TETRABENAZINE
Clinical safety rating: safe
Animal studies have demonstrated safety
Tetrabenazine reversibly inhibits vesicular monoamine transporter 2 (VMAT2), depleting monoamines (dopamine, serotonin, norepinephrine, histamine) from presynaptic vesicles.
| Metabolism | Primarily metabolized by carbonyl reductase (CBR1) to α-dihydrotetrabenazine (HTBZ), which is further metabolized by CYP2D6; minor metabolism by other CYP450 enzymes. |
| Excretion | Renal (70-80% as metabolites, <1% unchanged), fecal (20-25%) |
| Half-life | Tetrabenazine: 4-8 hours; active metabolite α-HTBZ: 7-10 hours; β-HTBZ: 4-6 hours. Clinical context: multiple daily dosing required; steady state in 2-3 days. |
| Protein binding | 82-85% bound to plasma proteins (primarily albumin). |
| Volume of Distribution | 5-13 L/kg; indicates extensive tissue distribution. |
| Bioavailability | Oral: approximately 100% (high first-pass metabolism, but parent drug and metabolites are active; absorption is complete). |
| Onset of Action | Oral: 1-2 hours for peak effect; clinical improvement may take weeks. |
| Duration of Action | Approximately 12-24 hours after a single dose; sustained effects with multiple doses. |
Initial: 12.5 mg orally twice daily; titrate by 12.5 mg per week up to a maximum of 100 mg daily in divided doses. Effective dose range: 25-75 mg daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR ≥30 mL/min). For severe renal impairment (GFR <30 mL/min), use with caution and consider dose reduction of 25-50% based on tolerability. |
| Liver impairment | Contraindicated in patients with hepatic impairment. For Child-Pugh class A, avoid use; no data available for class B or C; contraindicated per labeling. |
| Pediatric use | Not approved for pediatric use. Safety and efficacy not established. Limited data: initial 0.5 mg/kg/day orally in divided doses, titrate up to 2 mg/kg/day maximum, but not recommended outside clinical trials. |
| Geriatric use | Start at low end of dosing range (12.5 mg once daily) and titrate slowly. Monitor for hypotension, sedation, and QT prolongation. Maximum dose generally 50 mg daily due to increased sensitivity. |
| 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.
| Breastfeeding | It is not known whether tetrabenazine is excreted in human breast milk. Given its pharmacologic activity and potential for serious adverse reactions (e.g., extrapyramidal disorders, sedation) in nursing infants, breastfeeding is not recommended during therapy. M/P ratio is unknown. |
| Teratogenic Risk | Tetrabenazine is classified as FDA Pregnancy Category C. Animal studies have shown teratogenic effects (fetal malformations and embryotoxicity) at doses similar to human therapeutic doses. There are no adequate and well-controlled studies in pregnant women. The drug crosses the placenta. In first trimester, there is potential risk of major malformations; second and third trimester exposure may be associated with fetal/neonatal extrapyramidal symptoms, withdrawal syndrome, and decreased fetal growth. Use only if potential benefit justifies potential risk to fetus. |
■ FDA Black Box Warning
Increased risk of depression and suicidal thoughts and behavior in patients with Huntington's disease; monitor all patients for emergence or worsening of depression, suicidality, or unusual changes in behavior.
| Common Effects | Sedation |
| Serious Effects |
["Hypersensitivity to tetrabenazine or any component","Hepatic impairment (Child-Pugh B or C)","Concurrent use of MAOIs (MAO-A or MAO-B)","Untreated or inadequately treated depression (especially with suicidality)","Lactation (discontinue breastfeeding or drug)"]
| Precautions | ["Risk of depression and suicidality","QT prolongation","Neuroleptic malignant syndrome (NMS)-like events","Akathisia, restlessness, agitation","Parkinsonism","Sedation/somnolence","Hyperprolactinemia","Dysphagia and increased risk of aspiration","Hepatic impairment requires dose adjustment"] |
Loading safety data…
| Fetal Monitoring | Maternal: Monitor for extrapyramidal symptoms, sedation, depression, suicidality, QT prolongation (ECG), and akathisia. Fetal/neonatal: Monitor for signs of extrapyramidal dysfunction, withdrawal, sedation, and respiratory depression after delivery. Consider fetal growth assessments via ultrasound if used during pregnancy. |
| Fertility Effects | In animal studies, tetrabenazine caused decreased fertility in male and female rats at doses equivalent to human therapeutic doses. In humans, effects on fertility are unknown; however, due to central dopamine depletion, it may impair libido, erectile function, and menstrual cyclicity. Oligospermia and hyperprolactinemia may occur. |