Austedo

• Austedo^®

Dosage Forms & Strengths

tablet

• 6mg
• 9mg
• 12mg

Chorea

Indicated for chorea associated with Huntington disease

Dose is determined individually for each patient based on reduction of chorea and tolerability

Initial dose when not being switched from tetrabenazine: 6 mg PO qDay

May increased dose at weekly intervals in increments of 6 mg/day; not to exceed 48 mg/day

Administer doses ≥12 mg/day in 2 divided doses

Also see Administration for doses when switching from tetrabenazine

Tardive Dyskinesia

Indicated for treatment of tardive dyskinesia (TD)

Dose is determined individually for each patient based on reduction of TD and tolerability

Initial dose when not being switched from tetrabenazine: 6 mg PO BID

May increased dose at weekly intervals in increments of 6 mg/day; not to exceed 48 mg/day

Also see Administration for doses when switching from tetrabenazine

Dosage Modifications

Strong CYP2D6 inhibitors

• Deutetrabenazine daily dose: Not to exceed 36 mg/day (maximum single dose of 18 mg)
• Examples of strong CYP2D6 inhibitors include quinidine and antidepressants (eg, paroxetine, fluoxetine, bupropion)

Poor CYP2D6 metabolizers

• Deutetrabenazine daily dose: Not to exceed 36 mg/day (maximum single dose of 18 mg)

Hepatic impairment

• Contraindicated
• Effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied
• 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
• The clinical significance of this increased exposure has not been assessed, but because of concerns for a greater risk for serious adverse reactions, it is contraindicated

Dosing Considerations

For patients at risk for QT prolongation, assess QT interval before and after increasing doses to >24 mg/day

Safety and efficacy not established

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, crying spells, trouble concentrating, loss of interest in things you enjoyed before, changes in weight or appetite, or if you feel hopeless, guilty, extremely tired, irritable, hostile, aggressive, or have thoughts about suicide or hurting yourself.

Some side effects may actually be signs that your Huntington's disease is progressing. Your doctor will need to check your progress at regular intervals.

Call your doctor at once if you have:

• severe restlessness or agitation;

• tremors, shaking;

• muscle stiffness;

• problems with balance or coordination; or

• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Common side effects may include:

• drowsiness;

• feeling tired;

• dry mouth; or

• diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Deutetrabenazine has the following uses:

Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of chorea associated with Huntington’s disease.1

Deutetrabenazine also is indicated for the treatment of tardive dyskinesia in adults.1

General

Deutetrabenazine is available in the following dosage form(s) and strength(s):

Tablets: 6 mg, 9 mg, and 12 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:1

• 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 (24 mg twice daily).1

• Administer total daily dosages of 12 mg or above in two divided doses.1

• For patients at risk for QT prolongation, assess the QT interval before and after increasing the total dosage above 24 mg per day.1

• Administer with food.1

• Swallow tablets whole; do not chew, crush, or break.1

• If switching patients from tetrabenazine, discontinue tetrabenazine and initiate deutetrabenazine the following day. See full prescribing information for recommended conversion table.1

• Maximum recommended dosage of deutetrabenazine in poor CYP2D6 metabolizers is 36 mg per day (i.e., 18 mg twice daily).1

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

• Tell all of your health care providers that you take Austedo. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how this medicine affects you.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• If you have Huntington's disease, your signs can still get worse while you use drugs like this one. Call your doctor right away if you have any signs that are new or worse.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Austedo while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of 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 and any potential adverse effects on the breastfed infant from Austedo or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of 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 in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].

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 should not exceed 36 mg (maximum single dose of 18 mg) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies were performed with deutetrabenazine.

No increase in tumors was observed in p53+/– transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks.

Mutagenesis

Deutetrabenazine and its deuterated α-HTBZ and β-HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.

Impairment of Fertility

The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses; the lowest dose tested was similar to the maximum recommended human dose (48 mg/day) on a body surface area (mg/m2) basis.

Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation, resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine at doses of 5, 15 or 30 mg/kg/day prior to and throughout mating with untreated females.

How Supplied

Austedo tablets are available in the following strengths and packages:

6 mg: round, purple-coated tablets, with “SD” over “6” printed in black ink on one side.

Bottles of 60 tablets: NDC 68546-170-60.

9 mg: round, blue-coated tablets, with “SD” over “9” printed in black ink on one side.

Bottles of 60 tablets: NDC 68546-171-60.

12 mg: round, beige-coated tablets, with “SD” over “12” printed in black ink on one side.

Bottles of 60 tablets: NDC 68546-172-60.

Storage

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Protect from light and moisture.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, crying spells, trouble concentrating, loss of interest in things you enjoyed before, changes in weight or appetite, or if you feel hopeless, guilty, extremely tired, irritable, hostile, aggressive, or have thoughts about suicide or hurting yourself.

Some side effects may actually be signs that your Huntington's disease is progressing. Your doctor will need to check your progress at regular intervals.

Call your doctor at once if you have:

• severe restlessness or agitation;
• tremors, shaking;
• muscle stiffness;
• problems with balance or coordination; or
• severe nervous system reaction--very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out.

Common side effects may include:

• drowsiness;
• feeling tired;
• dry mouth;
• runny or stuffy nose, sore throat;
• sleep problems (insomnia); or
• diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Take Austedo exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

If you are switching from a similar medicine called tetrabenazine (Xenazine), take your first dose of deutetrabenazine one day after your last dose of tetrabenazine.

Austedo is usually taken 1 or 2 times per day with food and a whole glass of water.

Do not crush, chew, or break a tablet. Swallow the tablet whole. Tell your doctor if you have trouble swallowing the tablet whole.

Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG).

Do not stop taking this medicine without first asking your doctor.

Store at room temperature away from moisture, heat, and light.

If you stop taking Austedo for longer than 1 week, do not start taking it again without your doctor's advice.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include tremors or severe muscle stiffness, rapid eye movements, vomiting, sweating, severe drowsiness, confusion, hallucinations, diarrhea, or feeling light-headed.

Applies to deutetrabenazine: oral tablet

General

The most common adverse reactions occurring in greater than 8% were somnolence, diarrhea, dry mouth, and fatigue.[Ref]

Nervous system

Very common (10% or more): Sedation/somnolence (11%)
Common (1% to 10%): Dizziness[Ref]

Dermatologic

Common (1% to 10%): Contusion[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea, dry mouth, constipation[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection[Ref]

Other

Common (1% to 10%): Fatigue[Ref]

Psychiatric

Common (1% to 10%): Insomnia, anxiety, depression, suicidal ideation, akathisia/agitation/restlessness[Ref]

Some side effects of Austedo may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.