Tetrabenazine (Page 3 of 8)

5.11 Binding to Melanin-Containing Tissues

Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species, such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.

The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see CLINICAL PHARMACOLOGY (12.2)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

• Depression and Suicidality [see WARNINGS AND PRECAUTIONS (5.1)]
• Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS (5.4)]
• Akathisia, Restlessness, and Agitation [see WARNINGS AND PRECAUTIONS (5.5)]
• Parkinsonism [see WARNINGS AND PRECAUTIONS (5.6)]
• Sedation and Somnolence [see WARNINGS AND PRECAUTIONS (5.7)]
• QTc Prolongation [see WARNINGS AND PRECAUTIONS (5.8)]
• Hypotension and Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS (5.9)]
• Hyperprolactinemia [see WARNINGS AND PRECAUTIONS (5.10)]
• Binding to Melanin-Containing Tissues[see WARNINGS AND PRECAUTIONS (5.11)]

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	Placebo
	N = 54	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 (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). 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

* Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. † Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia.
	Tetrabenazine	Placebo
	n = 54	n = 30
	%	%
Akathisia *	19	0
Extrapyramidal event †	15	0
Any extrapyramidal event	33	0

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.