AUSTEDO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AUSTEDO (AUSTEDO).
Deuterated tetrabenazine; inhibits vesicular monoamine transporter 2 (VMAT2), reducing dopamine uptake into synaptic vesicles and leading to decreased presynaptic dopamine release, similar to tetrabenazine but with altered pharmacokinetics due to deuterium substitution.
| Metabolism | Primarily metabolized by carbonyl reductase (CBR) and aldo-keto reductase (AKR) to its main active metabolites α-HTBZ and β-HTBZ; minor contribution from CYP2D6. Deuteration slows metabolism compared to tetrabenazine. |
| Excretion | Urine (75-85% as metabolites, <5% unchanged); feces (10-15%) |
| Half-life | 5-9 hours (parent); 7-10 hours (active metabolite). Steady state within 2-3 days. |
| Protein binding | ~60% (primarily to albumin); active metabolite ~55% |
| Volume of Distribution | 5-8 L/kg; indicates extensive tissue distribution. |
| Bioavailability | ~80% (oral); food does not significantly affect. |
| Onset of Action | Oral: 1-2 weeks for initial effect; maximal at 4-6 weeks. |
| Duration of Action | Dosing interval: twice daily. Clinical effect persists for duration of therapy; no accumulation upon discontinuation. |
Initial 6 mg orally once daily; titrate by 6 mg increments at weekly intervals to a maximum of 48 mg/day. For tolerability, may divide into twice daily dosing (e.g., 12 mg twice daily).
| Dosage form | TABLET |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not studied in severe renal impairment (CrCl <30 mL/min) or ESRD. |
| Liver impairment | Child-Pugh A or B: no adjustment. Child-Pugh C: not recommended due to lack of data. |
| Pediatric use | Not established for patients <18 years of age. |
| Geriatric use | No specific adjustment; consider starting at lower end of dosing range due to potential for increased sensitivity and reduced renal/hepatic function. Monitor for QT prolongation and cognitive effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AUSTEDO (AUSTEDO).
| Breastfeeding | It is not known whether deutetrabenazine or its metabolites are excreted in human milk. The M/P ratio is not available. Given the potential for serious adverse reactions (e.g., sedation, extrapyramidal symptoms) in breastfed infants, advise patients that breastfeeding is not recommended during treatment and for 5 days after the last dose. |
| Teratogenic Risk | Deutetrabenazine (AUSTEDO) is a vesicular monoamine transporter 2 (VMAT2) inhibitor. In animal studies, deutetrabenazine caused developmental toxicity (reduced fetal weight, increased skeletal variations) at maternal exposures near the maximum recommended human dose. There are no adequate and well-controlled studies in pregnant women. Risk cannot be ruled out. Use during pregnancy only if potential benefit justifies potential risk to fetus. First trimester: potential for teratogenicity as with any drug; second/third trimester: risk of neonatal extrapyramidal symptoms, withdrawal, or sedation if exposure near term. |
■ FDA Black Box Warning
AUSTEDO can cause depression, suicidal thoughts or behavior in patients with Huntington's disease. Weigh risks of depression and suicidality against clinical need. Monitor patients closely for emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients and caregivers about risks.
| Serious Effects |
["Concurrent treatment with reserpine","Concurrent treatment with MAOIs (monoamine oxidase inhibitors)","Untreated or inadequately treated depression","Suicidal ideation or behavior (active)","Hepatic impairment (Child-Pugh class B or C)","Prolonged QT interval or concurrent use of QT-prolonging drugs"]
| Precautions | ["Depression and suicidality (especially in HD)","Sedation/somnolence","QT prolongation","Neuroleptic malignant syndrome (NMS)","Akathisia, restlessness, agitation","Parkinsonism","Dysphagia","Hyperprolactinemia","Binding to melanin-containing tissues"] |
| Food/Dietary | Take with or without food. Avoid high-fat meals as they can increase absorption and peak concentration, potentially worsening side effects. Grapefruit juice may modestly increase deutetrabenazine exposure; avoid excessive consumption. |
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| Fetal Monitoring | Pregnancy testing: consider based on individual case. Ultrasound monitoring: fetal growth and anatomy as per routine prenatal care. Neonatal monitoring: observe for extrapyramidal symptoms, sedation, or withdrawal signs (e.g., agitation, feeding difficulties) in newborns exposed in utero during the third trimester. No specific antidote; supportive care if needed. |
| Fertility Effects | Impairment of fertility: In animal studies, decreased fertility and increased preimplantation loss were observed in female rats at exposures similar to the maximum recommended human dose. Effects on human fertility have not been studied; however, VMAT2 inhibitors may affect reproductive function via central dopamine depletion. Advise patients of potential risk. |
| Clinical Pearls | AUSTEDO (deutetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor for chorea in Huntington's disease and tardive dyskinesia. Dose titration is mandatory to balance efficacy and tolerability, starting at 6 mg once daily for chorea and 12 mg once daily for tardive dyskinesia. Avoid concurrent use with reserpine, MAOIs, or tetrabenazine. Monitor for QT prolongation, especially in patients with electrolyte abnormalities or concurrent QT-prolonging drugs. Assess for worsening depression, suicidality, or parkinsonism. CYP2D6 poor metabolizers require dose reduction; genotyping recommended prior to initiation. Taper gradually when discontinuing to avoid withdrawal dyskinesias. |
| Patient Advice | Take exactly as prescribed; do not change dose without doctor approval. · May cause drowsiness; avoid driving or operating heavy machinery until you know how the medicine affects you. · Report any new or worsening depression, unusual thoughts, or suicidal feelings immediately. · Avoid alcohol and other CNS depressants. · Do not stop taking abruptly; taper under medical supervision to prevent withdrawal symptoms. · Inform your doctor if you are nursing, pregnant, or planning pregnancy. · Keep all appointments for blood tests and ECGs. |