AUSTEDO XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AUSTEDO XR (AUSTEDO XR).
Deuterated tetrabenazine; inhibits vesicular monoamine transporter 2 (VMAT2), reducing dopamine and monoamine uptake into synaptic vesicles, thereby depleting presynaptic dopamine and other monoamines.
| Metabolism | Primarily metabolized by carbonyl reductases (CBR1 and CBR2) to active metabolites (alpha-HTBZ and beta-HTBZ), which are further metabolized by aldehyde dehydrogenase (ALDH) and CYP2D6. Deuterium substitution slows metabolism compared to tetrabenazine. |
| Excretion | Primarily hepatic metabolism via CYP2D6 and CYP3A4; <5% excreted unchanged in urine; fecal excretion accounts for ~50% of metabolites. |
| Half-life | Deutetrabenazine: 9-10 hours; major active metabolites (α-HTBZ and β-HTBZ): 7-15 hours; allows twice-daily dosing for immediate-release, but AUSTEDO XR is once-daily. |
| Protein binding | 60-68% bound to human plasma proteins (primarily albumin). |
| Volume of Distribution | Apparent Vd: 500-1000 L (not weight-adjusted; extensive tissue distribution). |
| Bioavailability | Absolute bioavailability not established; relative bioavailability compared to immediate-release is approximately 100% for total AUC of deuterated metabolites. |
| Onset of Action | Peak plasma concentrations at 8-10 hours post-dose (extended-release); clinical effect on chorea typically observed within 1-2 weeks of titration. |
| Duration of Action | Once-daily dosing; sustained reduction in chorea over 24 hours due to extended-release formulation. |
Initial: 6 mg orally once daily. Titrate weekly by 6 mg/day increments to a maximum of 48 mg/day. Administer with food.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | Not recommended in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) due to limited data. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose by 50%. Child-Pugh C: Not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; use caution due to potential for increased sensitivity and renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AUSTEDO XR (AUSTEDO XR).
| Breastfeeding | Excretion into human milk unknown. M/P ratio not determined. Physicochemical properties suggest likely excretion. Potential for serious adverse reactions in breastfed infant (e.g., sedation, dystonia). Decision: Discontinue drug or discontinue breastfeeding, considering importance of drug to mother. |
| Teratogenic Risk | Pregnancy category: Not assigned. Animal studies: In rats, deutetrabenazine administered during organogenesis at doses up to 10 mg/kg/day (0.8 times the MRHD of 48 mg/day based on AUC) produced no fetal harm. In rabbits, doses up to 30 mg/kg/day (1.5 times the MRHD) caused no malformations but reduced fetal body weight in the presence of maternal toxicity. No adequate human studies exist. Risk cannot be ruled out during first trimester. Second and third trimester exposure may increase risk for neonatal adverse events (e.g., extrapyramidal symptoms, withdrawal). |
■ FDA Black Box Warning
WARNING: DEPRESSION AND SUICIDALITY. AUSTEDO XR increases 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. Balance risks with medical need. AUSTEDO XR is contraindicated in patients with suicidal ideation or untreated or inadequately treated depression.
| Serious Effects |
Patients with suicidal ideation or untreated/inadequately treated depression. Hepatic impairment (Child-Pugh score >6). Concurrent use with monoamine oxidase inhibitors (MAOIs) or reserpine (allow at least 20 days after stopping reserpine before starting AUSTEDO XR). Use with a vesicular monoamine transporter 2 (VMAT2) inhibitor other than tetrabenazine or deutetrabenazine.
| Precautions | May cause depression and suicidality; monitor for psychiatric events. Can cause extrapyramidal symptoms, parkinsonism, akathisia, restlessness, and agitation. May increase risk of QT prolongation; avoid in patients with congenital long QT syndrome or with other QT-prolonging drugs. May cause sedation/somnolence; impair ability to drive or operate machinery. Neuroleptic malignant syndrome (NMS) has been reported. Do not abruptly discontinue; taper to minimize withdrawal effects. |
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| Fetal Monitoring | Monitor for maternal extrapyramidal symptoms, depression/suicidality, and QT prolongation. Fetal: ultrasound for growth and well-being if exposure in second/third trimester. Neonatal: observe for extrapyramidal symptoms, sedation, and withdrawal (e.g., restlessness, hypertonia) for 48-72 hours after delivery. |
| Fertility Effects | No human fertility studies. In rats, deutetrabenazine (up to 10 mg/kg/day orally) had no effect on male or female fertility or reproductive performance. However, based on pharmacodynamics (VMAT2 inhibition, dopaminergic effects), theoretical potential for menstrual irregularities or decreased libido. |
| Food/Dietary | Take with food to reduce nausea and vomiting. Avoid high-fat meals if they affect tolerability; otherwise, no specific food restrictions. Avoid alcohol. |
| Clinical Pearls | AUSTEDO XR (deutetrabenazine extended-release) is a VMAT2 inhibitor for tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). Due to its extended-release formulation, it is dosed once daily, unlike immediate-release deutetrabenazine which is twice daily. Monitor for depression, suicidality, and QTc prolongation. Avoid use with reserpine or MAOIs. Dose reduction may be needed in CYP2D6 poor metabolizers or with strong CYP2D6 inhibitors. |
| Patient Advice | Take AUSTEDO XR once daily with food, swallowing the tablet whole; do not crush or chew. · Do not stop taking this medication abruptly; consult your doctor for dose adjustments. · Report any new or worsening depression, anxiety, or thoughts of self-harm immediately. · Avoid alcohol and medications that depress the central nervous system. · May cause drowsiness or dizziness; do not drive until you know how this medicine affects you. · Attend regular follow-up appointments for monitoring of heart rhythm (QTc interval) and mental health. |