ADVERSE REACTIONS
The information below is derived from a clinical trial database for INVEGA™ consisting of 2720 patients and/or normal subjects exposed to one or more doses of INVEGA™ for the treatment of schizophrenia.
Of these 2720 patients, 2054 were patients who received INVEGA™ while participating in multiple dose, effectiveness trials. The conditions and duration of treatment with INVEGA™ varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and flexible-dose studies, and short-term and longer-term exposure. Adverse events were assessed by collecting adverse events and performing physical examinations, vital signs, weights, laboratory analyses and ECGs.
Adverse events during exposure 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 MedDRA terminology.
The stated frequencies of adverse events represent the proportions of individuals who experienced a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
The information presented in these sections was derived from pooled data from the three placebo-controlled, 6-week, fixed-dose studies based on subjects with schizophrenia who received INVEGATM at daily doses within the recommended range of 3 to 12 mg (n = 850). Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGATM at daily doses within the range of 3 to 15 mg (n = 104), is also included.
Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Subjects with Schizophrenia
Adverse Events Occurring at an Incidence of 2% or More Among INVEGA™Treated Patients with Schizophrenia and More Frequent on Drug than Placebo
Table 1 enumerates the pooled incidences of treatment-emergent adverse events that were spontaneously reported in the three placebo-controlled, 6-week, fixed-dose studies, listing those events that occurred in 2% or more of subjects treated with INVEGA™ in any of the dose groups, and for which the incidence in INVEGA™ -treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.
Table 1. Treatment-Emergent Adverse Events in Short-Term, Fixed-Dose, Placebo-Controlled Trials in Adult Subjects with Schizophrenia Table includes adverse events that were reported in 2% or more of subjects in any of the INVEGA™ dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one included once-daily INVEGA™ doses of 3 and 9 mg, the second study included 6, 9, and 12 mg, and the third study included 6 and 12 mg (see CLINICAL PHARMACOLOGY: Clinical Trials). Events for which the INVEGA™ incidence was equal to or less than placebo are not listed in the table, but included the following: constipation, diarrhea, vomiting, nasopharyngitis, agitation, and insomnia. | Percentage of Patients Reporting Event |
|---|
| | INVEGA™ | | | |
|---|
Body System or Organ Class
Dictionary-derived Term | Placebo
(N=355) | 3 mg
once daily
(N=127) | 6 mg
once daily
(N=235) | 9 mg
once daily
(N=246) | 12 mg
once daily
(N=242) |
|---|
| Percentage of subjects with adverse events | 66 | 72 | 66 | 70 | 76 |
| | | | | |
| Cardiac disorders | | | | | |
| Atrioventricular block first degree | 1 | 2 | 0 | 2 | 1 |
| Bundle branch block | 2 | 3 | 1 | 3 | <1 |
| Sinus arrhythmia | 0 | 2 | 1 | 1 | <1 |
| Tachycardia | 7 | 14 | 12 | 12 | 14 |
| | | | | |
| Eye disorders | | | | | |
| Vision blurred | 1 | 1 | <1 | 0 | 2 |
| | | | | |
| Gastrointestinal disorders | | | | | |
| Abdominal pain upper | 1 | 1 | 3 | 2 | 2 |
| Dry mouth | 1 | 2 | 3 | 1 | 3 |
| Dyspepsia | 4 | 2 | 3 | 2 | 5 |
| Nausea | 5 | 6 | 4 | 4 | 4 |
| Salivary hypersecretion | <1 | 0 | <1 | 1 | 4 |
| | | | | |
| General disorders | | | | | |
| Asthenia | 1 | 2 | <1 | 2 | 2 |
| Fatigue | 1 | 2 | 1 | 2 | 2 |
| Pyrexia | 1 | 1 | <1 | 2 | 2 |
| | | | | |
| Investigations | | | | | |
| Blood insulin increased | 1 | 2 | 1 | 1 | <1 |
