Deutetrabenazine (Monograph)

Brand name: Austedo
Drug class: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors

Medically reviewed by Drugs.com on May 24, 2023. Written by ASHP.

Introduction

A vesicular monoamine transporter 2 (VMAT2) inhibitor; deuterium-substituted derivative of tetrabenazine.

Uses for Deutetrabenazine

Huntington's Chorea

Treatment of chorea associated with Huntington's disease in adults; designated an orphan drug by FDA for treatment of Huntington's disease.

Although no direct, comparative studies conducted to date, some evidence suggests that deutetrabenazine has a lower risk of moderate to severe adverse effects than tetrabenazine. In addition, immediate-release deutetrabenazine usually is given twice daily compared with 3 times daily for most patients receiving tetrabenazine. These clinical differences appear to be related to the different pharmacokinetic profiles of deutetrabenazine and tetrabenazine.

Tardive Dyskinesia

Treatment of tardive dyskinesia in adults.

Tardive dyskinesia is a hyperkinetic movement disorder associated with prolonged use of antipsychotic agents or other antidopaminergic drugs (e.g., metoclopramide).

The American Psychiatric Association (APA) recommends use of a VMAT2 inhibitor, such as deutetrabenazine, for treating moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy. Treatment may also be considered for patients with mild tardive dyskinesia.

Related/similar drugs

Xenazine, Ingrezza, amantadine, pyridoxine, vitamin e, Austedo, tetrabenazine

Deutetrabenazine Dosage and Administration

General

Pretreatment Screening

• Evaluate baseline liver function; deutetrabenazine is contraindicated in patients with hepatic impairment.

Patient Monitoring

• Monitor patients with Huntington’s disease closely for clinical worsening or emergence of depression, suicidal thoughts or behavior (suicidality), or unusual changes in behavior.

• Monitor patients with Huntington’s disease for worsening cognition, functional capacity, mood, or rigidity and periodically re-evaluate continued need for deutetrabenazine.

• Monitor for signs or symptoms of akathisia, parkinsonism, or neuroleptic malignant syndrome (NMS).

Other General Considerations

• At least 14 days must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor and initiation of deutetrabenazine; in addition, at least 20 days must elapse between discontinuance of reserpine and initiation of deutetrabenazine.

Administration

Oral Administration

Administer immediate-release formulation orally with food. Administer extended-release formulation orally with or without food. Swallow immediate- and extended-release tablets whole; do not chew, crush, or break tablets.

Total daily dosages <12 mg of the immediate-release tablet: Administer once daily.

Total daily dosages ≥12 mg of the immediate-release tablet: Administer in 2 divided doses.

Dosage

Individualize dosage based on symptom control (i.e., reduction of chorea or dyskinesia) and tolerability.

If used with a strong CYP2D6 inhibitor, dosage adjustment may be required.

If treatment is interrupted for >1 week, retitrate dosage as with initial therapy for both formulations. May resume treatment at the previous maintenance dosage (without titration) for treatment interruptions of <1 week.

May discontinue treatment of both formulations without tapering the dosage.

When switching between a twice daily immediate-release dosage regimen and a once daily extended-release dosage regimen, switch to the same total daily deutetrabenazine dosage.

Adults

Huntington's Chorea

Oral

Initially, 6 mg of immediate-release tablet twice daily or 12 mg of extended-release tablet once daily. May increase daily dosage of either formulation in 6-mg increments at weekly intervals up to the maximum recommended dosage of 48 mg daily.

Tardive Dyskinesia

Oral

Initially, 6 mg of immediate-release tablet twice daily or 12 mg of extended-release tablet once daily. May increase daily dosage of either formulation in 6-mg increments at weekly intervals up to the maximum recommended dosage of 48 mg daily.

Transferring Patients from Tetrabenazine to Deutetrabenazine

In patients being switched from tetrabenazine: Discontinue tetrabenazine and initiate deutetrabenazine the following day. See Table 1 for recommended initial deutetrabenazine dosages based on current total daily dosage of tetrabenazine. After switching, adjust deutetrabenazine dosage at weekly intervals.

Prescribing Limits

Adults

Huntington's Chorea

Oral

Maximum recommended daily dose of 48 mg.

