Valbenazine

Indications

• FDA-approved for the treatment of tardive dyskinesia in adults, regardless of whether the causative antipsychotic is continued.
• FDA-approved for chorea associated with Huntington disease in adults, an indication added in 2023 with the boxed warning.
• First-line pharmacologic treatment for moderate to severe tardive dyskinesia in current APA and movement disorder guidance.
• It treats tardive dyskinesia symptomatically without requiring the offending antipsychotic to be stopped or switched.
• Not indicated for acute dystonia, drug-induced parkinsonism, or akathisia, which respond to different interventions.
• Off-label use in other tardive syndromes such as tardive dystonia is described but has limited controlled evidence.

Mechanism of action

• Reversibly inhibits vesicular monoamine transporter 2, reducing packaging of dopamine into presynaptic vesicles and lowering synaptic release.
• Reduced striatal dopamine signaling counteracts the receptor supersensitivity thought to underlie tardive dyskinesia after chronic D2 blockade.
• Valbenazine is a prodrug hydrolyzed to the active [+]-alpha-dihydrotetrabenazine isomer, which binds VMAT2 with high selectivity.
• The single active isomer gives less off-target activity than tetrabenazine, which yields four isomers with broader receptor effects.
• It has negligible affinity for dopamine, serotonin, adrenergic, and muscarinic receptors, limiting sedation and autonomic effects.

Pharmacokinetics

• Oral absorption gives peak concentrations in about 30 minutes to 1 hour, and a high-fat meal reduces exposure modestly without clinical importance.
• Both valbenazine and its active metabolite have half-lives of roughly 15 to 22 hours, supporting reliable once-daily dosing.
• Hydrolysis produces the active metabolite, which is further metabolized by CYP3A4 and CYP3A5, while CYP2D6 handles the parent drug.
• Steady state is reached in about 1 week, and clinically meaningful benefit typically emerges within 2 to 6 weeks of the target dose.
• Excretion is largely as metabolites, and use is not recommended when creatinine clearance falls below 30 mL per minute.

Dosing

• For tardive dyskinesia start 40 mg once daily, then increase to the recommended 80 mg once daily after 1 week.
• For Huntington chorea start 40 mg once daily and titrate weekly in 20 mg increments to a recommended dose of 80 mg daily.
• Some patients respond adequately to 40 mg daily, and 60 mg is an option when 80 mg is not tolerated.
• Reduce to 40 mg daily with strong CYP3A4 inhibitors, with strong CYP2D6 inhibitors, and in known CYP2D6 poor metabolizers.
• Reduce to 40 mg daily in moderate to severe hepatic impairment, and avoid concomitant strong CYP3A4 inducers entirely.
• The capsule contents may be sprinkled on soft food for patients who cannot swallow capsules; no taper is required on discontinuation.

Adverse effects

• Somnolence and sedation are the most common effects, reported in roughly 10 percent versus 4 percent on placebo in registration trials.
• Balance problems, gait disturbance, and falls occur more often than with placebo and matter most in older or frail patients.
• Dose-dependent QT prolongation is small at usual doses but becomes clinically relevant in poor metabolizers or with enzyme inhibitors.
• Drug-induced parkinsonism and akathisia can emerge from excessive dopamine depletion and usually respond to dose reduction.
• Depression and suicidal ideation are the defining risk in Huntington disease and drive the boxed warning for that population.
• Headache, dry mouth, urinary retention, anticholinergic-like complaints, and arthralgia are reported at low but appreciable rates.

Monitoring

• Assess mood and suicidality at baseline and at every visit in Huntington disease, and involve caregivers in reporting behavior change.
• Use the AIMS at baseline and every 3 to 6 months to document response and to guide dose decisions objectively.
• Obtain an ECG at baseline and after dose escalation in patients with congenital long QT, arrhythmia history, or interacting drugs.
• Monitor for emergent parkinsonism, sedation, and gait instability, all of which signal excessive dopamine depletion.
• Review hepatic function and CYP2D6 status when choosing the dose, since both shift exposure substantially.

Interactions

• Strong CYP3A4 inhibitors such as ketoconazole and clarithromycin raise active metabolite exposure and require a 40 mg daily dose.
• Strong CYP3A4 inducers including rifampin, carbamazepine, phenytoin, and St. John's wort reduce exposure and should be avoided.
• Strong CYP2D6 inhibitors such as paroxetine, fluoxetine, and bupropion raise levels, so use the lower dose in those patients.
• Concomitant MAO inhibitors are not recommended because monoamine depletion combined with MAO inhibition has unpredictable effects.
• Additive QT effects with other QT-prolonging drugs warrant ECG monitoring; additive sedation occurs with alcohol and CNS depressants.

Special populations

• Pregnancy data are limited and animal data show developmental toxicity, so use only when the benefit clearly outweighs the risk.
• Because of a long half-life and animal lactation data, breastfeeding is not recommended during and for 5 days after treatment.
• Safety and efficacy in patients under 18 years have not been established for either approved indication.
• In older adults, sedation, gait instability, and falls are the main concerns; consider the 40 mg dose and monitor mobility.
• Use 40 mg daily in moderate to severe hepatic impairment, and avoid use when creatinine clearance is below 30 mL per minute.

Clinical pearls

• No need to stop the antipsychotic; valbenazine treats tardive dyskinesia while the antipsychotic continues.
• Anticholinergics do not help tardive dyskinesia and often worsen it; taper benztropine as valbenazine starts.
• Poor CYP2D6 metabolizers and patients on paroxetine or fluoxetine should stay at 40 mg daily.