What are the differences between giving verapamil 240 mg once daily versus 120 mg twice daily?

Verapamil 240mg Once Daily vs 120mg Twice Daily

For rate control or hypertension, verapamil 240mg once daily using extended-release formulation is preferred over 120mg twice daily, as it provides equivalent 24-hour blood pressure control with better tolerability, fewer side effects, and improved medication adherence. 1

Efficacy Comparison

Both regimens achieve similar blood pressure reduction over 24 hours, but the once-daily 240mg extended-release formulation provides superior sustained control. 1

• A randomized, double-blind study directly comparing verapamil SR 240mg once daily versus verapamil SR 120mg twice daily found that 240mg once daily led to greater reduction in both systolic and diastolic blood pressure over 24 hours compared to the 120mg twice-daily regimen 1
• Both formulations produced clinically and statistically significant blood pressure reductions compared to placebo, but the 240mg once-daily dosing achieved better overall 24-hour control 1
• The immediate-release formulation given three times daily (120mg TID) produces more rapid blood pressure drops that peak 3-4 hours post-dose, whereas extended-release formulations provide more gradual and sustained blood pressure reduction 2

Pharmacokinetic Differences

Extended-release verapamil 240mg once daily produces more stable plasma concentrations with less fluctuation between peak and trough levels. 2, 3

• Sustained-release formulations produce a more gradual rise and sustained elevation of plasma verapamil and norverapamil concentrations compared to immediate-release formulations 2
• Comparable trough concentrations (Cmin) are achieved with both formulations, but immediate-release produces 10-20% greater peak concentrations (Cmax) and area under the curve (AUC) 2
• The controlled-release formulation demonstrates less fluctuation between Cmax and Cmin values over the dosing interval, providing more consistent drug exposure 3

Tolerability and Side Effects

The once-daily 240mg extended-release formulation has significantly fewer side effects than divided-dose immediate-release regimens. 2

• The incidence of side effects (headache, palpitations, dizziness, and flushing) is dose-dependent and much higher with immediate-release verapamil given multiple times daily than with sustained-release formulations 2
• Side effects decrease with continuous treatment regardless of formulation 2
• Both regimens were well tolerated with no significant changes in heart rate, though small increases (mean 5 bpm) and decreases (mean 13 bpm to 62 bpm) were observed 2, 1

Guideline-Recommended Dosing

ACC/AHA guidelines support verapamil dosing of 120-480mg daily in divided or single doses with long-acting formulations for rate control. 4

• Initial dosing should start at 120mg daily in divided or single dose with long-acting formulations 4
• Maintenance doses range up to 480mg daily in divided or single dose with long-acting formulations 4
• The FDA label recommends initiating therapy with 180mg of extended-release verapamil given in the morning, with lower initial doses of 120mg daily warranted in elderly or small patients 5
• When switching from immediate-release to extended-release formulations, the total daily dose in milligrams may remain the same 5

Clinical Considerations for Dosing Selection

Once-daily extended-release formulations improve medication adherence and provide more consistent therapeutic effect throughout the 24-hour period. 1, 6

• Sustained-release verapamil formulations as a single daily dose are as effective in lowering blood pressure over 24 hours as equivalent doses of conventional verapamil given 3 times daily 6
• Verapamil does not cause reflex tachycardia, orthostatic hypotension, or development of tolerance 6
• Both PR interval prolongation on ECG occurs equally with 240mg and 480mg daily doses 2

Important Contraindications and Precautions

Verapamil is contraindicated in specific cardiac conditions regardless of dosing regimen. 4

• Absolute contraindications include: AV block greater than first degree or SA node dysfunction without a pacemaker, decompensated systolic heart failure or severe LV dysfunction, hypotension, and WPW syndrome with atrial fibrillation/flutter 4
• Potential adverse effects include hypotension, worsening heart failure in patients with pre-existing ventricular dysfunction, pulmonary edema in hypertrophic cardiomyopathy patients, bradycardia, and abnormal liver function 4
• Verapamil is a moderate CYP3A4 inhibitor and also inhibits P-glycoprotein, requiring caution with numerous drug interactions 4

Practical Recommendation

For new initiations, start with verapamil extended-release 180mg once daily in the morning, then titrate to 240mg once daily based on response. 5

• If adequate response is not obtained with 180mg, titrate upward to 240mg each morning 5
• Further titration options include 180mg morning plus 180mg evening, or 240mg morning plus 120mg evening, or 240mg every 12 hours 5
• The extended-release formulation should be administered with food 5