Tetrabenazineside effects

The following serious adverse reactions are described below and elsewhere in the labeling: Depression and Suicidality Neuroleptic Malignant Syndrome (NMS) Akathisia, Restlessness, and Agitation Parkinsonism Sedation and Somnolence QTc Prolongation Hypotension and Orthostatic Hypotension Hyperprolactinemia Binding to Melanin-Containing Tissues Most common adverse reactions (>10% and at least 5% greater than placebo) were: Sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, nausea. To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trials Experience 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 practice. During its development, tetrabenazine was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine varied greatly, and included single-dose and multiple-dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients. In a randomized, 12-week, placebo-controlled clinical trial of HD patients, adverse reactions were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received tetrabenazine experienced one or more adverse reactions at any time during the study. The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea. Adverse Reactions Occurring in ≥4% of Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in ≥4% of tetrabenazine-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1.

Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease Adverse Reaction Tetrabenazine n = 54 (%) Placebo n = 30 (%) Sedation/somnolence 31 3 Insomnia 22 0 Fatigue 22 13 Depression 19 0 Akathisia 19 0 Anxiety/anxiety aggravated 15 3 Fall 15 13 Nausea 13 7 Upper respiratory tract infection 11 7 Irritability 9 3 Balance difficulty 9 0 Parkinsonism/bradykinesia 9 0 Vomiting 6 3 Laceration (head) 6 0 Ecchymosis 6 0 Decreased appetite 4 0 Obsessive reaction 4 0 Dizziness 4 0 Dysarthria 4 0 Unsteady gait 4 0 Headache 4 3 Shortness of breath 4 0 Bronchitis 4 0 Dysuria 4 0 Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to tetrabenazine. These adverse reactions consisted of sedation, akathisia, parkinsonism, depression, anxiety, fatigue and diarrhea. Some patients had more than one AR and are, therefore, counted more than once. Adverse Reactions Due to Extrapyramidal Symptoms Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in tetrabenazine-treated patients compared to placebo-treated patients.

Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease Tetrabenazine n = 54 % Placebo n = 30 % Akathisia 1 19 0 Extrapyramidal event 2 15 0 Any extrapyramidal event 33 0 1 Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. 2 Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia. Patients may have had events in more than one category. Dysphagia Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of tetrabenazine-treated patients and 3% of placebo-treated patients. In 48-week and 80-week, open-label studies, dysphagia was observed in 10% and 8% of tetrabenazine-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of tetrabenazine tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system disorders: tremor Psychiatric disorders: confusion, worsening aggression Respiratory, thoracic and mediastinal disorders: pneumonia Skin and subcutaneous tissue disorders: hyperhidrosis, skin rash