What are the potential interactions between apixaban, diltiazem, bilastine, and azathioprine?

Drug Interactions Between Apixaban, Diltiazem, Bilastine, and Azathioprine

Critical Interaction: Apixaban and Diltiazem

The combination of apixaban and diltiazem carries a clinically significant increased risk of bleeding and requires careful consideration of whether the benefits outweigh the risks, with mandatory close monitoring for bleeding signs if co-prescribed. 1, 2

Bleeding Risk Evidence

• Concomitant use of diltiazem with apixaban increases major bleeding risk by 84% (adjusted hazard ratio 1.84,95% CI 1.18-2.85) and any bleeding-related hospitalization by 56% (adjusted hazard ratio 1.56,95% CI 1.15-2.12) compared to apixaban alone 1

• A 2026 meta-analysis confirmed that diltiazem/verapamil combined with DOACs significantly increases major bleeding (OR 1.38,95% CI 1.24-1.54) and gastrointestinal bleeding (OR 1.19,95% CI 1.03-1.37) 2

• This interaction occurs because diltiazem is a moderate CYP3A4 and P-glycoprotein inhibitor, which increases apixaban plasma concentrations through pharmacokinetic mechanisms 1, 3

Clinical Management Algorithm

• If diltiazem must be used with apixaban: Prescribe only when benefit clearly outweighs bleeding risk, with close monitoring for any signs of bleeding (bruising, hematuria, melena, hematemesis, unexplained anemia) 1

• Consider alternative rate control agents that do not interact with apixaban, such as beta-blockers without CYP3A4/P-gp inhibition properties 1

• The bleeding risk is present regardless of kidney function - increased bleeding occurs in both patients with and without chronic kidney disease (eGFR <60 mL/min/1.73 m²) 1

Azathioprine Interactions

No Direct Interaction with Apixaban, Diltiazem, or Bilastine

• The British Association of Dermatologists guidelines comprehensively list azathioprine drug interactions, and none of the three other medications (apixaban, diltiazem, bilastine) appear on the definite or probable interaction lists 4

Azathioprine's Documented Interactions

The guideline-established interactions that require attention include:

• Xanthine oxidase inhibitors (allopurinol, febuxostat): Risk of severe, life-threatening myelotoxicity - this is the most serious azathioprine interaction 4

• Other immunosuppressants: Increased myelotoxicity risk with cyclophosphamide, methotrexate, ciclosporin 4

• Warfarin: Causes warfarin resistance requiring at least 2.5-fold dose increase with careful INR monitoring 4

• Drugs causing hematological adverse reactions: Caution with co-trimoxazole, trimethoprim, clozapine - requires more frequent complete blood count monitoring 4

Bilastine Interactions

Bilastine has no clinically significant interactions with apixaban, diltiazem, or azathioprine based on available evidence. Bilastine is a second-generation antihistamine with minimal drug interaction potential as it undergoes minimal hepatic metabolism and is not a significant substrate of CYP450 enzymes or P-glycoprotein.

Monitoring Recommendations for This Combination

For Apixaban-Diltiazem Interaction:

• Monitor closely for bleeding signs: Unexplained bruising, petechiae, hematuria, melena, hematemesis, hemoptysis, intracranial bleeding symptoms (severe headache, altered mental status) 1, 2

• Check complete blood count if any bleeding symptoms develop to assess for anemia 1

• Consider measuring apixaban plasma levels if available, particularly if bleeding or thrombotic events occur, to guide personalized management 5

For Azathioprine:

• Complete blood count monitoring is standard for azathioprine regardless of other medications, but no additional monitoring is required specifically for this drug combination 4

• In elderly patients on azathioprine: Additional care with hematological monitoring and use lower-end dosing due to increased risk of side effects and polypharmacy interactions 4

Common Pitfalls to Avoid

• Do not assume all anticoagulants interact similarly with diltiazem - the evidence specifically shows this interaction with DOACs, not warfarin 1

• Do not overlook the interaction simply because both drugs are commonly prescribed - the 84% increased major bleeding risk is clinically significant and affects patient outcomes 1

• Do not confuse azathioprine's lack of interaction with these specific drugs as meaning it has few interactions overall - azathioprine has serious interactions with other medications, particularly allopurinol 4