Adult: Initially, 6 mg once daily, may be increased in increments of 6 mg at weekly intervals according to individual response and tolerability. Max: 48 mg daily. Total daily doses of ≥12 mg should be given in 2 divided doses. Re-titrate dosing if treatment is interrupted for >1 week.
Oral Tardive dyskinesia
Adult: Initially, 12 mg daily given in 2 divided doses, may be increased in increments of 6 mg at weekly intervals according to individual response and tolerability. Max: 48 mg daily. Total daily doses of ≥12 mg should be given in 2 divided doses. Re-titrate dosing if treatment is interrupted for >1 week.
Deutetrabenazine is rapidly and extensively metabolised primarily by carbonyl reductase to form its major active metabolites, α-HTBZ and β-HTBZ. CYP2D6 is the main enzyme that converts its major active metabolites into minor, reduced activity metabolites. Genetic variations in CYP2D6 may influence the pharmacokinetic response and safety of deutetrabenazine in individuals who have no CYP2D6 enzyme activity, known as CYP2D6 poor metabolisers.
CYP2D6 poor metabolisers (carriers of only non-functional alleles e.g. *3/*4, *4/*4, *5/*5, *5/*6) may have an increased risk for clinically relevant prolongation of QT interval. The pharmacokinetic data of deutetrabenazine and its major active metabolites have not been systematically studied in CYP2D6 poor metabolisers; however, studies suggest that they are likely to have 3- or 4-fold increased active metabolites exposure with the usual standard deutetrabenazine doses as compared to extensive metabolisers. The 2018 FDA-approved drug label for deutetrabenazine recommends a dose of up to Max 36 mg daily, with Max single dose of 18 mg given bid.
There are large inter-ethnic differences in the frequency of CYP2D6 alleles which are responsible for encoding enzymatic activity. The prevalence of CYP2D6 poor metabolisers is approx 6-10% in European Caucasians due to the frequency of *4 and *5 non-functional alleles. In contrast, Africans and African Americans, and approx 30% of Asians and individuals of Asian descent are more likely to be CYP2D6 intermediate metabolisers because of the prevalence of a wide range of decreased function alleles, such as *10.
CYP2D6 genotyping may be considered prior to deutetrabenazine treatment initiation.
Hepatic Impairment
Contraindicated.
Administration
Should be taken with food. Swallow whole, do not chew/crush/break.
Contraindications
Congenital long QT syndrome, history of cardiac arrhythmias; suicidality, or untreated or inadequately treated depression in patients with Huntington disease. Hepatic impairment. Concurrent use with tetrabenazine or valbenazine. Concomitant use with or within 14 days of discontinuing MAOIs or within 20 days of discontinuing reserpine.
Special Precautions
Patients with history of depression and previous suicide attempts or ideation; bradycardia, hypokalaemia or hypomagnesaemia. CYP2D6 poor metabolisers. Patients taking strong CYP2D6 inhibitors. Pregnancy and lactation.
Adverse Reactions
Significant: Worsening in mood, cognition, rigidity and functional capacity; QTc prolongation; parkinsonism, akathisia, agitation, and restlessness; CNS depression, hyperprolactinaemia, ophthalmic effects (e.g. binding to melanin-containing tissues causing toxicity). Gastrointestinal disorders: Diarrhoea, dry mouth, constipation. General disorders and administration site conditions: Fatigue. Injury, poisoning and procedural complications: Contusion. Nervous system disorders: Somnolence, dizziness. Psychiatric disorders: Insomnia, anxiety, dysthymic disorder. Renal and urinary disorders: UTI. Respiratory, thoracic and mediastinal disorders: Nasopharyngitis. Potentially Fatal: Neuroleptic malignant syndrome (NMS). New or worsening of depression, suicidal ideation and behaviour.
Patient Counseling Information
This drug may cause sedation and somnolence, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor serum electrolytes. Perform ECG to monitor QT interval before and after a dose increase to >24 mg daily in at-risk patients. Assess for signs and symptoms of depression, suicidal ideation, NMS, restlessness and agitation.
Overdosage
Symptoms: Acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, sedation, sweating, hypotension, confusion, hallucinations, rubor, and tremor. Management: Symptomatic and supportive treatment. Monitor cardiac rhythm and vital signs.
Drug Interactions
Increased systemic exposure by approx 3-fold with strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, bupropion). Increased risk of QT prolongation with other drugs known to prolong QT interval including antipsychotics (e.g. chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g. moxifloxacin), class IA antiarrhythmics (e.g. procainamide, quinidine), class III antiarrhythmics (e.g. amiodarone, sotalol). Potentially Fatal: Increased risk of major serotonin and norepinephrine depletion and toxicity with reserpine. Risk of antagonistic effects and increased toxicity with MAOIs. Deutetrabenazine enhances the adverse effects of tetrabenazine and valbenazine. Increased risk of NMS, parkinsonism and akathisia with dopamine antagonists or antipsychotics.
Food Interaction
Additive sedation and somnolence with alcohol. Increased peak plasma concentration with food.
Action
Description: Mechanism of Action: Deutetrabenazine is a tetrabenazine analogue. The exact mechanism is not yet fully known; however, its major active metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) act as reversible inhibitors of human vesicular monoamine transporter type 2 (VMAT-2), thereby decreasing the uptake of monoamines into the synaptic vesicles and depleting the monoamine stores. Monoamines include dopamine, serotonin, norepinephrine, and histamine. Pharmacokinetics: Absorption: Increased peak plasma concentration by approx 50% with food. Time to peak plasma concentration: 3-4 hours. Distribution: Rapidly distributed into CNS. Volume of distribution: Approx 500 L (α-HTBZ); 730 L (β-HTBZ). Plasma protein binding: 60-68% (α-HTBZ); 59-63% (β-HTBZ). Metabolism: Rapidly and extensively metabolised in the liver primarily by carbonyl reductase to form major active metabolites, α-HTBZ and β-HTBZ, which are subsequently metabolised mainly by CYP2D6 isoenzyme and to a lesser extent by CYP1A2 and CYP3A4/5 isoenzymes to form several minor metabolites. Excretion: Mainly via urine (75-86%; <10% as major active metabolites); faeces (8-11%). Elimination half-life: 9-10 hours.
Chemical Structure
Deutetrabenazine Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 73437646, Deutetrabenazine. https://pubchem.ncbi.nlm.nih.gov/compound/Deutetrabenazine. Accessed May 26, 2021.
Deutetrabenazine Therapy and CYP2D6 Genotype. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). 2012. Accessed 15/11/2019. PMID: 31046213Annotation of FDA Label for Deutetrabenazine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 15/11/2019.Anon. CYP2D6 - Deutetrabenazine (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/11/2019.Anon. Deutetrabenazine. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 15/11/2019.Anon. Deutetrabenazine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 15/11/2019.Austedo Tablet, Coated (Teva Neuroscience, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 15/11/2019.Buckingham R (ed). Deutetrabenazine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 15/11/2019.
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