Interaction Between Clarithromycin and Apixaban

Mechanism of Interaction

Clarithromycin is a strong CYP3A4 inhibitor and a moderate P‑glycoprotein (P‑gp) inhibitor, leading to a ≈1.5‑fold increase in apixaban exposure (38‑54 % rise in AUC). 1
Apixaban is eliminated through oxidative metabolism via CYP3A4, P‑gp–mediated transport, and renal/intestinal excretion. 2, 3

The magnitude of the clarithromycin‑induced increase in apixaban levels is generally not sufficient to mandate dose reduction in most patients, but it can become clinically important when additional bleeding risk factors are present (e.g., obesity, recent prolonged travel, acute deep‑vein thrombosis with inflammation). 2

Valsartan – No clinically significant interaction; does not inhibit CYP3A4 or P‑gp. 1
Amoxicillin – No interaction; not metabolized by CYP3A4 and does not affect P‑gp. 1
Lovastatin – No clinically relevant interaction despite being a CYP3A4 substrate; does not inhibit apixaban elimination pathways. 1
Hydrochlorothiazide – No interaction; does not influence CYP3A4 or P‑gp. 1

Dose reduction of apixaban (from 5 mg BID to 2.5 mg BID) is recommended only when combined with strong dual CYP3A4/P‑gp inhibitors (e.g., ketoconazole, ritonavir, itraconazole). Clarithromycin, being only a moderate P‑gp inhibitor, does not meet the criteria for automatic dose reduction; instead, enhanced bleeding surveillance is advised. 1

Enhanced monitoring for bleeding should be implemented during concurrent clarithromycin therapy, especially in patients with additional bleeding risk factors. 1
Consider completing the clarithromycin‑based H. pylori regimen before initiating apixaban when clinically feasible, or otherwise apply intensified bleeding surveillance if concurrent use is unavoidable. 1

The American College of Cardiology recommends avoiding the use of rivaroxaban with combined strong CYP3A4 and P-gp inhibitors, such as ketoconazole, ritonavir, and cobicistat, due to significantly increased exposure 4, 5, 6, 7
The National Comprehensive Cancer Network suggests that itraconazole is contraindicated with many CYP3A4/P-gp substrates due to profound increases in plasma concentrations 8, 9, 10
The American College of Cardiology states that clarithromycin acts as a strong inhibitor of both pathways, increasing drug exposure 1.5-fold 4, 5

Erythromycin increases drug exposure by 1.3-fold, according to the Chest journal 4, 5
Cyclosporin is contraindicated with colchicine due to increased toxicity risk, as reported by the Annals of the Rheumatic Diseases 11

The National Comprehensive Cancer Network recommends avoiding the use of strong CYP3A4 inducers, such as rifampin, rifabutin, and rifapentin, with most CYP3A4 substrates due to significant reductions in drug exposure and efficacy 8, 4, 5, 9
St. John's wort is a potent herbal inducer that must be avoided, according to the Journal of the National Comprehensive Cancer Network 8, 4, 5, 9

The American College of Cardiology recommends reducing the dose of apixaban from 5 mg twice daily to 2.5 mg twice daily when combined with strong dual CYP3A4/P-gp inhibitors 7
The Journal of the American College of Cardiology states that dabigatran is contraindicated with ciclosporin, itraconazole, ketoconazole, and tacrolimus 10
The Circulation: Arrhythmia and Electrophysiology journal suggests staggering the administration of dabigatran by 2 hours when using P-gp inhibitors to minimize peak concentration increases 6