Poor CYP2D6 metabolizer phenotype: Maximum total daily dose of 36 mg.

Tardive Dyskinesia

Oral

Maximum recommended daily dose of 48 mg.

Poor CYP2D6 metabolizer phenotype: Maximum total daily dose of 36 mg.

Special Populations

Hepatic Impairment

Contraindicated in patients with hepatic impairment.

Renal Impairment

Not studied; manufacturer provides no specific dosage recommendations.

Geriatric Patients

Select dosage with caution, usually beginning with the lower end of the dosage range, because of greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in geriatric patients.

Poor CYP2D6 Metabolizers

Do not exceed 36 mg daily.

Cautions for Deutetrabenazine

Contraindications

• Patients with Huntington's disease who are suicidal or have untreated or inadequately treated depression.

• Hepatic impairment.

• Concomitant therapy with reserpine. At least 20 days should elapse between discontinuance of reserpine and initiation of deutetrabenazine.

• Concomitant therapy with a monoamine oxidase (MAO) inhibitor. At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of deutetrabenazine.

• Concomitant therapy with tetrabenazine or valbenazine.

Warnings/Precautions

Warnings

Depression and Suicidality in Patients with Huntington's Disease

Increased risk for depression and suicidal ideation or behavior (suicidality) in patients with Huntington's disease. Deutetrabenazine may increase this risk. In the principal efficacy study, depression and suicidal ideation reported; however, no suicide attempts or completed suicides. (See Boxed Warning.)

Balance potential risks of depression and suicidality with clinical need for treatment of chorea. Closely monitor patients for emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, caregivers, and families of these risks and instruct them to promptly report any behaviors of concern to the treating clinician. Immediately evaluate patients with Huntington's disease who express suicidal ideation. Consider drug discontinuance if depression or suicidality does not resolve.

Exercise particular caution when treating patients with a history of depression or prior suicide attempts or ideation, which are increased in patients with Huntington's disease.

Other Warnings and Precautions

Clinical Worsening and Adverse Effects in Patients with Huntington's Disease

Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including deutetrabenazine, may cause worsening in mood, cognition, rigidity, and functional capacity.

Periodically reevaluate need for continued deutetrabenazine therapy by assessing its effect on chorea and possible adverse effects (e.g., sedation or somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, cognitive decline). Dosage reduction or drug discontinuance may help distinguish between drug-induced adverse effects and disease progression. Underlying chorea may improve over time, thereby possibly decreasing the need for deutetrabenazine.

Prolongation of QT Interval

Small increase in corrected QT (QT_c ) interval observed but not considered clinically important when administered within recommended dosage range. No clinically relevant effect observed in extensive, intermediate, or poor CYP2D6 metabolizers following single doses of 24 and 48 mg.

Factors that may increase risk of torsades de pointes and/or sudden death in association with drugs that prolong the QT_c interval include bradycardia, hypokalemia or hypomagnesemia, concomitant use of other drugs that prolong the QT_c interval, and presence of congenital long QT syndrome.

Avoid use in patients with congenital long QT syndrome or history of cardiac arrhythmias.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with drugs that reduce dopaminergic transmission. Although not reported with deutetrabenazine, NMS has been reported with tetrabenazine (a closely related VMAT2 inhibitor).

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs. Carefully monitor for recurrence if therapy is reinstituted following recovery from NMS.

Akathisia, Agitation, and Restlessness

Increased risk of akathisia, agitation, or restlessness in patients with Huntington's disease or tardive dyskinesia.

Monitor for akathisia, restlessness, and agitation. If akathisia develops, reduce deutetrabenazine dosage; drug discontinuance may be necessary in some patients.

Parkinsonism

Parkinsonism may develop in patients with Huntington’s disease or tardive dyskinesia; may be difficult to distinguish between drug-induced effect and rigidity associated with progression of Huntington's disease. For some patients, drug-induced parkinsonism may result in more functional disability than untreated chorea. In patients with tardive dyskinesia, parkinson-like symptoms (e.g., bradykinesia, gait disturbance, falls, emergence or worsening of tremor) usually occur within 2 weeks after starting treatment or increasing the dose and resolve following discontinuation of therapy.

If parkinsonism develops, consider dosage reduction; some patients may require drug discontinuance.

