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. |
| Molecular Weight | 571.59 |
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 | No adequate human data; animal studies show no evidence of teratogenicity but use only if benefit outweighs risk. |
| 2nd trimester | Limited data; potential for extrapyramidal effects in fetus; avoid unless necessary. |
| 3rd trimester | Risk of neonatal extrapyramidal symptoms and withdrawal; avoid in third trimester. |
Clinical note
Comprehensive clinical and safety monograph for VALBENAZINE TOSYLATE (VALBENAZINE TOSYLATE).
| Placental transfer | Crosses placenta; estimated fetal-to-maternal ratio ~0.5-0.8 based on animal data. |
| Breastfeeding | Excreted into breast milk in low amounts; monitor infant for drowsiness, extrapyramidal symptoms; not recommended during breastfeeding. |
| Lactation Rating |
■ FDA Black Box Warning
Valbenazine has no FDA black box warning.
| Serious Effects |
Hypersensitivity to valbenazine or any componentConcurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI discontinuation
| 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). |
| Food/Dietary | Administer with food to enhance absorption (high-fat meal increases AUC by 70%). Avoid grapefruit juice and grapefruit products as they inhibit CYP3A4 and may increase valbenazine levels. |
Loading safety data…
| L4 - Possibly Hazardous |
| 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. |
| 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. |
| Clinical Pearls | Valbenazine is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor used for tardive dyskinesia. It does not block dopamine receptors; thus, it avoids parkinsonian side effects. Titrate slowly: start at 40 mg daily, increase to 80 mg after one week. Monitor for somnolence, QT prolongation, and akathisia. Avoid use with strong CYP3A4 inducers (e.g., rifampin) or inhibitors (e.g., ketoconazole); reduce dose to 40 mg if combined with moderate CYP3A4 inhibitors. Administration with food increases AUC by 70%, take with food. May cause dysphagia; assess swallowing ability. Not recommended in severe hepatic impairment. |
| Patient Advice | Take this medication once daily with food to increase absorption and reduce stomach upset. · Do not drive or operate heavy machinery until you know how valbenazine affects you; it can cause drowsiness and dizziness. · Report any new or worsening abnormal movements, difficulty swallowing, or thoughts of suicide to your doctor immediately. · Avoid grapefruit juice and grapefruit products while taking valbenazine. · Do not stop taking valbenazine abruptly without consulting your doctor; taper is not required, but your condition may worsen if discontinued. |