Diltiazem CR Twice Daily Dosing
Yes, Diltiazem CR can be dosed twice daily, though once-daily formulations are specifically designed for single daily dosing and should not be split into twice-daily regimens. The key distinction is between controlled-release (CR) formulations designed for twice-daily use versus extended-release (CD/XR) formulations designed for once-daily use.
Formulation-Specific Dosing
Diltiazem CR (controlled-release) formulations are specifically designed and FDA-approved for twice-daily administration, typically dosed at 60-180 mg twice daily, with a maximum of 360 mg total daily dose divided into two administrations 1, 2. This differs fundamentally from extended-release formulations (CD/XR), which are engineered for once-daily dosing at 120-540 mg as a single daily dose 1, 3, 4.
Key Formulation Differences:
- CR (Controlled-Release): Designed for twice-daily dosing, maintains therapeutic levels over 12-hour intervals 2
- CD/XR (Extended-Release): Designed for once-daily dosing, delivers diltiazem at a constant rate over 24 hours 4
- Immediate-Release: Requires 3-4 times daily dosing at 30-90 mg per dose 1
Clinical Evidence for Twice-Daily Dosing
A multicenter, double-blind trial directly compared once-daily (CD) versus twice-daily (SR) diltiazem formulations in 111 hypertensive patients, demonstrating equivalent efficacy and safety profiles 5. Both groups achieved similar blood pressure control (60% vs 55% reaching goal DBP <90 mmHg, p=0.685) with comparable adverse effect profiles 5.
For stable angina, a crossover study of 41 patients confirmed that diltiazem CR twice daily (b.i.d.) was equally potent and safe as conventional diltiazem four times daily, with maximal workload increasing from 127W on placebo to 146W on CR tablets 2.
Critical Dosing Considerations
Do not attempt to split or divide extended-release (CD/XR) capsules for twice-daily dosing, as this destroys the controlled-release mechanism and can result in dangerous immediate drug release 6. If twice-daily dosing is clinically indicated, use a formulation specifically designed for that purpose 1.
Dose Requirements by Indication:
- Hypertension: Typically requires 240-360 mg daily, with doses up to 540 mg studied and found safe 3, 7
- Angina: Typically requires 240 mg daily 7
- Starting dose: 120-180 mg daily represents the minimum effective dose 1, 6
Common Pitfalls to Avoid
The most significant prescribing error is underdosing diltiazem for hypertension. Analysis of FDA data from six randomized controlled trials demonstrates a clear linear dose-response relationship through 480-540 mg/day, with 90-120 mg/day representing a "no-effect dose" 7. Despite this, over 70% of diltiazem prescriptions for hypertension use the 180-240 mg strengths, which are often subtherapeutic 7.
Contraindications (Absolute):
- Second or third-degree AV block without functioning pacemaker 1, 8
- Wolff-Parkinson-White syndrome with atrial fibrillation/flutter 1, 8
- Decompensated systolic heart failure or severe LV dysfunction 1, 8
- Cardiogenic shock 1
- Sick sinus syndrome without pacemaker 1
Drug Interactions Requiring Caution:
Diltiazem is both a CYP3A4 substrate and moderate CYP3A4 inhibitor, requiring careful monitoring when combined with apixaban, cyclosporine, simvastatin, and other CYP3A4 substrates 1.
Monitoring Requirements
- Blood pressure and heart rate at baseline and 1 month after initiation or dose changes 1
- ECG monitoring in patients with conduction system disease 1
- Liver function tests if clinically indicated 1
- Signs and symptoms of heart failure in at-risk patients 1