Austedo Xr

Dosing Information

The dose of AUSTEDO XR and AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. Table 1 displays the recommended dosage and important administration instructions of AUSTEDO XR and AUSTEDO when first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor).

Table 1: Recommended Dosage and Important Administration Instructions for AUSTEDO XR and AUSTEDO

Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO

Discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO XR or AUSTEDO in patients switching from tetrabenazine to AUSTEDO XR or AUSTEDO is shown in Table 2.

Table 2: Recommended Initial Dosing Regimen when Switching from Tetrabenazine to AUSTEDO XR or AUSTEDO

After patients are switched to AUSTEDO XR or AUSTEDO, the dose may be adjusted at weekly intervals [see Dosage and Administration ].

Dosage Adjustment with Strong CYP2D6 Inhibitors

In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions and Clinical Pharmacology ].

Dosage Adjustment in Poor CYP2D6 Metabolizers

In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Use in Specific Populations ].

Discontinuation and Interruption of Treatment

Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, AUSTEDO XR or AUSTEDO therapy should be re-titrated when resumed. For treatment interruption of less than one week, treatment can be resumed at the previous maintenance dose without titration.

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of AUSTEDO XR or AUSTEDO in pregnant women. Administration of deutetrabenazine to rats during organogenesis produced no clear adverse effect on embryofetal development. However, administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m2) basis.

The effects of deutetrabenazine when administered during organogenesis to rabbits or during pregnancy and lactation to rats have not been assessed.

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. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) 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.

Lactation

Risk Summary

There are no data on the presence of deutetrabenazine 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 AUSTEDO XR or AUSTEDO and any potential adverse effects on the breastfed infant from AUSTEDO XR or AUSTEDO or from the underlying maternal condition.

Pediatric Use

Chorea associated with Huntington’s Disease and Tardive Dyskinesia 

The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntington’s disease or for the treatment of tardive dyskinesia.

Tourette Syndrome 

The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of Tourette syndrome.

Efficacy was not demonstrated in two randomized, double-blind, placebo-controlled studies in pediatric patients aged 6 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included a total of 274 pediatric patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of deutetrabenazine on the YGTSS-TTS was not statistically significantly different from placebo in either study. The placebo subtracted least squares means difference in YGTSS-TTS from baseline to end-of-treatment was -0.7 (95% CI: -4.1, 2.8) in the flexible dose study and -0.8 (95% CI: -3.9, 2.3) for the primary analysis in the fixed dose study.

The following adverse reactions were reported in frequencies of at least 5% of pediatric patients treated with AUSTEDO and with a greater incidence than in pediatric patients receiving placebo (AUSTEDO vs placebo): headache (includes: migraine, migraine with aura, and headache; 13% vs 9%), somnolence (includes: sedation, hypersomnia, and somnolence; 11% vs 2%), fatigue (8% vs 3%), increased appetite (5% vs <1%), and increased weight (5% vs <1%).

Juvenile Animal Toxicity Data

Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 70 (at 2.5, 5, or 10 mg/kg/day) resulted in an increased incidence of tremor, hyperactivity, and adverse increases in motor activity at ≥5 mg/kg/day, and reduced body weight and food consumption at 10 mg/kg/day. There was no reproductive or early embryonic toxicity up to the highest dose. All drug-related findings were reversible after a drug-free period. The no observed adverse effect level (NOAEL) in juvenile rats was 2.5 mg/kg/day. These drug-related findings were similar to those observed in adult rats; however, the juvenile rats were more sensitive.

Geriatric Use

Clinical studies of AUSTEDO XR and AUSTEDO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of hepatic, renal, and cardiac dysfunction, and of concomitant disease or other drug therapy.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied; however, in a clinical study conducted with tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its active metabolites in patients with hepatic impairment. The clinical significance of this increased exposure has not been assessed, but because of concerns for a greater risk for serious adverse reactions, the use of AUSTEDO XR or AUSTEDO in patients with hepatic impairment is contraindicated [see Contraindications , Clinical Pharmacology ].

Poor CYP2D6 Metabolizers

Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Dosage and Administration and Clinical Pharmacology ].