Can ranolazine be co‑administered with isosorbide mononitrate in an adult with chronic stable angina and no severe hepatic impairment?

Can Ranolazine and ISMN Be Taken Together?

Yes, ranolazine can be safely co-administered with isosorbide mononitrate (ISMN) in adults with chronic stable angina and no severe hepatic impairment. This combination is explicitly supported by major cardiology guidelines and FDA labeling.

Guideline Support for Combination Therapy

• The ACC/AHA guidelines explicitly recommend ranolazine "alone or in combination with amlodipine, beta-blockers, or nitrates for the treatment of chronic angina that has failed to respond to standard antianginal therapy" 1
• The FDA-approved prescribing information states that ranolazine "may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers" 2
• The European Society of Cardiology guidelines suggest that "long-acting nitrates or ranolazine should be considered as add-on therapy in patients with inadequate control of symptoms while on treatment with beta-blockers and/or CCBs" 1

Complementary Mechanisms of Action

The combination is pharmacologically rational because these drugs work through different mechanisms:

• ISMN (nitrates) primarily reduce myocardial oxygen demand through venodilation and coronary vasodilation, with hemodynamic effects on blood pressure 1
• Ranolazine exerts antianginal effects through inhibition of the late sodium current without reducing heart rate or blood pressure, making it an ideal complement to nitrates 1, 3

Clinical Application Algorithm

Step 1: Initial Therapy

• Start with beta-blockers and/or calcium channel blockers as first-line therapy (Class I, Level A) 4

Step 2: Add Second Agent if Inadequate Control

• Add either long-acting nitrates (ISMN) OR ranolazine if symptoms persist 1

Step 3: Triple Therapy if Needed

• If monotherapy with either ISMN or ranolazine plus first-line therapy is insufficient, both can be used together 1

Step 4: Acute Symptom Relief

• Short-acting sublingual nitroglycerin remains the standard for acute angina episodes and can be used as needed even in patients on chronic ranolazine plus ISMN therapy 1

Dosing Considerations

• Ranolazine: Initiate at 500 mg twice daily, increase to 1000 mg twice daily as needed based on clinical symptoms 2
• ISMN: Standard long-acting nitrate dosing applies
• No dose adjustment of either drug is required when used in combination 2

Absolute Contraindications to Ranolazine

Before prescribing this combination, verify the patient does NOT have:

• Liver cirrhosis (absolute contraindication to ranolazine) 4, 2
• Concurrent use of strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) 2
• Concurrent use of CYP3A inducers (e.g., rifampin, phenytoin) 2

Dose Modifications Required

• Moderate CYP3A inhibitors (diltiazem, verapamil, erythromycin): Limit ranolazine to maximum 500 mg twice daily 2
• P-gp inhibitors (cyclosporine): Titrate ranolazine based on clinical response 2
• Digoxin co-administration: Ranolazine increases digoxin plasma concentrations; adjust digoxin dose accordingly 4

Important Clinical Caveats

• QT prolongation: Ranolazine causes dose-related QT interval prolongation, though torsades de pointes has not been observed at therapeutic doses 4
• Renal impairment: Acute renal failure has been observed in patients with severe renal impairment (CrCl <30 mL/min); use with caution 2
• Prognostic limitation: Neither ranolazine nor nitrates improve long-term cardiovascular outcomes (mortality, MI) in chronic coronary syndromes—they are purely symptomatic therapies 1

Patient Populations That May Particularly Benefit

• Patients with diabetes mellitus (ranolazine reduces HbA1c levels) 4, 3
• Patients with bradycardia or hypotension (ranolazine has neutral hemodynamic profile) 4, 3
• Patients with left ventricular hypertrophy (may experience greater efficacy with ranolazine) 3
• Patients with microvascular angina (combination therapy provides superior symptom control) 4