Atazanavir × Ticagrelor

CYP3A4 clears ticagrelor, and atazanavir inhibits this enzyme (atazanavir SmPC, EMA, section 4.5). The ticagrelor SmPC classes atazanavir as a strong CYP3A4 inhibitor and expects the same effect as with ketoconazole. With ketoconazole, ticagrelor Cmax rose 2.4-fold and AUC 7.3-fold, while the active metabolite fell by 89% (Cmax) and 56% (AUC) (Brilique SmPC, EMA, section 4.5). Ticagrelor acts on platelets on its own, without the metabolite, so the antiplatelet effect and its adverse reactions rise with its concentration. The labels describe no effect of ticagrelor on atazanavir. When atazanavir is boosted with ritonavir, the booster is itself a strong CYP3A4 inhibitor and also appears in the ticagrelor contraindications (Brilique SmPC, EMA, section 4.3).

The main risk is bleeding: bruising, nosebleeds, blood in urine or stool, gastrointestinal bleeding and, at worst, intracranial bleeding. The second typical sign of excess ticagrelor is dyspnea: the FDA ticagrelor label links strong CYP3A4 inhibitors directly to a higher risk of dyspnea, bleeding and other adverse events (section 7.1). The atazanavir SmPC (EMA) warns of a possible increase in the antiplatelet activity of ticagrelor (section 4.5).

The combination is contraindicated: the ticagrelor SmPC bars it with strong CYP3A4 inhibitors and names atazanavir explicitly (Brilique SmPC, EMA, sections 4.3 and 4.5). The atazanavir labels are softer: "not recommended" because of a possible increase in antiplatelet activity (atazanavir SmPC, EMA, section 4.5; Reyataz prescribing information, FDA, section 7). The FDA ticagrelor label says to avoid strong CYP3A4 inhibitors including atazanavir (section 7.1). The strictest document wins, and in Spain the ban applies. For a patient on atazanavir who needs a P2Y12 inhibitor after an acute coronary syndrome, choose a different drug. Clopidogrel with atazanavir is also not recommended because its effect may weaken, while prasugrel needs no dose adjustment according to the atazanavir label (atazanavir SmPC, EMA, section 4.5; FDA, section 7). Whether prasugrel suits the individual patient is a question for its own label. If the patient is already taking both, do not drop ticagrelor without a replacement: stopping an antiplatelet drug in coronary artery disease raises the risk of myocardial infarction, stroke and death (Brilinta prescribing information, FDA, section 5.2). Plan the switch at once, and until then keep the higher risk of bleeding and dyspnea in mind (Brilinta, FDA, section 7.1). Investigate new, prolonged or worsening dyspnea on ticagrelor, and if the patient cannot tolerate it, stop ticagrelor (Brilique SmPC, EMA, section 4.4).