Sedation and Somnolence

Sedation or somnolence is a common dose-limiting adverse effect.

May impair cognitive and/or physical abilities required to perform potentially hazardous tasks such as driving or operating machinery.

Hyperprolactinemia

Elevated serum prolactin concentrations reported with tetrabenazine (a closely related VMAT2 inhibitor).

If contemplating deutetrabenazine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro. In addition, chronic hyperprolactinemia has been associated with low estrogen concentrations and an increased risk of osteoporosis.

Perform appropriate laboratory testing and consider drug discontinuance if symptomatic hyperprolactinemia (e.g., amenorrhea, galactorrhea, gynecomastia, impotence) suspected.

Binding to Melanin-containing Tissues

Binds to melanin-containing tissues, possibly resulting in accumulation and toxicity with long-term use; clinical importance unknown. Ophthalmologic monitoring in clinical studies was inadequate to exclude possibility of injury after long-term drug exposure.

Specific Populations

Pregnancy

Manufacturer states no adequate data available on developmental risk associated with deutetrabenazine in pregnant women. No clear adverse effects on embryofetal development observed in animal studies at supratherapeutic dosages. However, increased stillbirths, reduced pup survival, and delayed pup maturation observed when tetrabenazine (a closely related VMAT2 inhibitor) was administered to rats throughout pregnancy and lactation.

Lactation

Not known whether deutetrabenazine or its metabolites distribute into human milk. Effects of the drug or its metabolites on breast-fed infants and on milk production also not known. Consider developmental and health benefits of breast-feeding along with mother's clinical need for deutetrabenazine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Manufacturer states that safety and efficacy not established in pediatric patients for treatment of chorea associated with Huntington’s disease, tardive dyskinesia, or Tourette's syndrome^{† [off-label]}.

In randomized placebo-controlled trials evaluating deutetrabenazine for treatment of Tourette's syndrome^{† [off-label]} in patients 6 to 16 years of age, the drug failed to demonstrate an effect. Adverse events were mild to moderate.

Has been used with some success and appeared to be well tolerated in a limited number of adolescents with Tourette's syndrome^{† [off-label]} in a short-term, open-label study.

Geriatric Use

Insufficient experience from clinical studies in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Other clinical experience has not identified differences in responses between geriatric and younger adult patients. Select dosage with caution.

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment; however, substantially increased exposure of tetrabenazine and its active metabolites observed. Clinical importance of increased exposure of tetrabenazine and its metabolites unknown. Because of potential for serious adverse reactions, deutetrabenazine is contraindicated in patients with hepatic impairment.

Renal Impairment

Pharmacokinetics not evaluated in renal impairment.

Poor CYP2D6 Metabolizers

Increased exposure of active metabolites deuterated α-dihydrotetrabenazine (deuterated α-HTBZ) and deuterated β-dihydrotetrabenazine (deuterated β-HTBZ) expected; limit daily dosage to ≤36 mg.

Common Adverse Effects

Adverse effects in patients with Huntington's disease (>8%): somnolence, diarrhea, dry mouth, fatigue.

Adverse effects in patients with tardive dyskinesia (>4%): nasopharyngitis, insomnia.

Drug Interactions

Drug interaction studies evaluating the effect of deutetrabenazine or its active metabolites (deuterated α-HTBZ and deuterated β-HTBZ) on CYP isoenzymes or P-glycoprotein (P-gp) not conducted to date. Other metabolites of deutetrabenazine (M1 and M4) not expected to cause clinically important drug interactions.

Deutetrabenazine's active metabolites (deuterated α-HTBZ and deuterated β-HTBZ) are substrates of CYP2D6.

Tetrabenazine (a closely related VMAT2 inhibitor) and its α-HTBZ and β-HTBZ metabolites do not substantially inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor do they substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Neither tetrabenazine nor its α-HTBZ and β-HTBZ metabolites are likely to be substrates or inhibitors of the P-gp transport system.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP2D6 inhibitors: Potential pharmacokinetic interaction (increased exposure to deuterated α-HTBZ and deuterated β-HTBZ). During concurrent use, limit deutetrabenazine daily dosage to ≤36 mg (See Specific Drugs under Interactions.)