| Blood pressure increased | 1 | 2 | <1 | <1 | 1 |
| Electrocardiogram QT corrected interval prolonged | 3 | 3 | 4 | 3 | 5 |
| Electrocardiogram T wave abnormal | 1 | 2 | 1 | 2 | 1 |
| | | | | |
| Musculoskeletal and connective tissue disorders | | | | | |
| Back pain | 1 | 1 | 1 | 1 | 2 |
| Pain in extremity | 1 | 0 | 1 | 0 | 2 |
| | | | | |
| Nervous system disorders | | | | | |
| Akathisia | 4 | 4 | 3 | 8 | 10 |
| Dizziness | 4 | 6 | 5 | 4 | 5 |
| Dystonia | 1 | 1 | 1 | 5 | 4 |
| Extrapyramidal disorder | 2 | 5 | 2 | 7 | 7 |
| Headache | 12 | 11 | 12 | 14 | 14 |
| Hypertonia | 1 | 2 | 1 | 4 | 3 |
| Parkinsonism | 0 | 0 | <1 | 2 | 1 |
| Somnolence | 7 | 6 | 9 | 10 | 11 |
| Tremor | 3 | 3 | 3 | 4 | 3 |
| | | | | |
| Psychiatric disorders | | | | | |
| Anxiety | 8 | 9 | 7 | 6 | 5 |
| | | | | |
| Respiratory, thoracic and mediastinal disorders | | | | | |
| Cough | 1 | 3 | 2 | 3 | 2 |
| | | | | |
| Vascular disorders | | | | | |
| Orthostatic hypotension | 1 | 2 | 1 | 2 | 4 |
Dose-Related Adverse Events in Clinical Trials
Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, adverse events that occurred with a greater than 2% incidence in the subjects treated with INVEGA™, the incidences of the following adverse events increased with dose: somnolence, orthostatic hypotension, salivary hypersecretion, akathisia, dystonia, extrapyramidal disorder, hypertonia and Parkinsonism. For most of these, the increased incidence was seen primarily at the 12 mg, and in some cases the 9 mg dose.
Common and Drug-Related Adverse Events in Clinical Trials
In the pooled data from the three placebo-controlled, 6–week, fixed-dose studies, adverse events reported in 5% or more of subjects treated with INVEGA™ and at least twice the placebo rate for at least one dose included: akathisia and extrapyramidal disorder.
Extrapyramidal Symptoms (EPS) in Clinical Trials
Pooled data from the three placebo-controlled, 6-week, fixed-dose studies provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS, and (4) incidence of spontaneous reports of EPS. For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and INVEGATM 3 mg and 6 mg doses for any of these EPS measures.
| Percentage of Patients |
|---|
| | INVEGA™ |
|---|
| EPS Group | Placebo
(N=355) | 3 mg
once daily
(N=127) | 6 mg
once daily
(N=235) | 9 mg
once daily
(N=246) | 12 mg
once daily
(N=242) |
|---|
| Parkinsonism : For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items) | 9 | 11 | 3 | 15 | 14 |
| Akathisia : For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 | 6 | 6 | 4 | 7 | 9 |
| Use of anticholinergic medications : Percent of patients who received anticholinergic medications to treat emergent EPS | 10 | 10 | 9 | 22 | 22 |
| Percentage of Patients |
|---|
| | INVEGA™ |
|---|
| EPS Group | Placebo
(N=355) | 3 mg
once daily
(N=127) | 6 mg
once daily
(N=235) | 9 mg
once daily
(N=246) | 12 mg
once daily
(N=242) |
|---|
Dyskinesia group includes: Dyskinesia, Extrapyramidal disorder, Muscle twitching, Tardive dyskinesia
Dystonia group includes: Dystonia, Muscle spasms, Oculogyration, Trismus
Hyperkinesia group includes: Akathisia, Hyperkinesia
Parkinsonism group includes: Bradykinesia, Cogwheel rigidity, Drooling,
Hypertonia, Hypokinesia, Muscle rigidity, Musculoskeletal stiffness, Parkinsonism
Tremor group includes: Tremor |
Overall percentage of patients
with EPS-related AE | 11.0 | 12.6 | 10.2 | 25.2 | 26.0 |
| Dyskinesia | 3.4 | 4.7 | 2.6 | 7.7 | 8.7 |
| Dystonia | 1.1 | 0.8 | 1.3 | 5.3 | 4.5 |
| Hyperkinesia | 3.9 | 3.9 | 3.0 | 8.1 | 9.9 |
| Parkinsonism | 2.3 | 3.1 | 2.6 | 7.3 | 6.2 |
| Tremor | 3.4 | 3.1 | 2.6 | 4.5 | 3.3 |
Adverse Events Associated with Discontinuation of Treatment in Controlled Clinical Studies
