Austedo Xr Drug Information

• AUSTEDO XR ® and AUSTEDO ® are indicated in adults for the treatment of: chorea associated with Huntington’s disease tardive dyskinesia AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated in adults for the treatment of: Chorea associated with Huntington’s disease Tardive dyskinesia

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 may be increased at weekly intervals in increments of 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg.

Important Administration Instructions Administer AUSTEDO XR with or without food. Swallow AUSTEDO XR whole. Do not chew, crush, or break tablets.

Administer AUSTEDO XR once daily. Administer AUSTEDO with food. Swallow AUSTEDO whole.

Administer AUSTEDO total daily dosages of 12 mg or above in two divided doses.

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, the dose may be adjusted at weekly intervals.

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.

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.

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.

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. The studies described below were conducted with AUSTEDO tablets; adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets. Patients with Huntington’s Disease Study 1 was a randomized, 12-week, placebo-controlled study in patients with chorea associated with Huntington’s disease.

A total of 45 patients received AUSTEDO, and 45 patients received placebo. The most common adverse reactions occurring in greater than 8% of AUSTEDO-treated patients were somnolence, diarrhea, dry mouth, and fatigue. Adverse reactions occurring in 4% or more of patients treated with AUSTEDO, and with a greater incidence than in patients on placebo, are summarized in Table 3.

The most common adverse reaction resulting in dose reduction in patients receiving AUSTEDO was dizziness (4%). Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1. Patients with Tardive Dyskinesia The data described below reflect 410 tardive dyskinesia patients participating in clinical trials.

AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed dose, dose escalation). In these studies, AUSTEDO was administered in doses ranging from 12-48 mg per day. All patients continued on previous stable regimens of antipsychotics; 71% and 14% respective atypical and typical antipsychotic medications at study entry.

The most common adverse reactions occurring in greater than 3% of AUSTEDO-treated patients and greater than placebo were nasopharyngitis and insomnia. The adverse reactions occurring in >2% or more patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo patients in two double-blind, placebo-controlled studies in patients with tardive dyskinesia (Study 1 and Study 2) are summarized in Table 4.

Strong CYP2D6 Inhibitors

A reduction in AUSTEDO XR or AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of AUSTEDO XR or AUSTEDO. Concomitant use of strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. The daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg per day in patients taking strong CYP2D6 inhibitors.

Reserpine

Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea or dyskinesia to reemerge before administering AUSTEDO XR or AUSTEDO to help reduce the risk of overdosage and major depletion of serotonin and norepinephrine in the central nervous system. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO.

AUSTEDO XR and AUSTEDO should not be used concomitantly with reserpine.

Monoamine Oxidase Inhibitors (MAOIs) AUSTEDO XR and AUSTEDO are contraindicated in patients taking MAOIs. AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI.

Neuroleptic Drugs

The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics.

Alcohol or Other Sedating Drugs

Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Concomitant Tetrabenazine or Valbenazine AUSTEDO XR and AUSTEDO are contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO XR or AUSTEDO may be initiated the day following discontinuation of tetrabenazine.

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.

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. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m 2 ) 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.

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 in the flexible dose study and for the primary analysis in the fixed dose study. Juvenile Animal Toxicity Data Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 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.

AUSTEDO XR and AUSTEDO are contraindicated in patients: With Huntington’s disease who are suicidal, or have untreated or inadequately treated depression. With hepatic impairment. Taking reserpine.

At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO. Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI.

Taking tetrabenazine or valbenazine. Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease Hepatic impairment Taking reserpine, MAOIs, tetrabenazine, or valbenazine

Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related VMAT2 inhibitor. The following adverse reactions occurred with overdosing: acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. Treatment should consist of those general measures employed in the management of overdosage with any central nervous system-active drug.

General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered.

The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed on the American Association of Poison Control Centers website www.aapcc.org.