastrointestinal Disorders

Frequent: nausea, vomiting, abdominal pain. Infrequent: gastritis, gastroesophageal reflux, flatulence, hemorrhoids, melena, dysphagia, rectal hemorrhage, stomatitis, colitis, gastric ulcer, gingivitis, irritable bowel syndrome, ulcerative stomatitis.

Respiratory System Disorders

Frequent: dyspnea. Infrequent: pneumonia, stridor, hemoptysis. Rare: pulmonary edema.

Skin and Appendage Disorders

Frequent: rash. Infrequent: eczema, pruritus, erythematous rash, dermatitis, alopecia, seborrhea, photosensitivity reaction, increased sweating.

Metabolic and Nutritional Disorders

Infrequent: hyperuricemia, hyperglycemia, hyperlipemia, hypokalemia, glycosuria, hypercholesterolemia, obesity, dehydration, diabetes mellitus, hyponatremia.

Musculo-Skeletal System Disorders

Frequent: arthralgia, skeletal pain. Infrequent: torticollis, arthrosis, muscle weakness, tendinitis, arthritis, arthropathy.

Heart Rate and Rhythm Disorders

Frequent: tachycardia. Infrequent: bradycardia, AV block, palpitation, bundle branch block. Rare: T-wave inversion.

Cardiovascular Disorders

Frequent: hypotension. Infrequent: postural hypotension.

Urinary System Disorders

Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal pain, urinary retention.

Vision Disorders

Infrequent: conjunctivitis, eye pain, abnormal accommodation.

Reproductive Disorders, Female

Frequent: amenorrhea. Infrequent: nonpuerperal lactation, vaginitis, dysmenorrhea, breast pain, leukorrhea.

Resistance Mechanism Disorders

Infrequent: abscess.

Liver and Biliary System Disorders

Frequent: increased hepatic enzymes. Infrequent: hepatomegaly, increased SGPT. Rare: bilirubinemia, increased GGT, hepatitis, hepatocellular damage, jaundice, fatty liver, increased SGOT.

Reproductive Disorders, Male

Infrequent: ejaculation failure.

Application Site Disorders

Frequent: injection site pain. Infrequent: injection site reaction.

Hearing and Vestibular Disorders

Infrequent: earache, deafness, hearing decreased.

Red Blood Cell Disorders

Frequent: anemia.

White Cell and Resistance Disorders

Infrequent: lymphadenopathy, leucopenia, cervical lymphadenopathy. Rare: granulocytopenia, leukocytosis, lymphopenia.

Endocrine Disorders

Infrequent: hyperprolactinemia, gynecomastia, hypothyroidism.

Platelet, Bleeding and Clotting Disorders

Infrequent: purpura, epistaxis. Rare: pulmonary embolism, hematoma, thrombocytopenia.

Myo-, Endo-, and Pericardial and Valve Disorders

Infrequent: myocardial ischemia, angina pectoris, myocardial infarction.

Vascular (Extracardiac) Disorders

Infrequent: phlebitis. Rare: intermittent claudication, flushing, thrombophlebitis.

Postintroduction Reports

Adverse events reported since market introduction which were temporally (but not necessarily causally) related to oral 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, and QT prolongation. There have been rare reports of sudden death and/or cardiopulmonary arrest in patients receiving oral RISPERDAL®. A causal relationship with oral 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.

Retinal artery occlusion after injection of RISPERDAL® CONSTA® has been reported during postmarketing surveillance. This has been reported in the presence of abnormal arteriovenous anastomosis.

Drug Abuse And Dependence

Controlled Substance Class

RISPERDAL® CONSTA (risperidone) is not a controlled substance.

Physical and Psychological Dependence

RISPERDAL® CONSTA® has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. Because RISPERDAL® CONSTA® is to be administered by health care professionals, the potential for misuse or abuse by patients is low.

The interactions of RISPERDAL® CONSTA® and other drugs have not been systematically evaluated. Given the primary CNS effects of risperidone, caution should be used when RISPERDAL® CONSTA® is administered in combination with other centrally-acting drugs or alcohol.

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

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

Amitriptyline did not affect the pharmacokinetics of risperidone or the active moiety. Cimetidine and ranitidine increased the bioavailability of risperidone by 64% and 26%, respectively. However, cimetidine did not affect the AUC of the active moiety, whereas ranitidine increased the AUC of the active moiety by 20%.

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

Carbamazepine and Other CYP 3A4 Enzyme Inducers

In a drug interaction study in schizophrenic patients, 11 subjects received oral risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent administration of carbamazepine for an additional 3 weeks. During co-administration, the plasma concentrations of risperidone and its pharmacologically active metabolite, 9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of carbamazepine did not appear to be affected. Co-administration of other known CYP 3A4 enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital) with risperidone may cause similar decreases in the combined plasma concentrations of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy of RISPERDAL® CONSTA® treatment. At the initiation of therapy with carbamazepine or other known CYP 3A4 hepatic enzyme inducers, patients should be closely monitored during the first 4-8 weeks, since the dose of RISPERDAL® CONSTA® may need to be adjusted. A dose increase, or additional oral RISPERDAL®, may need to be considered. On discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of RISPERDAL® CONSTA® should be re-evaluated and, if necessary, decreased. Patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned discontinuation of carbamazepine or other CYP 3A4 enzyme inducers to adjust for the expected increase in plasma concentrations of risperidone plus 9-hydroxyrisperidone. For patients treated with the recommended dose of 25 mg RISPERDAL® CONSTA® and discontinuing from carbamazepine or other CYP 3A4 enzyme inducers, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDAL® CONSTA®dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. (See also DOSAGE AND ADMINISTRATION.) The efficacy of the 12.5 mg dose has not been investigated in clinical trials.

Fluoxetine and Paroxetine

Fluoxetine (20 mg QD) and paroxetine (20 mg QD), CYP 2D6 inhibitors, have been shown to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold, respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone. Paroxetine lowered the concentration of 9-hydroxyrisperidone by about 10%. When either concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should re-evaluate the dose of RISPERDAL® CONSTA®. When initiation of fluoxetine or paroxetine is considered, patients may be placed on a lower dose of RISPERDAL® CONSTA® between 2 to 4 weeks before the planned start of fluoxetine or paroxetine therapy to adjust for the expected increase in plasma concentrations of risperidone. When fluoxetine or parozetine is initiated in patients receiving the recommended dose of 25 mg RISPERDAL® CONSTA®, it is recommended to continue treatment with the 25-mg dose unless clinical judgment necessitates lowering the RISPERDALR CONSTAR dose to 12.5 mg or necessitates interruption of RISPERDAL® CONSTA® treatment. When RISPERDAL® CONSTA® is initiated in patients already receiving fluoxetine or paroxetine, a starting dose of 12.5 mg can be considered. The efficacy of the 12.5 mg dose has not been investigated in clinical trials. (See also DOSAGE AND ADMINISTRATION.). The effects of discontinuation of concomitant fluoxetine or paroxetine therapy on the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.

Lithium

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

Valproate

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

Digoxin

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

Drugs that Inhibit CYP 2D6 and Other CYP Isozymes

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

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

There were no significant interactions between risperidone and erythromycin (see CLINICAL PHARMACOLOGY).

Drugs Metabolized by CYP 2D6

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

REFERENCES

^a In the integrated database of multiple-dose studies (1499 patients with schizophrenia or schizoaffective disorder), 9 patients (0.6%) treated with RISPERDAL® CONSTA® (all dosages combined) experienced an adverse event of tardive dyskinesia.

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