Dosage & Administration
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Xenazine Prescribing Information
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)].
XENAZINE is indicated for the treatment of chorea associated with Huntington’s disease.
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)].
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)].
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)].
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)].
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.
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.”
Pregnancy
Risk Summary
There are no adequate data on the developmental risk associated with the use of XENAZINE in pregnant women. Administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. Administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). The adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses [see Data].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
Tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m2 basis). Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m2 basis).
When tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. A no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. The lowest dose tested (5 mg/kg/day) was less than the MRHD on a mg/m2 basis.
Because rats dosed orally with tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. Oral administration of 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-β-DHTBZ in pregnant rats lower than that in humans at the MRHD.
Lactation
Risk Summary
There are no data on the presence of tetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XENAZINE and any potential adverse effects on the breastfed infant from XENAZINE or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
The pharmacokinetics of XENAZINE and its primary metabolites have not been formally studied in geriatric subjects.
Hepatic Impairment
Because the safety and efficacy of the increased exposure to XENAZINE and other circulating metabolites are unknown, it is not possible to adjust the dosage of XENAZINE in hepatic impairment to ensure safe use. The use of XENAZINE in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].
Poor or Extensive CYP2D6 Metabolizers
Patients who require doses of XENAZINE greater than 50 mg/day, should be first tested and genotyped to determine if they are poor (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 either poor (PMs) or extensive metabolizers (EMs) [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].
Poor Metabolizers
Poor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to a patient’s CYP2D6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a maximum of 50 mg/day in patients who are CYP2D6 PMs [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].
Extensive/Intermediate Metabolizers
In extensive (EMs) or intermediate metabolizers (IMs), the dosage of XENAZINE can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg [see Dosage and Administration (2.2), Drug Interactions (7.1), Clinical Pharmacology (12.3)].
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 ].
- Taking deutetrabenazine or valbenazine [see Drug Interactions ].