Xenazine

XENAZINE- tetrabenazine tablet
Lundbeck Pharmaceuticals LLC

WARNING: DEPRESSION AND SUICIDALITY

XENAZINE can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of XENAZINE must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician.

Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington’s disease. XENAZINE is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4), Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

XENAZINE is indicated for the treatment of chorea associated with Huntington’s disease.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

The chronic daily dose of XENAZINE used to treat chorea associated with Huntington’s disease (HD) is determined individually for each patient. When first prescribed, XENAZINE therapy should be titrated slowly over several weeks to identify a dose of XENAZINE that reduces chorea and is tolerated. XENAZINE can be administered without regard to food [see Clinical Pharmacology (12.3)].

2.2 Individualization of Dose

The dose of XENAZINE should be individualized.

Dosing Recommendations Up to 50 mg/day

The starting dose should be 12.5 mg/day given once in the morning. After 1 week, the dose should be increased to 25 mg/day given as 12.5 mg twice a day. XENAZINE should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg/day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse reactions such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing XENAZINE treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions (6.1)].

Dosing Recommendations Above 50 mg/day

Patients who require doses of XENAZINE greater than 50 mg/day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of XENAZINE should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Extensive and Intermediate CYP2D6 Metabolizers

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of XENAZINE above 50 mg/day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg/day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing XENAZINE treatment or initiating other specific treatment (e.g., antidepressants) [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Poor CYP2D6 Metabolizers

In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment with CYP2D6 Inhibitors

Strong CYP2D6 Inhibitors

Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ; therefore, the total dose of XENAZINE should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg [see Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.4 Discontinuation of Treatment

Treatment with XENAZINE can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of XENAZINE [see Drug Abuse and Dependence (9.2)].

2.5 Resumption of Treatment

Following treatment interruption of greater than 5 days, XENAZINE therapy should be re-titrated when resumed. For short-term treatment interruption of less than 5 days, treatment can be resumed at the previous maintenance dose without titration.

3 DOSAGE FORMS AND STRENGTHS

XENAZINE 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.”

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

4 CONTRAINDICATIONS

XENAZINE is contraindicated in patients:

Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1)].
With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Taking monoamine oxidase inhibitors (MAOIs). XENAZINE should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3)].
Taking reserpine. At least 20 days should elapse after stopping reserpine before starting XENAZINE [see Drug Interactions (7.2)].
Taking deutetrabenazine or valbenazine [see Drug Interactions (7.7)].

5 WARNINGS AND PRECAUTIONS

5.1 Depression and Suicidality

Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). XENAZINE increases the risk for suicidality in patients with HD.

In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with XENAZINE were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received XENAZINE for up to 48 weeks; in the second study, 75 patients received XENAZINE for up to 80 weeks), the rate of depression/worsening depression was 35%.

In all of the HD chorea studies of XENAZINE (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.

When considering the use of XENAZINE, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with XENAZINE should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with XENAZINE.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with XENAZINE, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.

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