Ranolazine Can Be Safely Combined with Isosorbide Mononitrate
Yes, ranolazine can be taken concomitantly with isosorbide mononitrate—this combination is explicitly approved and does not cause clinically significant hemodynamic interactions.
FDA-Approved Combination Therapy
Ranolazine is specifically indicated for use in combination with nitrates (including isosorbide mononitrate), along with amlodipine or beta-blockers, for the treatment of chronic angina that has failed to respond to standard antianginal therapy 1.
The recommended dosing is ranolazine 500 mg orally twice daily initially, which can be escalated as needed to a maximum of 1000 mg twice daily when combined with nitrates 1.
Evidence of Safety and Lack of Hemodynamic Interaction
Preclinical studies demonstrate no significant blood pressure interaction: In conscious dogs, ranolazine at therapeutic plasma concentrations (4-10 μM) did not alter the prolonged decreases in mean arterial pressure induced by isosorbide dinitrate 2.
Ranolazine exerts its antianginal effects without reducing heart rate or blood pressure, making it mechanistically compatible with nitrates that work primarily through preload reduction 1.
The mechanism of action differs fundamentally: ranolazine works through membrane ion-channel effects (inhibiting late sodium current), while isosorbide acts as a nitric oxide donor causing venous vasodilation 1, 3.
Clinical Trial Evidence
In the large MERLIN-TIMI 36 trial (N=6,560), ranolazine was safely administered to patients with unstable angina/NSTEMI, many of whom were receiving concomitant nitrate therapy, with no safety concerns regarding the combination 1.
Multiple randomized controlled trials have evaluated ranolazine in combination with long-acting nitrates, demonstrating modest but statistically significant improvements in exercise duration and reductions in angina frequency 4.
Important Prescribing Considerations
Contraindication: Ranolazine is contraindicated in patients with QT-prolonging conditions, so obtain a baseline ECG before initiating therapy 1.
Nitrate tolerance prevention: When using isosorbide mononitrate with ranolazine, maintain a nitrate-free interval of at least 10-14 hours daily to prevent tolerance development, as continuous nitrate exposure leads to loss of anti-ischemic efficacy within 24 hours 3, 5.
Common adverse effects of the combination include dizziness, nausea, constipation, and headache (the latter primarily from the nitrate component) 4, 3.
Ranolazine does not require dose adjustment when combined with nitrates, as there are no significant pharmacokinetic interactions 6.
Clinical Bottom Line
The combination is not only safe but represents standard practice for refractory chronic angina. The two agents work through complementary mechanisms—ranolazine reduces myocardial oxygen demand through metabolic effects while nitrates reduce preload—without causing additive hypotension or other hemodynamic complications 1, 2.