DEUTETRABENAZINE
Clinical safety rating: safe
Strong CYP2D6 inhibitors may increase levels Can cause depression and suicidal ideation and is contraindicated in untreated depression.
Deutetrabenazine is a deuterated form of tetrabenazine that inhibits the vesicular monoamine transporter 2 (VMAT2), thereby reducing the uptake of monoamines (primarily dopamine) into synaptic vesicles and depleting monoamine stores in presynaptic neurons.
| Metabolism | Primarily metabolized by carbonyl reductase (CBR) to form α-dihydrodeutetrabenazine and β-dihydrodeutetrabenazine, which are the major active metabolites. These metabolites are further metabolized by CYP2D6 to minor metabolites. Deutetrabenazine itself is not a substrate of CYP enzymes. |
| Excretion | Primarily renal excretion of metabolites; unchanged drug minimal. Approximately 75-85% of dose recovered in urine, 15-25% in feces. |
| Half-life | Deutetrabenazine: 9-10 hours; active metabolites (α-dihydrotetrabenazine and β-dihydrotetrabenazine): 10-12 hours. Steady state reached within 4-5 days. |
| Protein binding | Deutetrabenazine: 60-68% bound to plasma proteins; metabolites: similar binding (not fully characterized). |
| Volume of Distribution | Apparent Vd: approximately 500-1000 L (about 6-14 L/kg for a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is low due to extensive first-pass metabolism; absolute bioavailability not established (estimated <10%). |
| Onset of Action | Oral: Clinical effect on chorea noted within 1-2 weeks; some benefit may occur within days. |
| Duration of Action | Duration of effect on chorea lasts throughout dosing interval due to twice-daily dosing; exact duration of action per dose is not well defined, but pharmacodynamic effects persist for 12-24 hours. |
Initial dose: 6 mg orally twice daily. Titrate in increments of 6 mg per week up to a maximum of 48 mg per day (24 mg twice daily).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended for GFR ≥30 mL/min. Insufficient data for GFR <30 mL/min; use caution. |
| Liver impairment | Mild hepatic impairment (Child-Pugh A): 6 mg orally twice daily; maximum 36 mg per day. Moderate to severe (Child-Pugh B or C): 6 mg orally once daily; maximum 18 mg per day. |
| Pediatric use | No established pediatric dosing. Safety and efficacy not evaluated; use not recommended. |
| Geriatric use | No specific dose adjustment required; titrate slowly due to potential increased sensitivity to adverse effects (e.g., sedation, orthostatic hypotension). |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP2D6 inhibitors may increase levels Can cause depression and suicidal ideation and is contraindicated in untreated depression.
| FDA category | Animal |
| Breastfeeding | It is unknown if deutetrabenazine or its metabolites are excreted in human milk. No M/P ratio data available. Because of potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: DEPRESSION AND SUICIDALITY. Deutetrabenazine may increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Patients with a history of depression or prior suicide attempts or ideation may be at greater risk.
| Common Effects | Sedation |
| Serious Effects |
["Concurrent use of reserpine or monoamine oxidase inhibitors (MAOIs)","Concurrent use of tetrabenazine or valbenazine","Moderate to severe hepatic impairment (Child-Pugh score >6)","Untreated or inadequately treated depression","Suicidal ideation or behavior"]
| Precautions | ["Depression and suicidality (see black box warning)","QT prolongation: Avoid use with drugs that prolong QT interval or in patients with congenital long QT syndrome","Neuroleptic malignant syndrome (NMS): Discontinue if NMS occurs","Akathisia, restlessness, and parkinsonism: Dose reduction or discontinuation may be necessary","Tardive dyskinesia: May develop, especially with chronic use","PR interval prolongation: Caution in patients with conduction abnormalities or drugs that prolong PR interval","Hyperprolactinemia: May occur, but clinical significance is unknown","Avoid in patients with hepatic impairment: Contraindicated in moderate to severe impairment"] |
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| Deutetrabenazine is classified as Pregnancy Category C. Animal studies have shown fetal harm at doses equivalent to human doses. There are no adequate well-controlled studies in pregnant women. Use only if potential benefit justifies potential risk to the fetus. First trimester: potential for teratogenic effects based on animal data (increased incidence of fetal malformations). Second and third trimesters: may cause extrapyramidal symptoms, withdrawal symptoms, or exacerbation of maternal condition. |
| Fetal Monitoring | Monitor for maternal adverse effects including extrapyramidal symptoms, sedation, QT prolongation, neuroleptic malignant syndrome, and depression/suicidality. No specific fetal monitoring established; standard prenatal care with monitoring of fetal growth and development if exposure occurs. |
| Fertility Effects | In animal studies, deutetrabenazine caused no impairment of fertility at doses up to 30 mg/kg/day in rats. Effects on human fertility are unknown. |