Moderate or weak CYP2D6 inhibitors: Effects on pharmacokinetics of deutetrabenazine and its metabolites not evaluated.

Specific Drugs

Deutetrabenazine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, ≥80% absorbed.

Rapidly and extensively metabolized to active metabolites deuterated α-HTBZ and deuterated β-HTBZ; plasma concentrations of parent drug are generally undetectable.

Peak plasma concentrations of active metabolites reached within 3–4 hours.

Food

Administration with food increases peak plasma concentrations of deuterated α-HTBZ and deuterated β-HTBZ by approximately 50% with the immediate-release formulation, but has no effect on AUC.

Special Populations

Tetrabenazine, a closely related VMAT2 inhibitor: Mean peak plasma concentration up to 190-fold higher and exposure of tetrabenazine's active metabolites (α-HTBZ and β-HTBZ) up to 40% higher in patients with hepatic impairment compared with healthy individuals.

Poor CYP2D6 metabolizers: Exposures to deuterated α-HTBZ and deuterated β-HTBZ expected to be increased approximately threefold.

Distribution

Extent

Not known whether the drug or its metabolites are distributed into milk in humans.

Distributes rapidly into CNS, with highest and lowest concentrations occurring in the striatum and cortex, respectively.

Elimination

Metabolism

Deutetrabenazine: Rapidly and extensively metabolized, mainly by carbonyl reductase, to deuterated α-HTBZ and deuterated β-HTBZ.

Deuterated α-HTBZ and deuterated β-HTBZ: Metabolized primarily by CYP2D6 with minor contributions by CYP isoenzymes 1A2 and 3A4/5 to several minor metabolites.

Elimination Route

Eliminated in urine (75–86%) and feces (8–11%); <10% eliminated as unchanged deuterated α-HTBZ and deuterated β-HTBZ.

Half-life

Deuterated α-HTBZ and deuterated β-HTBZ (combined): 9–10 hours.

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C). Protect from light and moisture.

Actions

• Deuterium-substituted analog of tetrabenazine; deuterium, a nontoxic, naturally occurring isotope of hydrogen with a higher relative mass, forms a stronger bond with carbon molecules that hinders metabolism by CYP isoenzymes. Deutetrabenazine's active metabolites have a longer half-life, higher AUC, and lower peak plasma concentrations than those of an equivalent dose of tetrabenazine.

• Precise mechanism in tardive dyskinesia and chorea associated with Huntington's disease not established, but appears to be related to drug's ability to reversibly and selectively inhibit VMAT2 in CNS, thereby decreasing uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles and depleting monoamine stores from nerve terminals.

• Preferentially affects dopaminergic neurotransmission in the CNS over adrenergic, serotonergic, and histaminergic neurotransmission at clinically relevant plasma concentrations.

Advice to Patients

• Advise patients and their caregivers to read the manufacturer's patient information (medication guide).

• Inform patients that immediate-release deutetrabenazine should be taken with food and that immediate- and extended-release tablets should be swallowed whole and not chewed, crushed, or broken.

• Risk of depression, worsening of depression, and suicidality in patients with Huntington's disease. Advise patients and caregivers to immediately notify clinicians of emergence of suicidality, emergence or worsening of depression, or unusual changes in behavior in such patients.

• Risk of corrected QT (QT_c )-interval prolongation. Importance of patients immediately notifying clinicians if they feel faint, lose consciousness, or experience heart palpitations. Importance of patients advising clinicians that they are taking deutetrabenazine before any new drug is taken.

• Risk of parkinson-like symptoms. Advise patients to inform clinicians if they experience slight shaking, body stiffness, trouble moving, trouble keeping their balance, or falls.

• Risk of sedation and somnolence. Advise patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination such as operating a motor vehicle or other dangerous machinery until they are receiving a maintenance dosage of deutetrabenazine and the effects of the drug on the individual are known.

• Inform patients that concomitant use of alcohol or other CNS depressants may worsen the sedative effects of deutetrabenazine.

• Advise patients to inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., depression or other psychiatric disorders, liver disease, arrhythmias).

• Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• Austedo (deutetrabenazine) vs Xenazine (tetrabenazine): How do they compare?
• What condition is Austedo used to treat?
• Austedo vs Ingrezza: How do they compare?

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