Pharmacy & Therapeutics - October 2008 - (Page 588)

Antiemetic effect [see Warnings and Precautions] Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions] • Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions] The most common adverse reactions in clinical trials (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were akathisia and extrapyramidal disorder. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders [see Adverse Reactions]. The safety of INVEGA ® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, doubleblind trials, of whom 850 subjects received INVEGA® at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA® at daily doses within the range of 3 mg to 15 mg (n=104), is also included. Adverse events during exposure to study treatment 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. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Commonly-Observed Adverse Reactions in Double-Blind, PlaceboControlled Clinical Trials: Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixeddose studies, listing those 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. Adverse Reactions in Short-Term, Fixed-Dose, PlaceboControlled Trials in Adult Subjects with Schizophrenia*: Body System or Organ Class (Dictionary-derived Term) Percent of Patients Reporting Event Placebo (N=355) first, INVEGA® 3 mg once daily (N=127) second, 6 mg once daily (N=235) third, 9 mg once daily (N=246) fourth, 12 mg once daily (N=242) fifth, Total percentage of subjects with adverse reactions 37, 48, 47, 54, 60; 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; Gastrointestinal disorders: Abdominal pain upper 1, 1, 3, 2, 2; Dry mouth 1, 2, 3, 1, 3; Salivary hypersecretion <1, 0, <1, 1, 4; General disorders: Asthenia 1, 2, <1, 2, 2; Fatigue 1, 2, 1, 2, 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, 0.3 (Global score defined as total sum of items score divided by the number of items) b: For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 c: Percent of patients who received anticholinergic medications to treat emergent EPS Table 3. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term: EPS Group Percentage of Patients Placebo (N=355) first, INVEGA® 3 mg once daily (N=127) second, 6 mg once daily (N=235) third, 9 mg once daily (N=246) fourth, 12 mg once daily (N=242) fifth, Overall percentage of patients with EPSrelated AE 11, 13, 10, 25, 26; Dyskinesia 3, 5, 3, 8, 9; Dystonia 1, 1, 1, 5, 5; Hyperkinesia 4, 4, 3, 8, 10; Parkinsonism 2, 3, 3, 7, 6; Tremor 3, 3, 3, 4, 3; 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 Laboratory Test Abnormalities: In the pooled data from the three placebocontrolled, 6-week, fixed-dose studies, a between-group comparison revealed no medically important differences between INVEGA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® was associated with increases in serum prolactin [see Warnings and Precautions]. Weight Gain: In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA ® 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA® 9 mg and 12 mg (9% and 9%, respectively). Other Findings Observed During Clinical Trials: The safety of INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® in adults with schizophrenia [see Clinical Studies]. In general, adverse reaction 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 reactions 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.

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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