Deutetrabenazine

Deutetrabenazine is used for chorea with Huntington’s disease and tardive dyskinesia (TD).

Deutetrabenazine is available under the following different brand names: Austedo.

Dosages of Deutetrabenazine:

Dosage Forms and Strengths

Tablet

• 6mg
• 9mg
• 12mg

Dosage Considerations – Should be Given as Follows:

Chorea with Huntington’s Disease

• Initial dose when not being switched from tetrabenazine: 6 mg orally once daily
• May increase dose at weekly intervals in increments of 6 mg/day; not to exceed 48 mg/day
• Administer doses 12 mg/day or more in 2 divided doses

Tardive Dyskinesia (TD)

• Initial dose when not being switched from tetrabenazine: 6 mg orally twice daily
• May increase dose at weekly intervals in increments of 6 mg/day; not to exceed 48 mg/day

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 (e.g., paroxetine, fluoxetine, bupropion)

Poor CYP2D6 metabolizers

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

Hepatic impairment

• Contraindicated
• The 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

• Determine dose for each patient based on reduction of chorea or tardive dyskinesia and tolerability
• For patients at risk for QT prolongation, assess QT interval before and after increasing doses to more than 24 mg/day
• Safety and efficacy not established in pediatric patients

Common side effects of deutetrabenazine include:

• Somnolence
• Diarrhea
• Dry mouth
• Fatigue
• Urinary tract infection (UTI)
• Insomnia
• Anxiety
• Constipation
• Contusion
• Dizziness
• Akathisia, agitation, or restlessness
• Depression in patients with Huntington’s disease
• Suicidal ideation in patients with Huntington’s disease
• Parkinsonism in patients with Huntington’s disease

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Severe interactions of deutetrabenazine include:
  • isocarboxazid
  • linezolid
  • methylene blue
  • phenelzine
  • rasagiline
  • safinamide
  • selegiline
  • selegiline transdermal
  • tetrabenazine
  • tranylcypromine
  • valbenazine
• Serious interactions of deutetrabenazine include:
  • hydroxychloroquine sulfate
  • iobenguane I 131
  • safinamide
• Deutetrabenazine has moderate interactions with at least 168 different drugs.
• Deutetrabenazine has no listed mild interactions with other drugs.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains deutetrabenazine. Do not take Austedo if you are allergic to deutetrabenazine or any ingredients contained in this drug.
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Black Box Warnings

• Can increase the risk for depression and suicidality in patients with Huntington’s disease; when prescribing, consider this risk with the clinical need for chorea treatment
• Closely monitor for the emergence or worsening of depression, suicidality, or unusual changes in behavior
• Inform patients, caregivers, and families of the risk of depression and suicidality; instruct them to report behaviors of concern promptly to the treating physician
• Particular caution is needed with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington disease
• Deutetrabenazine is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression

Contraindications

• Patients with Huntington disease who are suicidal, or in patients with untreated or inadequately treated depression
• Hepatic impairment
• Coadministration with monoamine oxidase inhibitors (MAOIs); deutetrabenazine should not be used in combination with an MAOI or within 14 days of discontinuing an MAOI
• Coadministration with reserpine; at least 20 days should elapse after stopping reserpine before initiating deutetrabenazine
• Coadministration with tetrabenazine or valbenazine

Effects of Drug Abuse

• No information available

Short-Term Effects

• See "What Are Side Effects Associated with Using Deutetrabenazine?”

Long-Term Effects

• See "What Are Side Effects Associated with Using Deutetrabenazine?”

Cautions

• Huntington 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; periodically reevaluate the need for deutetrabenazine by assessing the effect on chorea and adverse effects
• Patients with Huntington disease are at increased risk for depression and suicidality; deutetrabenazine may increase this risk
• Neuroleptic malignant syndrome (NMS) reported with drugs that reduce dopaminergic transmission; while not observed with deutetrabenazine, it has been reported with tetrabenazine; monitor for manifestations of NMS (e.g., hyperpyrexia, muscle rigidity, altered mental status, autonomic instability, increased creatinine phosphokinase, myoglobinuria, rhabdomyolysis, acute renal failure); manage NMS by immediately discontinuing the drug and intensively treating symptoms and any concomitant serious medical problems
• May increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia; reduce the dose or discontinue if this occurs
• Sedation/somnolence reported; may impair patient’s ability to drive or operate complex machinery
• Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 milliseconds) in the corrected QT (QTc) interval; avoid in patients with congenital long QT syndrome or history of cardiac arrhythmias; for deutetrabenazine doses greater than 24 mg/day in patients who are using other drugs known to prolong QTc, assess the QTc interval before and after increasing the deutetrabenazine dose or other medications that are known to prolong QTc
• Elevated serum prolactin levels may occur; 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; if there is clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing, and discontinuation of therapy should be considered
• Deutetrabenazine and its metabolites bind to melanin-containing tissues and can accumulate in these tissues over time; ophthalmologic monitoring in humans was inadequate in clinical trials to exclude the possibility of injury after long-term exposure

Parkinsonism

• May cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia
• Parkinsonism has been observed with other VMAT2 inhibitors
• Difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntington’s disease
• Parkinsonism in patients treated with the drug for tardive dyskinesia reported; symptoms have included bradykinesia, gait disturbances
• In most cases, parkinsonism occurred within the first two weeks after starting or increasing the dose
• Parkinsonism was reported to resolve following discontinuation of therapy
• If parkinsonism develops during treatment, the dose should be reduced; some patients may require discontinuation of therapy

Drug interaction overview

• Coadministration with dopamine antagonists or antipsychotics may increase the risk for parkinsonism, NMS, and akathisia
• Coadministration with alcohol and other sedating drugs may worsen somnolence associated with deutetrabenazine
• Strong CYP2D6 inhibitors
  • Deutetrabenazine is extensively biotransformed to its major active dihydro-metabolites, alpha, and beta-HTBZ, which are subsequently metabolized primarily by CYP2D6
  • Dose reduction of deutetrabenazine may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose
  • Systemic exposure of the active dihydro-metabolites is increased ~3-fold when co-administered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion)
  • Do not exceed 36 mg/day or a single dose of 18 mg if co-administered with a strong CYP2D6 inhibitor

• QTc prolongation
  • 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; see above information (strong CYP2D6 inhibitors) for dose modifications/limitations
  • For patients requiring deutetrabenazine doses greater than 24 mg/day and are taking other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of deutetrabenazine or other medications known to prolong QTc
  • Assess other risks for QT prolongation; 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 bradycardia, hypokalemia, or hypomagnesemia; concomitant use of other drugs that prolong the QTc interval; and presence of congenital prolongation of the QT interval
• Contraindicated drug combinations
  • Coadministration with MAOIs is contraindicated; deutetrabenazine should not be used in combination with an MAOI or within 14 days of discontinuing an MAOI
  • Coadministration with reserpine is contraindicated; at least 20 days should elapse after stopping reserpine before initiating deutetrabenazine; reserpine binds irreversibly to VMAT2 and the duration of its effects is several days; wait for chorea to reemerge before administering deutetrabenazine to reduce risk of overdosage and major depletion of serotonin and norepinephrine in the CNS
  • Coadministration with tetrabenazine is contraindicated

• There are no adequate data on the developmental risk of the use of deutetrabenazine in pregnant women. Consult your doctor. It is unknown if deutetrabenazine is distributed in human breast milk.
• Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for deutetrabenazine, and any potential adverse effects on the breastfed infant from the drug or the underlying maternal condition.