Introduction
Ingrezza (valbenazine) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved by the FDA in 2017. It represents a significant advancement in the treatment of tardive dyskinesia, a potentially disabling movement disorder associated with long-term antipsychotic use. As the first FDA-approved medication specifically indicated for tardive dyskinesia, Ingrezza offers a targeted therapeutic approach for this challenging condition.
Mechanism of Action
Valbenazine is a highly selective reversible inhibitor of vesicular monoamine transporter 2 (VMAT2). VMAT2 is responsible for packaging monoamines (dopamine, norepinephrine, serotonin) into synaptic vesicles for storage and release. By inhibiting VMAT2, valbenazine reduces the uptake of monoamines into synaptic vesicles, particularly dopamine, thereby decreasing dopamine release in the striatum. This mechanism modulates dopaminergic neurotransmission without completely blocking dopamine receptors, which differentiates it from typical antipsychotics and explains its efficacy in treating hyperkinetic movement disorders like tardive dyskinesia.
Indications
- Treatment of tardive dyskinesia in adults
- Not indicated for the treatment of psychotic disorders
Dosage and Administration
Initial dose: 40 mg once daily After one week: Increase to 80 mg once daily (recommended maintenance dose) Dosage adjustments:- Hepatic impairment (Child-Pugh B): Maximum 40 mg daily
- Hepatic impairment (Child-Pugh C): Not recommended
- Renal impairment: No dosage adjustment required
- CYP2D6 poor metabolizers: Maximum 40 mg daily
- Concomitant use with strong CYP3A4 inhibitors: Maximum 40 mg daily
- Concomitant use with strong CYP3A4 inducers: Not recommended
- Oral administration with or without food
- Capsules should be swallowed whole
Pharmacokinetics
Absorption: Tmax approximately 0.5-1 hour Distribution: Volume of distribution ~92 L; 99% protein-bound Metabolism: Extensive hepatic metabolism primarily via hydrolysis (to active metabolite [+]-α-dihydrotetrabenazine) and CYP3A4/2D6 metabolism Elimination: Half-life of valbenazine ~15-22 hours; active metabolite half-life ~22 hours Excretion: Primarily fecal (60%) and renal (40%)Contraindications
- Hypersensitivity to valbenazine or any component of the formulation
- Concomitant use with strong CYP3A4 inducers
Warnings and Precautions
Sedation/Somnolence: May impair mental or physical abilities; caution patients about operating machinery QTc Prolongation: Small dose-related increases in QTc interval observed Parkinsonism: May cause or worsen parkinsonian symptoms Suicidal Ideation and Behavior: Monitor for emergence or worsening of depression Hepatic Impairment: Use with caution and dose adjustment in moderate impairment; avoid in severe impairment CYP2D6 Poor Metabolizers: Reduced clearance requires dose reductionDrug Interactions
Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): Increase valbenazine exposure; limit to 40 mg daily Strong CYP3A4 inducers (rifampin, carbamazepine): Decrease valbenazine exposure; contraindicated CYP2D6 inhibitors (paroxetine, fluoxetine): May increase active metabolite exposure; monitor QTc-prolonging drugs: Additive effects possible; monitor ECG if co-administered Dopamine antagonists: Potential for additive effects on movement disordersAdverse Effects
Common (≥5% and twice placebo):- Somnolence (15%)
- Fatigue (6%)
- Anticholinergic effects (dry mouth, constipation)
- Balance disorders/falls
- Headache
- Nausea
- QTc prolongation
- Parkinsonism
- Neuroleptic malignant syndrome (theoretical risk)
- Suicidal ideation
- Severe sedation
Monitoring Parameters
- Tardive dyskinesia symptoms (AIMS scale recommended)
- Sedation/somnolence
- Parkinsonian symptoms (rigidity, tremor, bradykinesia)
- Mood changes and suicidal ideation
- QTc interval in patients at risk or on concomitant QTc-prolonging drugs
- Hepatic function in patients with liver disease
- Fall risk assessment in elderly patients
Patient Education
- Take medication exactly as prescribed; do not adjust dose without medical supervision
- Be aware of potential sedation; avoid driving or operating machinery until effects are known
- Report any new or worsening movement symptoms
- Inform all healthcare providers about Ingrezza use
- Do not stop taking antipsychotic medications unless directed by prescriber
- Report mood changes, depression, or suicidal thoughts immediately
- Avoid alcohol and other CNS depressants
- Store at room temperature away from moisture
References
1. FDA Prescribing Information: Ingrezza (valbenazine) capsules. April 2023 2. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: A phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484 3. Anderson KE, Stamler D, Davis MD, et al. Valbenazine for the treatment of tardive dyskinesia: A review of clinical trials. Neuropsychiatr Dis Treat. 2021;17:3475-3487 4. Citrome L. Valbenazine for tardive dyskinesia: Systematic review of the efficacy and safety profile for this newly approved novel medication—what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2017;71(9) 5. Marder SR, Singer C, Lindenmayer JP, et al. A phase 3, 48-week, open-label study to evaluate the long-term safety and tolerability of valbenazine in adults with tardive dyskinesia. J Clin Psychopharmacol. 2020;40(1):36-43