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
| RISPERDAL ® CONSTA ®|
| WHO Body System Disorder/ |
| 25 mg |
| 50 mg |
| Placebo |
|a Includes adverse events of bradykinesia, extrapyramidal disorder, and hypokinesia. |
|Insomnia ||16 ||13 ||14 |
|Hallucination ||7 ||6 ||5 |
|Somnolence ||5 ||6 ||3 |
|Suicide attempt ||1 ||4 ||3 |
|Abnormal thinking ||0 ||3 ||2 |
|Abnormal dreaming ||2 ||0 ||0 |
|Central & peripheral nervous system |
|Headache ||15 ||22 ||12 |
|Dizziness ||8 ||11 ||6 |
|Akathisia ||2 ||9 ||4 |
|Parkinsonisma||4 ||10 ||3 |
|Tremor ||0 ||3 ||0 |
|Hypoaesthesia ||2 ||0 ||0 |
|Dyspepsia ||7 ||7 ||2 |
|Constipation ||5 ||7 ||1 |
|Mouth dry ||0 ||7 ||1 |
|Toothache ||1 ||3 ||0 |
|Saliva increased ||6 ||2 ||1 |
|Tooth disorder ||4 ||2 ||0 |
|Diarrhea ||5 ||1 ||3 |
|Body as a whole - general |
|Fatigue ||3 ||7 ||0 |
|Pain ||10 ||3 ||4 |
|Peripheral edema ||2 ||3 ||1 |
|Leg pain ||4 ||1 ||1 |
|Fever ||2 ||1 ||0 |
|Syncope ||2 ||0 ||0 |
|Respiratory system |
|Rhinitis ||14 ||4 ||8 |
|Coughing ||5 ||2 ||4 |
|Sinusitis ||3 ||1 ||0 |
|Upper respiratory tract infection ||2 ||0 ||1 |
|Metabolic & nutritional |
|Weight increase ||5 ||4 ||2 |
|Weight decrease ||4 ||1 ||1 |
|Hypertension ||3 ||3 ||2 |
|Hearing & vestibular |
|Ear disorder (NOS) ||0 ||3 ||0 |
|Vision abnormal ||2 ||3 ||0 |
|Skin & appendages |
|Acne ||2 ||2 ||0 |
|Skin dry ||2 ||0 ||0 |
|Myalgia ||4 ||2 ||1 |
Dose Dependency of Adverse Events
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 ).
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.
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.
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.
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 dyskinesiaa, involuntary muscle contractions, paraesthesia, abnormal gait, bradykinesia, convulsions, hypokinesia, ataxia, fecal incontinence, oculogyric crisis, tetany, apraxia, dementia, migraine. Rare: neuroleptic malignant syndrome.
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.
Body as a Whole/General Disorders
Frequent: back pain, chest pain, asthenia. Infrequent: malaise, choking.
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.
Frequent: hypotension. Infrequent: postural hypotension.
Urinary System Disorders
Frequent: urinary incontinence. Infrequent: hematuria, micturition frequency, renal pain, urinary retention.
Infrequent: conjunctivitis, eye pain, abnormal accommodation.
Reproductive Disorders, Female
Frequent: amenorrhea. Infrequent: nonpuerperal lactation, vaginitis, dysmenorrhea, breast pain, leukorrhea.
Resistance Mechanism Disorders
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
White Cell and Resistance Disorders
Infrequent: lymphadenopathy, leucopenia, cervical lymphadenopathy. Rare: granulocytopenia, leukocytosis, lymphopenia.
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.
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.