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Austedo

Generic Name: Deutetrabenazine
Class: Central Nervous System Agents, Miscellaneous
Chemical Name: (3RS,11bRS)-9,10-Di([2H3]methoxy)-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-2-one
Molecular Formula: C19H21D6NO3

Warning(s)

Warning: Depression and Suicidality in Patients with Huntington’s Disease

See full prescribing information for complete boxed warning.

  • Deutetrabenazine increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease.1

  • Balance risks of depression and suicidality with the clinical need for treatment of chorea when considering the use of deutetrabenazine.1

  • Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior.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.1

  • Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation.1

  • Deutetrabenazine is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.1

Introduction

Deutetrabenazine is a central nervous system agent.

Uses for Austedo

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

Austedo Dosage and Administration

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

Initial Dose

Recommended Dose

Maximum Dose

Chorea associated with Huntington’s disease

6 mg/day

6 mg–48 mg/day

48 mg/day

Tardive dyskinesia

12 mg/day

12 mg–48 mg/day

48 mg/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 (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

Cautions for Austedo

Contraindications

  • Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease.1

  • Hepatic impairment.1

  • Taking reserpine, MAO inhibitors, tetrabenazine (Xenazine), or valbenazine.1

Warnings/Precautions

Depression and Suicidality in Patients with Huntington’s Disease

Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). Deutetrabenazine may increase the risk for suicidality in patients with Huntington’s disease.1

In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with deutetrabenazine, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with deutetrabenazine.1

When considering the use of deutetrabenazine, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with deutetrabenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with deutetrabenazine.1

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with deutetrabenazine, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately.1

Clinical Worsening and Adverse Events 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 a worsening in mood, cognition, rigidity, and functional capacity.1

Prescribers should periodically reevaluate the need for deutetrabenazine in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for deutetrabenazine.1

Prolongation of QT Interval

Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the corrected QT (QTc) interval.1

A clinically relevant QT prolongation may occur in some patients treated with deutetrabenazine who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor.1

For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary.1

The use of deutetrabenazine in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongations.1

For patients requiring deutetrabenazine doses greater than 24 mg per day who are using deutetrabenazine with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications that are known to prolong QTc.1

Deutetrabenazine should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.1

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. While NMS has not been observed in patients receiving deutetrabenazine, it has been observed in patients receiving tetrabenazine (a closely related VMAT2 inhibitor). Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.1

The management of NMS should include (1) immediate discontinuation of deutetrabenazine; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.1

Recurrence of NMS has been reported with resumption of drug therapy. If treatment with deutetrabenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.1

Akathisia, Agitation, and Restlessness

Deutetrabenazine may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia.1

In a 12-week, double-blind, placebo-controlled trial in Huntington’s disease patients, akathisia, agitation, or restlessness was reported by 4% of patients treated with deutetrabenazine, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with deutetrabenazine and 1% of patients on placebo experienced these events.1

Patients receiving deutetrabenazine should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with deutetrabenazine, the deutetrabenazine dose should be reduced; some patients may require discontinuation of therapy.1

Parkinsonism in Patients with Huntington’s Disease

Deutetrabenazine may cause parkinsonism in patients with Huntington’s disease.1

Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between this potential drug-induced adverse reaction and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. If a patient develops parkinsonism during treatment with deutetrabenazine, the deutetrabenazine dose should be reduced; some patients may require discontinuation of therapy.1

Sedation and Somnolence

Sedation is a common dose-limiting adverse reaction of deutetrabenazine. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of deutetrabenazine-treated patients reported somnolence compared with 4% of patients on placebo and 9% of deutetrabenazine-treated patients reported fatigue compared with 4% of placebo-treated patients.1

Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of deutetrabenazine and know how the drug affects them.1

Hyperprolactinemia

Serum prolactin levels were not evaluated in the deutetrabenazine development program. Tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. Following administration of 25 mg of tetrabenazine to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold.1

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if deutetrabenazine is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown.1

Chronic increase in serum prolactin levels (although not evaluated in the deutetrabenazine or tetrabenazine development programs) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of deutetrabenazine.1

Binding to Melanin-containing Tissues

Since deutetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that deutetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.1

The clinical relevance of deutetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.1

Specific Populations

Pregnancy

Risk Summary: There are no adequate data on the developmental risk associated with the use of deutetrabenazine 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.1

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.1

Lactation

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.1

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for deutetrabenazine and any potential adverse effects on the breastfed infant from deutetrabenazine or from the underlying maternal condition.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.1

Geriatric Use

Clinical studies of deutetrabenazine 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.1

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 deutetrabenazine in patients with hepatic impairment is contraindicated.1

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 deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg).1

Common Adverse Effects

Most common adverse reactions (>8% of deutetrabenazine-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue.1

Most common adverse reactions (that occurred in 4% of deutetrabenazine-treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of deutetrabenazine is 36 mg per day (18 mg twice daily).1

  • Alcohol or other sedating drugs: May have additive sedation and somnolence.1

Actions

Mechanism of Action

The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.1

Advice to Patients

Patient Counseling Information

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).1

Advise patients to take deutetrabenazine with food. Deutetrabenazine tablets should be swallowed whole and not chewed, crushed, or broken.1

Advise patients, their caregivers, and families that deutetrabenazine may increase the risk of depression, worsening depression, and suicidality, and to immediately report any symptoms to a healthcare provider.1

Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations. Advise patients to inform physicians that they are taking deutetrabenazine before any new drug is taken.1

Advise patients that deutetrabenazine may cause sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Until they learn how they respond to a stable dose of deutetrabenazine, patients should be careful doing activities that require them to be alert, such as driving a car or operating machinery.1

Advise patients that alcohol or other drugs that cause sleepiness will worsen somnolence.1

Advise patients to notify their physician of all medications they are taking and to consult with their healthcare provider before starting any new medications because of a potential for interactions.1

Additional Information

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.

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.

Deutetrabenazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Coated

6 mg

Austedo

Teva Neuroscience Inc.

9 mg

Austedo

Teva Neuroscience Inc.

12 mg

Austedo

Teva Neuroscience Inc.

AHFS Drug Information. © Copyright 2017, Selected Revisions September 25, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Teva Neuroscience, Inc. Austedo (deutetrabenazine) tablets prescribing information. 2017 Sep.

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