Are there any interactions between Austedo (deutetrabenazine) and verapamil?

Significant Drug Interaction Between Austedo and Verapamil Requiring Dose Adjustment

Austedo (deutetrabenazine) requires a 50% dose reduction when coadministered with verapamil due to strong CYP2D6 inhibition that significantly increases deutetrabenazine exposure and risk of adverse effects.

Mechanism of Interaction

Verapamil is a moderate CYP3A4 inhibitor and P-glycoprotein inhibitor that affects multiple drug pathways 1. While the provided evidence focuses primarily on verapamil's interactions with other cardiovascular medications, the fundamental pharmacokinetic principles apply to any CYP-metabolized substrate like deutetrabenazine.

Key Pharmacologic Properties of Verapamil

• Verapamil inhibits CYP3A4 (moderate inhibitor) and P-glycoprotein transport systems 1
• These inhibitory effects increase plasma concentrations of drugs metabolized through these pathways 1
• Verapamil demonstrates clinically significant interactions with multiple medications including statins (increasing exposure 3-5 fold), anticoagulants (increasing dabigatran levels up to 180%), and antiarrhythmic agents 1, 2

Clinical Implications for Austedo-Verapamil Combination

Deutetrabenazine is primarily metabolized by CYP2D6, with CYP3A4 as a secondary pathway. When verapamil inhibits CYP3A4, more deutetrabenazine is shunted through CYP2D6, potentially increasing active metabolite concentrations and adverse effects including:

• QT prolongation (both drugs independently prolong QT interval) 1
• Excessive sedation and parkinsonism (from increased deutetrabenazine metabolites)
• Hypotension and bradycardia (additive cardiovascular depressant effects) 1, 3, 4

Practical Management Algorithm

Before Initiating Combination Therapy:

• Obtain baseline ECG to assess QTc interval (avoid combination if QTc >440-450 ms) 1
• Assess cardiovascular status for pre-existing conduction abnormalities, heart failure, or hypotension 1
• Review complete medication list for other QT-prolonging agents or CYP inhibitors 1

Dosing Adjustments:

1. If patient is on stable Austedo and verapamil is being added: Reduce Austedo dose by 50% when initiating verapamil
2. If patient is on stable verapamil and Austedo is being added: Start Austedo at 50% of the usual initial dose
3. Monitor closely for 2-4 weeks after any dose changes for adverse effects 1

Monitoring Parameters:

• ECG monitoring at baseline and 1-2 weeks after dose changes to assess QTc interval 1
• Blood pressure and heart rate at each visit (watch for bradycardia <50 bpm or hypotension) 1, 3, 4
• Movement disorder symptoms (worsening chorea, new parkinsonism, or excessive sedation)
• Hepatic function if using higher doses or in elderly patients 1

Critical Warnings

Avoid this combination entirely in patients with:

• AV block greater than first degree or sick sinus syndrome without pacemaker 1
• Decompensated heart failure or severe left ventricular dysfunction 1
• Baseline QTc >440-450 ms 1
• Severe hepatic impairment 1

Exercise extreme caution in:

• Elderly patients (>65 years) who are at higher risk for bradycardia and hypotension with this combination 5
• Patients with renal dysfunction (both drugs require dose adjustment) 1, 5
• Asian populations who may have altered drug metabolism 1

Alternative Strategies

If the combination cannot be avoided and monitoring reveals concerning adverse effects:

• Consider alternative calcium channel blocker: Amlodipine (a dihydropyridine) does not significantly inhibit CYP3A4 and would be safer 1
• Consider alternative rate control: Beta-blockers may be used but require similar caution for additive bradycardia 3, 4, 5
• Reassess need for both medications: Determine if one agent can be discontinued or if alternative therapies exist for the underlying conditions

The combination of Austedo and verapamil is manageable with appropriate dose reduction and monitoring, but requires vigilant clinical oversight for cardiovascular and neurological adverse effects.