Verapamil and Ingrezza (Valbenazine) Combination: Critical Precautions
Primary Recommendation
Reduce Ingrezza dose by 50% when coadministered with verapamil due to strong CYP2D6 and moderate CYP3A4 inhibition by verapamil, which significantly increases valbenazine and its active metabolite concentrations, raising the risk of QT prolongation, excessive sedation, parkinsonism, and additive cardiovascular depression. 1
Mechanism of Drug Interaction
Verapamil acts as a dual inhibitor affecting Ingrezza metabolism through two critical pathways:
- CYP3A4 inhibition: Verapamil moderately inhibits CYP3A4, increasing plasma concentrations of valbenazine's active metabolites 2, 1
- CYP2D6 inhibition: Verapamil strongly inhibits CYP2D6, further elevating deutetrabenazine-related compound exposure 1
- P-glycoprotein inhibition: Verapamil inhibits P-glycoprotein transport, affecting multiple drug elimination pathways 1
Cardiovascular Risks Requiring Immediate Assessment
The combination creates additive cardiovascular depressant effects that can be life-threatening:
- Hypotension and bradycardia: Both drugs independently cause these effects, which synergize when combined 1
- QT prolongation: Increased active metabolite concentrations from Ingrezza potentiate QT interval prolongation risk 1
- AV conduction abnormalities: Verapamil's negative dromotropic effects combined with potential Ingrezza effects increase heart block risk 2, 1
Absolute Contraindications to This Combination
Do not combine verapamil and Ingrezza in patients with: 1
- AV block greater than first degree without a pacemaker
- Sick sinus syndrome without a pacemaker
- Decompensated heart failure
- Severe left ventricular dysfunction (LVEF <40%)
- Baseline QTc >440-450 ms
Pre-Initiation Assessment Algorithm
Before starting this combination, systematically evaluate: 1
- Obtain baseline ECG to assess QTc interval and conduction abnormalities
- Assess cardiovascular status for pre-existing heart failure, conduction disease, or hypotension
- Review complete medication list for other QT-prolonging agents or CYP inhibitors that would compound risk
- Screen for high-risk populations: elderly patients, those with renal dysfunction, and Asian populations who may have altered drug metabolism
Dosing Adjustment Protocol
If Adding Verapamil to Stable Ingrezza:
Reduce Ingrezza dose by 50% immediately when initiating verapamil 1
If Adding Ingrezza to Stable Verapamil:
Start Ingrezza at 50% of the usual initial dose 1
Mandatory Monitoring Parameters
ECG Monitoring:
- Baseline ECG before combination initiation 1
- Repeat ECG 1-2 weeks after any dose changes to reassess QTc interval 1
Cardiovascular Monitoring:
- Blood pressure and heart rate at each visit to detect bradycardia or hypotension 1
- Watch for symptoms of heart failure, dizziness, syncope, or excessive fatigue
Neurological Monitoring:
- Assess for excessive sedation, worsening parkinsonism, or akathisia from elevated Ingrezza levels 1
High-Risk Patient Populations
Exercise extreme caution in: 1
- Elderly patients: Increased sensitivity to both cardiovascular and neurological adverse effects
- Renal dysfunction: Altered drug clearance increases exposure
- Asian populations: Genetic polymorphisms in CYP2D6 may result in higher drug concentrations
- Patients on multiple QT-prolonging medications: Additive risk of torsades de pointes
Alternative Therapeutic Strategies
If Cardiovascular Risk Is Unacceptable:
Consider amlodipine instead of verapamil, as it does not significantly inhibit CYP3A4 or CYP2D6 and lacks the negative chronotropic and dromotropic effects of verapamil 1
Reassess Clinical Necessity:
Determine if both medications are truly required or if alternative therapies exist for the underlying conditions (e.g., different rate control agent for atrial fibrillation, alternative treatment for tardive dyskinesia) 1
Critical Clinical Pitfalls to Avoid
- Never assume standard Ingrezza dosing is safe when verapamil is present—dose reduction is mandatory, not optional 1
- Do not combine with beta-blockers unless absolutely necessary, as verapamil plus beta-blockers already creates profound cardiovascular depression that would be further compounded by Ingrezza 2, 3, 4
- Avoid in wide-complex tachycardias or uncertain rhythm diagnoses, as verapamil is contraindicated and the combination increases proarrhythmic risk 2
- Do not overlook baseline conduction abnormalities on ECG—even first-degree AV block warrants extreme caution 1