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Deutetrabenazine

FDA Drug Information • Also known as: Austedo, Austedo Xr

Brand Names
Austedo, Austedo Xr
Route
ORAL
Dosage Form
TABLET, FILM COATED, EXTENDED RELEASE
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of AUSTEDO XR or AUSTEDO must balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. 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. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE See full prescribing information for complete boxed warning. Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease ( 5.1 ) Balance risks of depression and suicidality with the clinical need for treatment of chorea when considering the use of AUSTEDO XR or AUSTEDO ( 5.1 ) Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior ( 5.1 ) Inform patients, caregivers, and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician ( 5.1 ) Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation ( 5.1 ) AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression ( 4 , 5.1 )

Description

11 DESCRIPTION AUSTEDO XR extended-release tablets and AUSTEDO tablets are formulated with deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31. Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: ( RR, SS )-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. The molecular formula for deutetrabenazine is C 19 H 21 D 6 NO 3 . Deutetrabenazine is a racemic mixture containing the following structures: Deutetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol. AUSTEDO XR AUSTEDO XR extended-release tablets contain 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended-release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. AUSTEDO XR Delivery System Components and Performance AUSTEDO XR uses osmotic pressure to deliver deutetrabenazine at a controlled rate. The delivery system, which resembles a round tablet in appearance, consists of a bilayer core tablet that contains deutetrabenazine along with other excipients. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool. AUSTEDO AUSTEDO tablets...

What Is Deutetrabenazine Used For?

1 INDICATIONS AND USAGE AUSTEDO XR ® and AUSTEDO ® are indicated in adults for the treatment of: chorea associated with Huntington’s disease [see Clinical Studies ( 14.1 )] tardive dyskinesia [see Clinical Studies ( 14.2 )] AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated in adults for the treatment of: Chorea associated with Huntington’s disease ( 1 ) Tardive dyskinesia ( 1 )

Dosage and Administration

2 DOSAGE AND ADMINISTRATION AUSTEDO XR AUSTEDO Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Titrate at weekly intervals by 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg ( 2.1 ) Administer AUSTEDO XR with or without food in once-daily doses ( 2.1 ) Administer AUSTEDO with food and administer total daily dosages of 12 mg or above in two divided doses ( 2.1 ) Swallow tablets whole; do not chew, crush, or break ( 2.1 ) If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. See full prescribing information for recommended conversion table ( 2.2 ) Maximum recommended dosage of AUSTEDO XR or AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day ( 2.4 , 8.7 ) 2.1 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 AUSTEDO XR extended-release tablet AUSTEDO tablet Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Recommended Dose Titration The dosage of AUSTEDO XR or AUSTEDO 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 [see Clinical Trials ( 14.1 , 14.2 )] . Important Administration Instructions Administer AUSTEDO XR with or without food [see Clinical Pharmacology ( 12.3 )] . Swallow AUSTEDO XR whole. Do not chew, crush, or break tablets. Administer AUSTEDO XR once daily. Administer AUSTEDO with food [see Clinical Pharmacology ( 12.3 )] . Swallow AUSTEDO whole. Do not chew, crush, or break tablets. Administer AUSTEDO total daily dosages of 12 mg or above in two divided doses. Switching Between AUSTEDO and AUSTEDO XR When switching between AUSTEDO tablets (twice daily) and AUSTEDO XR extended-release tablets (once daily), switch to the same total daily dosage. 2.2 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 Current tetrabenazine daily dosage Initial regimen of AUSTEDO XR extended-release tablet Initial regimen of AUSTEDO tablet 12.5 mg 6 mg once daily 6 mg once daily 25 mg 12 mg once daily 6 mg twice daily...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Depression and Suicidality in Patients with Huntington’s disease [see Warnings and Precautions ( 5.1 )] QTc Prolongation [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.4 )] Akathisia, Agitation, and Restlessness [see Warnings and Precautions ( 5.5 )] Parkinsonism [see Warnings and Precautions ( 5.6 )] Sedation and Somnolence [see Warnings and Precautions ( 5.7 )] Hyperprolactinemia [see Warnings and Precautions ( 5.8 )] Binding to Melanin-Containing Tissues [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (>8% of AUSTEDO-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue ( 6.1 ) Most common adverse reactions (that occurred in 4% of AUSTEDO-treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies ( 14.1 )] 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. Patients ranged in age between 23 and 74 years (mean 54 years); 56% were male, and 92% were Caucasian. 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. Table 3: Adverse Reactions in Patients with Huntington's Disease (Study 1) Experienced by at Least 4% of Patients on AUSTEDO and with a Greater Incidence than on Placebo Adverse Reaction AUSTEDO (N = 45) % Placebo (N = 45) % Somnolence 11 4 Diarrhea 9 0 Dry mouth 9 7 Fatigue 9 4 Urinary tract infection 7 2 Insomnia 7 4 Anxiety 4 2 Constipation 4 2 Contusion 4 2 One or more adverse reactions resulted in a reduction of the dose of study medication in 7% of patients in Study 1. 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) [see Clinical Studies ( 14.2 )] . The population was 18 to 80 years of age, and had tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or schizophrenia/schizoaffective disorder (63%). 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...

Drug Interactions

7 DRUG INTERACTIONS Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day ( 2.3 , 7.1 ) Alcohol or other sedating drugs: May have additive sedation and somnolence ( 7.5 ) 7.1 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 [see Dosage and Administration ( 2.3 ) and Clinical Pharmacology ( 12.3 )]. 7.2 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 [see Contraindications ( 4 )] . 7.3 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 [see Contraindications ( 4 )] . 7.4 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. 7.5 Alcohol or Other Sedating Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions ( 5.7 )]. 7.6 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 [see Dosage and Administration ( 2.2 )].

Contraindications

4 CONTRAINDICATIONS AUSTEDO XR and AUSTEDO are contraindicated in patients: With Huntington’s disease who are suicidal, or have 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 reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO [see Drug Interactions ( 7.2 )] . 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 [see Drug Interactions ( 7.3 )] . Taking tetrabenazine or valbenazine [see Drug Interactions ( 7.6 )] . Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease ( 4 , 5.1 ) Hepatic impairment ( 4 , 8.6 , 12.3 ) Taking reserpine, MAOIs, tetrabenazine, or valbenazine ( 4 , 7.2 , 7.3 , 7.6 )

Pregnancy and Breastfeeding

8.1 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/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.

Overdosage

10 OVERDOSAGE 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AUSTEDO XR extended-release tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, grey-coated tablets, with “Q6” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-470-56 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-471-56 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-479-56 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-472-56 30 mg Round, light orange-coated tablets, with “Q30” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-473-56 36 mg Round, light purple-coated tablets, with “Q36” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-474-56 42 mg Round, orange-coated tablets, with “Q42” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-475-56 48 mg Round, pink-coated tablets, with “Q48” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-476-56 AUSTEDO XR Patient Titration Kits are supplied in the following configuration: Strength Description Package Configuration NDC Code 4-Week Patient Titration Kit 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Titration Kit / 28 count Each Titration Kit contains 1 child-resistant blister pack, containing one foil card with extended-release tablets in the following configuration: Seven 12 mg tablets taken during Week 1; seven 18 mg tablets taken during Week 2; seven 24 mg tablets taken during Week 3; and seven 30 mg tablets taken during Week 4. 68546-477-29 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side 24 mg Round, purple-coated tablets,...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.