Valbenazine (Ingrezza)
VMAT2 inhibitor • Last reviewed 2025-09-23
General information
Valbenazine is a highly selective VMAT2 inhibitor indicated for tardive dyskinesia (TD) in adults, producing clinically meaningful AIMS score reductions without compromising antipsychotic therapy (valbenazine_label_2024, hauser2017).
Capsules (40, 60, 80 mg) are administered once daily; titration begins at 40 mg for one week before increasing to 80 mg daily. Patients who experience adverse effects or are taking strong CYP2D6 or CYP3A4 inhibitors may remain at 40 mg (valbenazine_label_2024).
By reversibly inhibiting VMAT2, valbenazine reduces presynaptic dopamine packaging and release within nigrostriatal terminals, thereby diminishing hyperkinetic movements while sparing other monoaminergic pathways (hauser2017, carbon2022).
Valbenazine is metabolized primarily by CYP3A4/5 and CYP2D6 to the active metabolite NBI-98782; both parent and metabolite have half-lives near 20 hours, supporting once-daily dosing and sustained symptom control in 48-week extension trials (valbenazine_label_2024, hauser2019).
Dosing & administration
Tardive dyskinesia: start 40 mg once daily for 1 week; increase to 80 mg once daily.
CYP2D6 poor metabolizers or strong CYP2D6 inhibitors: consider 40 mg once daily.
Strong CYP3A4 inhibitors: reduce dose to 40 mg once daily.
Severe renal impairment (eGFR <30 mL/min): avoid use.
Dose adjustments
- Strong CYP3A4 inhibitors
- Limit to 40 mg/day and monitor for somnolence and QT prolongation.
- Strong CYP3A4 inducers
- Contraindicated—exposure decreases markedly.
- Strong CYP2D6 inhibitors / poor metabolizers
- Maintain 40 mg/day; titrate cautiously if higher dose needed.
- Hepatic impairment
- Avoid in moderate/severe impairment due to increased exposure.
Mechanism of action
Valbenazine and its active metabolite selectively inhibit VMAT2, reducing presynaptic dopamine release in the basal ganglia, which alleviates TD movements without blocking postsynaptic dopamine receptors (hauser2017).
VMAT2 selectivity (>2,000-fold over VMAT1) and minimal affinity for other receptors contribute to a favourable tolerability profile even with long-term administration (carbon2022, hauser2019).
- VMAT2 Ki ≈ 1.0 nM (parent); metabolite Ki ≈ 0.1 nM.
- Negligible affinity for D2, 5-HT2A, α-adrenergic, or muscarinic receptors.
- No clinically relevant effect on monoamine transporter reuptake.
Metabolism & pharmacokinetics
Valbenazine reaches peak concentrations in 4-8 hours. Exposure is dose-proportional between 40 and 80 mg (valbenazine_label_2024).
Valbenazine is ~99% protein bound, metabolised via CYP3A4/5 and CYP2D6, and eliminated primarily in urine and faeces as metabolites. NBI-98782 contributes substantially to pharmacologic activity with half-life ~18 hours (valbenazine_label_2024, hauser2019).
Drug interactions
Strong CYP3A4 inhibitors increase exposure; limit dose to 40 mg/day and monitor QTc.
Strong CYP3A4 inducers (rifampin, carbamazepine) markedly reduce exposure; avoid combination.
Valbenazine prolongs QTc by ~6 msec at 80 mg; additive effects with other QT-prolonging agents mandate ECG monitoring.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP3A4 inhibition | Ketoconazole, itraconazole | Limit to 40 mg/day and obtain ECG in high-risk patients. |
| CYP3A4 induction | Rifampin, carbamazepine | Avoid coadministration; consider alternative VMAT2 inhibitor. |
| QT prolongation | Ziprasidone, methadone, quinidine | Baseline and follow-up ECG when combining; correct electrolytes. |
Monitoring & safety checks
Abnormal Involuntary Movement Scale (AIMS)
Baseline, week 2, week 6, then quarterly • Quantify TD response and titrate dose.
Baseline in patients with cardiac risk or QT-prolonging co-therapy • Detect clinically significant QT prolongation.
Somnolence/fall risk
Each visit • Sedation is the most common adverse effect.
Bedtime dosing may minimise daytime sedation without compromising efficacy.
Assess mood and suicidality periodically; although uncommon, depressive symptoms have been reported in TD populations (carbon2022).
Discontinuation guidance
No taper required; TD symptoms typically return toward baseline within several weeks after stopping.
If discontinuation is due to lack of response, reassess antipsychotic exposure and consider alternative VMAT2 inhibitors or clozapine transition.
Special populations
Older adults: similar efficacy and tolerability to younger adults; nonetheless monitor for orthostasis and falls (hauser2019).
Pregnancy: limited human data; enrol in pregnancy registry when possible and weigh maternal benefit against fetal risk.
Hepatic impairment: avoid in moderate/severe impairment; exposure increases ~60%.
Adverse effects
Common: somnolence, fatigue, dry mouth, mild akathisia.
Less common: balance disorder, urinary retention, paresthesia; adjust dose if clinically significant.
Serious but rare: hypersensitivity reactions, clinically significant QT prolongation.
References
- INGREZZA (valbenazine) prescribing information — DailyMed (2024)
- KINECT 3: randomized placebo-controlled trial of valbenazine — JAMA Neurology (2017) DOI: 10.1001/jamaneurol.2017.1141
- KINECT 4: long-term valbenazine safety and efficacy — CNS Drugs (2019) DOI: 10.1007/s40263-019-00682-4
- Treatment of tardive dyskinesia with VMAT2 inhibitors — Journal of Psychopharmacology (2022) DOI: 10.1177/02698811211070326
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.