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, XENAZINE was administered to 773 unique subjects and patients. The conditions and duration of exposure to XENAZINE 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 XENAZINE group than in the placebo group. Forty-nine of 54 (91%) patients who received XENAZINE 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 Greater Than or Equal to 4% of Patients

The number and percentage of the most common adverse reactions that occurred at any time during the study in greater than or equal to 4% of XENAZINE-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	XENAZINE 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 XENAZINE. 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 XENAZINE-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
	XENAZINE n=54 %	Placebo n=30 %
* 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.
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 XENAZINE-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 XENAZINE-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 XENAZINE. 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