Based on the pooled data from the three placebo-controlled, 6–week, fixed-dose studies, there was no difference in the incidence of discontinuation due to adverse events between INVEGA™-treated (5%) and placebo-treated (5%) subjects. The types of adverse events that led to discontinuation were similar for the INVEGA™-and placebo-treated subjects, except for Nervous System Disorders events which were more common among INVEGA™-treated subjects than placebo-treated subjects (2% and 0%, respectively), and Psychiatric Disorders events which were more common among placebo-treated subjects than INVEGA™-treated subjects (3% and 1%, respectively).
Demographic Differences in Adverse Reactions in Clinical Trials
An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race (see PRECAUTIONS: Geriatric Use).
Laboratory Test Abnormalities in Clinical Trials
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, between-group comparisons revealed no medically important differences between INVEGA™ and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. Similarly, there were no differences between INVEGA™ and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry. However, INVEGA™ was associated with increases in serum prolactin (see PRECAUTIONS: General: Hyperprolactinemia).
Weight Gain in Clinical Trials
In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of subjects having a weight gain of ≥ 7% of body weight were similar for INVEGA™ 3 mg and 6 mg (7% and 6%, respectively) and placebo (5%), but there was a higher incidence of weight gain for INVEGA™ 9 mg and 12 mg (9% and 9%, respectively).
Other Events Observed During the Premarketing Evaluation of INVEGA™
The following list contains all serious and non-serious treatment-emergent adverse events reported at any time by individuals taking INVEGA™ during any phase of a trial within the premarketing database (n = 2720), except (1) those listed in Table 1 above or elsewhere in labeling, (2) those for which a causal relationship to INVEGA™ use was considered remote, and (3) those occurring in only one subject treated with INVEGA™ and that were not acutely life-threatening.
Events are classified within body system categories using the following definitions: very frequent adverse events are defined as those occurring on one or more occasions in at least 1/10 subjects, frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 subjects, infrequent adverse events are those occurring on one or more occasions in 1/100 to 1/1000 subjects, and rare events are those occurring on one or more occasions in less than 1/1000 subjects.
Blood and Lymphatic System Disorders: rare: thrombocytopenia
Cardiac Disorders: frequent: palpitations; infrequent: bradycardia
Gastrointestinal Disorders: frequent: abdominal pain; infrequent: swollen tongue
General Disorders: infrequent: edema
Immune Disorder: rare: anaphylactic reaction
Nervous System Disorders: rare: coordination abnormal
Psychiatric Disorders: infrequent: confusional state
Respiratory, Thoracic and Mediastinal Disorders: frequent: dyspnea; rare: pulmonary embolus
Vascular Disorders: rare: ischemia, venous thrombosis
The safety of INVEGATM was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGATM in adults with schizophrenia (see CLINICAL PHARMACOLOGY: Clinical Trials). In general, adverse event types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse events reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.
Adverse Events Reported With Risperidone
Paliperidone is the major active metabolite of risperidone. Adverse events reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.
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