deutetrabenazine

General

Genetic Implications:

Pronunciation:
du-tet-ra-ben-a-zeen

Trade Name(s)

• Austedo

Ther. Class.
antichoreas

Pharm. Class.
reversible monoamine depleters

Indications

• Chorea due to Huntington's Disease.
• Tardive dyskinesia.

Action

Its major metabolites act as reversible inhibitors of the vesicle monoamine transporter type 2 (VMAT-2) resulting in decreased reuptake of monoamines (including serotonin, norepinephrine and dopamine) into vesicles in presynaptic neurons and depletion of monoamine stores.

Therapeutic Effect(s):

• Decreased chorea due to Huntington's Disease.
• Reduced severity of tardive dyskinesia.

Pharmacokinetics

Absorption: ≥80% absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Metabolism and Excretion:  Metabolized in liver to two active metabolites (α-dihydrotetrabenazine (α-HTBZ) and β-HTBZ), which are subsequently metabolized primarily via CYP2D6 (and to lesser extent by CYP1A2 and CYP3A4/5) to several minor metabolites (the CYP2D6 enzyme system exhibits genetic polymorphism; 7% of population may be poor metabolizers and may have significantly ↑ concentrations and an ↑ risk of adverse effects). Primarily excreted in the urine as metabolites.

Half-life: 9–10 hr.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• Hepatic impairment;
• Concurrent use of reserpine, MAO inhibitors, tetrabenazine, or valbenazine;
• Patients who are suicidal or have untreated or inadequately treated depression;
• Congenital long QT syndrome or cardiac arrhythmias.

Use Cautiously in:

• History of/propensity for depression or history of psychiatric illness; history of suicidality;
•  Poor CYP2D6 metabolizers; initial dose ↓ required;
• Concurrent use of strong CYP2D6 inhibitors; initial dose ↓ required;
• Bradycardia, hypokalemia, hypomagnesemia, or concurrent use of QT-interval prolonging drugs;
• History of breast cancer;
• OB:  Use only when potential benefit justifies potential risk to the fetus;
• Lactation: Weigh benefits of breast feeding against possible adverse effects;
• Pedi:  Safety and effectiveness in children not established.

Adverse Reactions/Side Effects

CNS: SUICIDAL THOUGHTS/IDEATION, sedation/somnolence, agitation, anxiety, depression, dizziness, insomnia

CV: QTc interval prolongation

GI: constipation, diarrhea, dry mouth

Endo: hyperprolactinemia

GU: urinary tract infection

Neuro: akathisia, parkinsonism, restlessness

Misc: NEUROLEPTIC MALIGNANT SYNDROME, fatigue

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Concurrent use of  MAO inhibitors  ↑ risk of serious adverse reactions and are contraindicated; wait ≥14 days after discontinuing to initiate deutetrabenazine.
•  Reserpine  binds to VMAT-2 and depletes monoamines in the CNS; concurrent use contraindicated; wait 3 wk after discontinuing to initiate deutetrabenazine.
• Concurrent use of  tetrabenazine  or  valbenazine  is contraindicated.
• Strong CYP2D6 inhibitors, including bupropion, fluoxetine, paroxetine, and  quinidine  may ↑ levels; ↓ dose of deutetrabenazine.
•  QTc interval prolonging drugs  may ↑ risk of QTc interval prolongation.
• Concurrent use with  dopamine antagonists  or  antipsychotics  may ↑ risk of neuroleptic malignant syndrome and extrapyramidal disorders.
• Concurrent use of  alcohol  or other  CNS depressants  may ↑ risk of CNS depression.

Route/Dosage

Huntington's Disease

PO  (Adults)  6 mg once daily; may ↑ dose by 6 mg/day at weekly intervals (max dose = 48 mg/day). Daily doses exceeding 12 mg should be administered in two divided doses.  Concurrent use of strong CYP2D6 inhibitors or poor CYP2D6 metabolizers– Do not exceed dose of 36 mg/day.

Tardive Dyskinesia

PO  (Adults)  6 mg twice daily; may ↑ dose by 6 mg/day at weekly intervals (max dose = 48 mg/day). Daily doses exceeding 12 mg should be administered in two divided doses.  Concurrent use of strong CYP2D6 inhibitors or poor CYP2D6 metabolizers– Do not exceed dose of 36 mg/day.

Availability

Tablets: 6 mg, 9 mg, 12 mg

Assessment

• Assess signs of Huntington's disease (changes in mood, cognition, chorea, rigidity, and functional capacity) periodically during therapy. Re-evaluate need for deutetrabenazine periodically by assessing beneficial effect and side effects; determination may require dose reduction or discontinuation. Underlying chorea may improve over time, decreasing need for deutetrabenazine.
• Monitor closely for new or worsening depression or suicidality. If depression or suicidality occurs ↓ dose and may initiate or ↑ dose of antidepressants.
• Monitor for signs of neuroleptic malignant syndrome (hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or BP, tachycardia, diaphoresis, cardiac arrhythmia) periodically during therapy. If symptoms occur discontinue deutetrabenazine and manage symptomatically. If re-introduction of deutetrabenazine is considered monitor carefully; recurrences of neuroleptic malignant syndrome have occurred.
• Monitor patient for onset of akathisia (restlessness or desire to keep moving) and parkinsonism (difficulty speaking or swallowing, loss of balance control, pill rolling of hands, mask-like face, shuffling gait, rigidity, tremors). Notify health care professional if these symptoms occur; reduction in dose or discontinuation may be necessary.

Potential Diagnoses

• Risk for suicide (Adverse Reaction) 

Implementation

• PO  Administer with food. Swallow tablet whole; do not crush, break, or chew.
• To switch from tetrabenazine to deutetrabenazine, stop tetrabenazine and administer deutetrabenazine the following day. If patient taking 12.5–25 mg of tetrabenazine, administer 6 mg deutetrabenazine; if taking 37.5 mg give 9 mg deutetrabenazine; if taking 50 mg, give 12 mg deutetrabenazine; if taking 62.5 mg tetrabenazine, give 15 mg deutetrabenazine; if taking 75 mg, give 18 mg deutetrabenazine; if 87.5 mg tetrabenazine, give 21 mg deutetrabenazine; if taking 100 mg tetrabenazine, give 24 mg deutetrabenazine. Dose adjustments can be made weekly.
• Deutetrabenazine may be stopped without taper. If therapy interrupted >1 wk, re-titrate when resuming therapy. If <1 wk since discontinuation, may restart at previous dose.

Patient/Family Teaching

• Instruct patient to take deutetrabenazine as directed. Advise patient to read  Medication Guide  before starting therapy and with each Rx refill in case of changes.
• Advise patient and family to monitor for changes, especially sudden changes, in mood, behaviors, thoughts or feelings. If new or worse feelings of sadness or crying spells, lack of interest in friends or activities, sleeping a lot more or less, feelings of unimportance, guilt, hopelessness or helplessness, irritability or aggression, more or less hungry, difficulty paying attention, or thoughts of hurting self or ending life occur, notify health care professional promptly.
• Causes sedation. Caution patient to avoid driving and other activities requiring alertness until response to medication is known.
• Inform patient of potential side effects and instruct to notify health care professional if side effects occur.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
• Advise female patients to notify health care professional if pregnancy is planned or suspected or if breast feeding.

Evaluation/Desired Outcomes

↓ in chorea due to Huntington's disease.