Drug Interactions Between Eliquis/Nifedipine and Melatonin/Trazodone
No clinically significant pharmacokinetic drug interactions exist between Eliquis (apixaban) or nifedipine and either melatonin or trazodone, as neither melatonin nor trazodone are strong inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp).
Apixaban (Eliquis) Interaction Profile
Relevant Metabolic Pathways
- Apixaban is metabolized by CYP3A4 and is a substrate of P-glycoprotein, requiring caution only with strong dual inhibitors or inducers of both pathways 1.
- Clinically significant interactions occur primarily with combined strong CYP3A4 and P-gp inhibitors (e.g., ketoconazole, clarithromycin, ritonavir) or strong inducers (e.g., rifampin, carbamazepine, phenytoin) 1.
- Moderate inhibitors of CYP3A4 or P-gp alone do not require dose adjustment of apixaban 1.
Melatonin and Apixaban
- Melatonin is not a CYP3A4 or P-gp inhibitor or inducer and therefore does not alter apixaban plasma concentrations 1.
- The American Academy of Sleep Medicine guideline discusses melatonin for insomnia but makes no mention of anticoagulant interactions, supporting the absence of clinically relevant interaction 1.
- No dose adjustment of apixaban is needed when co-administered with melatonin 1, 2.
Trazodone and Apixaban
- Trazodone is not a strong CYP3A4 or P-gp inhibitor or inducer and does not meet criteria for clinically significant interaction with apixaban 1.
- Trazodone is primarily metabolized by CYP3A4 but does not significantly inhibit or induce this enzyme at therapeutic doses 1.
- The bleeding risk with apixaban is not increased by trazodone through pharmacokinetic mechanisms 3, 2.
Nifedipine Interaction Profile
Relevant Metabolic Pathways
- Nifedipine is extensively metabolized by CYP3A4 but is not a P-gp substrate or significant CYP3A4 inhibitor/inducer 1.
- Nifedipine's interactions are primarily as a victim drug (affected by CYP3A4 inhibitors/inducers), not as a perpetrator drug affecting other medications 1.
Melatonin and Nifedipine
- One preclinical study showed melatonin and nifedipine may inhibit the same calcium channels in rabbit basilar arteries, but this has no established clinical relevance in humans at therapeutic doses 4.
- No clinical evidence supports dose adjustment of either medication when used together 4.
- Both medications can be safely co-administered without monitoring for interaction 4.
Trazodone and Nifedipine
- No pharmacokinetic or pharmacodynamic interaction exists between trazodone and nifedipine 1.
- Neither medication significantly affects the metabolism or action of the other 1.
Practical Management Recommendations
For Apixaban Users
- Continue apixaban at standard doses (5 mg twice daily or 2.5 mg twice daily if dose-reduction criteria met) when taking melatonin or trazodone 1.
- Monitor for bleeding signs as with any anticoagulant therapy, but do not attribute increased bleeding risk to melatonin or trazodone interaction 3.
- Educate patients that melatonin and trazodone do not require apixaban dose modification 1, 2.
For Nifedipine Users
- No dose adjustment of nifedipine is required when co-administered with melatonin or trazodone 1, 4.
- Monitor blood pressure as clinically indicated, but not specifically for drug interaction 1.
Common Pitfalls to Avoid
- Do not confuse the lack of interaction between melatonin/trazodone with apixaban with the significant interactions that occur with strong CYP3A4/P-gp inhibitors like clarithromycin or ketoconazole 1.
- Do not discontinue or reduce apixaban doses unnecessarily when these sleep medications are prescribed, as this increases thrombotic risk without benefit 1.
- Remember that pharmacodynamic bleeding risk from NSAIDs or antiplatelet agents is far more clinically relevant than the absent pharmacokinetic interaction with melatonin or trazodone 5, 3.