Xenazine (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine (5, 15, and 30 mg/kg/day) for 26 weeks.

No increase in tumors was observed in Tg.rasH2 transgenic mice treated orally with a major human metabolite, 9-desmethyl-β-DHTBZ (20, 100, and 200 mg/kg/day), for 26 weeks.

Mutagenesis

Tetrabenazine and metabolites α-HTBZ, β-HTBZ, and 9-desmethyl-β-DHTBZ were negative in an in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in an in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. 9-desmethyl-β-DHTBZ was not clastogenic in an in vitro chromosomal aberration assay in human peripheral blood mononuclear cells in the presence or absence of metabolic activation. In vivo micronucleus assays were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.

Impairment of Fertility

Oral administration of tetrabenazine (5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis).

No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (5, 15, or 30 mg/kg/day; up to 3 times the MRHD on a mg/m2 basis) prior to and throughout mating with untreated females.

Because rats dosed with tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to impair fertility in humans.

14 CLINICAL STUDIES

Study 1

The efficacy of XENAZINE as a treatment for the chorea of Huntington’s disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. XENAZINE was started at a dose of 12.5 mg/day, followed by upward titration at weekly intervals, in 12.5 mg increments until satisfactory control of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 100 mg/day was reached.

The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.

As shown in Figure 1, Total Chorea Scores for patients in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving XENAZINE returned to baseline.

Figure 1: Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Patients Treated with XENAZINE (n=54) or Placebo (n=30)

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Figure 2 illustrates the cumulative percentages of patients from the XENAZINE and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for the XENAZINE-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. For example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of XENAZINE-treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3 points from baseline to Week 12 are shown in the inset table.

Figure 2: Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients Within Each Treatment Group Who Completed Study 1 Were: Placebo 97%, Tetrabenazine 91%

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A Physician-rated Clinical Global Impression (CGI) favored XENAZINE statistically. In general, measures of functional capacity and cognition showed no difference between XENAZINE and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with XENAZINE compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with XENAZINE compared to placebo, but the difference was not statistically significant.

Study 2

A second controlled study was performed in patients who had been treated with open-label XENAZINE for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of XENAZINE at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared. Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

XENAZINE® (tetrabenazine) tablets are available in the following strengths and packages:

The 12.5 mg XENAZINE tablets are white, cylindrical, biplanar tablets with beveled edges, non-scored, embossed on one side with “CL” and “12.5”.

NDC 67386-421-01 12.5 mg 112-count bottle

The 25 mg XENAZINE tablets are yellowish-buff, cylindrical, biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25”.

NDC 67386-422-01 25 mg 112-count bottle

16.2 Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risk of Suicidality

Inform patients and their families that XENAZINE may increase the risk of suicidal thinking and behaviors. Counsel patients and their families to remain alert to the emergence of suicidal ideation and to report it immediately to the patient’s physician [see Contraindications (4), Warnings and Precautions (5.1)].

Risk of Depression

Inform patients and their families that XENAZINE may cause depression or may worsen pre-existing depression. Encourage patients and their families to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and to report such symptoms promptly to the patient’s physician [see Contraindications (4), Warnings and Precautions (5.1)].

Dosing of XENAZINE

Inform patients and their families that the dose of XENAZINE will be increased slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician, and the XENAZINE dose may need to be reduced or discontinued [see Dosage and Administration (2.2)].

Risk of Sedation and Somnolence

Inform patients that XENAZINE may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to XENAZINE, they should be careful doing activities that require them to be alert, such as driving a car or operating machinery [see Warnings and Precautions (5.7)].

Interaction with Alcohol

Advise patients and their families that alcohol may potentiate the sedation induced by XENAZINE [see Drug Interactions (7.4)].

Usage in Pregnancy

Advise patients and their families to notify the physician if the patient becomes pregnant or intends to become pregnant during XENAZINE therapy, or is breastfeeding or intending to breastfeed an infant during therapy [see Use in Specific Populations (8.1)].

Manufactured by:
Recipharm Fontaine SAS
Rue des Prés Potets
21121 Fontaine-lés-Dijon, France

Manufactured for:
Lundbeck
Deerfield, IL 60015 USA

Xenazine is a trademark of Bausch Health Companies Inc. or its affiliates.

All other product/brand names and/or logos are trademarks of the respective owners.

© 2020 Bausch Health Companies Inc. or its affiliates

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