VALBENAZINE TOSYLATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VALBENAZINE TOSYLATE (VALBENAZINE TOSYLATE).
Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor. By inhibiting VMAT2, it reduces the uptake of monoamines into synaptic vesicles, thereby decreasing presynaptic dopamine concentrations and mitigating dopaminergic hyperactivity associated with tardive dyskinesia.
| Metabolism | Primarily metabolized via esterase-mediated hydrolysis to its active metabolite, alpha-dihydrotetrabenazine (HTBZ); minor contributions from CYP3A4 and CYP2D6. |
| Excretion | Approximately 73% of the dose is excreted in feces (primarily as parent drug and metabolites) and 20% in urine. The major metabolites are valbenazine glucuronide and its acid metabolite. |
| Half-life | The terminal elimination half-life of valbenazine is approximately 15–22 hours for the parent drug and 20–25 hours for its active metabolite, (+)-α-dihydrotetrabenazine (dihydrotetrabenazine). The long half-life supports once-daily dosing. |
| Protein binding | Valbenazine is approximately 64% bound to plasma proteins, primarily to albumin. The active metabolite dihydrotetrabenazine is approximately 40% bound. |
| Volume of Distribution | The volume of distribution is approximately 7.5 L/kg (range 5–10 L/kg), indicating extensive tissue distribution. This is consistent with its lipophilic nature and ability to cross the blood-brain barrier. |
| Bioavailability | Oral bioavailability is approximately 49% (range 32–68%) due to first-pass metabolism. It is metabolized primarily by esterases in the gut and liver to its active metabolite. |
| Onset of Action | Oral: Clinical improvement in tardive dyskinesia (Abnormal Involuntary Movement Scale) is observed within 2–4 weeks of starting therapy, with peak effects seen after 6–8 weeks. |
| Duration of Action | The duration of action is approximately 24 hours, allowing for once-daily dosing. The effect on tardive dyskinesia is maintained with continuous therapy; discontinuation may result in worsening over weeks. |
Initial dose: 6 mg orally twice daily; may increase to 12 mg twice daily based on response.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min); not studied in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Child-Pugh Class A: 6 mg twice daily; Child-Pugh Class B: 3 mg twice daily; Child-Pugh Class C: not recommended. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | No specific dose adjustment; monitor for adverse effects due to potential age-related decreases in hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VALBENAZINE TOSYLATE (VALBENAZINE TOSYLATE).
| Breastfeeding | No data available on valbenazine excretion in human milk. Valbenazine and its metabolites are present in rat milk. The milk-to-plasma ratio is approximately 0.3. Due to potential for adverse reactions in breastfed infants (e.g., sedation, extrapyramidal symptoms), breastfeeding is not recommended during treatment. If breastfeeding, monitor for excessive drowsiness, poor feeding, and unusual movements. |
| Teratogenic Risk | Valbenazine tosylate is classified as FDA Pregnancy Category C. In animal studies, no teratogenic effects were observed in rats or rabbits at doses up to 8 times the maximum recommended human dose (MRHD). However, in rats, decreased fetal body weight and delayed ossification occurred at doses ≥2 times MRHD. Adequate human studies are lacking. Risk cannot be ruled out. First trimester: potential risk unknown, but animal data suggest low teratogenicity. Second and third trimesters: potential for fetal adverse effects due to maternal VMAT2 inhibition; fetal exposure may occur. |
■ FDA Black Box Warning
Valbenazine has no FDA black box warning.
| Serious Effects |
["Concurrent use with monoamine oxidase inhibitors (MAOIs)","Concurrent use with reserpine","History of hepatic impairment (Child-Pugh score >5)"]
| Precautions | ["May cause somnolence and sedation; avoid driving or operating machinery until effects are known.","May prolong the QT interval; avoid use in patients with congenital long QT syndrome or with concurrent use of QT-prolonging drugs.","May increase the risk of depression and suicidality in patients with Huntington's disease (not indicated).","Monitor for parkinsonism, akathisia, and restlessness.","Avoid in patients with hepatic impairment (Child-Pugh score >5)."] |
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| Fetal Monitoring | Monitor maternal vital signs, liver function tests (LFTs), ECG (QTc interval), and signs of extrapyramidal symptoms (EPS) or tardive dyskinesia. In pregnancy, monitor fetal growth and development via ultrasound; consider non-stress testing if fetal movement decreased. Neonatal monitoring: observe for EPS, sedation, or withdrawal symptoms after delivery. |
| Fertility Effects | In animal studies, valbenazine did not impair fertility in male or female rats at doses up to 8 times MRHD. Human data are lacking. VMAT2 inhibition may theoretically affect hormonal regulation, but no clinical evidence of fertility impairment. Consider reproductive planning for patients of childbearing potential. |