deutetrabenazine (Rx)

Brand and Other Names:Austedo
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and deutetrabenazine

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Somnolence (11%)

            1-10%

            Diarrhea (9%)

            Dry mouth (9%)

            Fatigue (9%)

            Urinary tract infection (7%)

            Insomnia (7%)

            Anxiety (4%)

            Constipation (4%)

            Contusion (4%)

            Dizziness (4%)

            Akathisia, agitation, or restlessness (4%)

            Depression (4%)

            Suicidal ideation (2%)

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            Warnings

            Black Box Warnings

            Can increase risk for depression and suicidality in patients with Huntington disease; when prescribing, consider this risk with the clinical need for chorea treatment

            Closely monitor for 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 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

            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 effect on chorea and adverse effects

            Patients with Huntington disease are at increased risk for depression and suicidality; deutetrabenazine may increase this risk (see Black Box Warnings and Contraindications)

            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 (eg, 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 risk of akathisia, agitation, restlessness, and parkinsonism; reduce 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 msec) in the corrected QT (QTc) interval; avoid in patients with long QT syndrome, history of cardiac arrhythmias, and other drugs known to prolong QT (also see drug interaction overview)

            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

            Drug interaction overview

            • Coadministration with dopamine antagonists or antipsychotics may increase 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 coadministered with strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine, bupropion)
              • Do not exceed 36 mg/day or a single dose of 18 mg if coadministered 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 coadministered a strong CYP2D6 inhibitor
              • Avoided coadministration with other drugs that are known to prolong QTc
              • Also avoid in patients with congenital long QT syndrome or 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 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 (see Dosing information on how to switch from tetrabenazine)
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            Pregnancy

            Pregnancy

            There are no adequate data on the developmental risk in pregnant women

            Animal studies

            • 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

            Lactation

            Unknown if distributed in human breast milk

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Oral vesicular monoamine transporter-2 (VMAT-2) inhibitor; decreases uptake of monoamines (eg, dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles and depletes monoamine stores from nerve terminals

            The precise mechanism by which deutetrabenazine exerts its antichorea effects is unknown, but is believed to be related to its effect on reversible depletion of monoamines from nerve terminals

            Absorption

            Bioavailability: 80%

            Plasma concentrations of deutetrabenazine are generally below the limit of detection because of the extensive hepatic metabolism

            Peak plasma time (active metabolites): 3-4 hr

            Distribution

            Vd: 500 L (alpha-HTBZ); 730 L (beta-HTBZ)

            Binds to melanin-containing tissues (eg, skin, eyes)

            Following IV administration of tetrabenazine: Rapidly distributed to the brain, with the highest binding in the striatum and the lowest in the cortex

            Protein bound

            • Tetrabenazine: 82-85%
            • Alpha-HTBZ: 60-68%
            • Beta-HTBZ: 59-63%

            Metabolism

            Deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites alpha-HTBZ and beta­HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites

            Elimination

            Half-life (active metabolites): 9-10 hr

            Clearance: 47 L/hr (alpha-HTBZ); 70 L/hr (beta-HTBZ)

            Excretion: 75-86% urine; 8-11% feces

            Pharmacogenomics

            CYP2D6 poor 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 alpha and beta-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (~3-fold)
            • Decrease deutetrabenazine dose if administered in CYP2D6 poor metabolizers
            • Also see Cautions and Dosage Modification
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            Administration

            Oral Administration

            Administer with food

            Swallow tablet whole; do not chew, crush, or break

            Discontinuing treatment: Can be discontinued without tapering

            Switching from tetrabenazine to deutetrabenazine

            • Discontinue tetrabenazine and initiate deutetrabenazine the following day
            • Recommended initial deutetrabenazine dose when switched from tetrabenazine
              • Tetrabenazine 12.5 mg/day: Initiate with deutetrabenazine 6 mg/day
              • Tetrabenazine 25 mg/day: Initiate with deutetrabenazine 6 mg/day
              • Tetrabenazine 37.5 mg/day: Initiate with deutetrabenazine 9 mg/day
              • Tetrabenazine 50 mg/day: Initiate with deutetrabenazine 12 mg/day
              • Tetrabenazine 62.5 mg/day: Initiate with deutetrabenazine 15 mg/day
              • Tetrabenazine 75 mg/day: Initiate with deutetrabenazine 18 mg/day
              • Tetrabenazine 87.5 mg/day: Initiate with deutetrabenazine 21 mg/day
              • Tetrabenazine 100 mg/day: Initiate with deutetrabenazine 24 mg/day

            Treatment interruption

            • ≥1 week: Must titrate dose when resumed (as with initial treatment)
            • <1 week: May resume at previous maintenance dose without titration

            Storage

            Store at 25C (77F); excursions permitted to 15-30C (59-86F)

            Protect from light and moisture

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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