Effects of other drugs: Ticagrelor is predominantly metabolized by CYP3A4 and to a lesser extent by CYP3A5.
Ticagrelor is also a P-glycoprotein (P-gp) substrate.
CYP3A inhibitors: Avoid use of strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin) (see Precautions).
CYP3A inducers: Avoid use with potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, and phenobarbital) (see Precautions).
Aspirin: Use of ticagrelor with aspirin maintenance doses above 100 mg reduced the effectiveness of ticagrelor (see Precautions).
Effects of ticagrelor on other drugs: Ticagrelor is an inhibitor of CYP3A4/5 and the P-glycoprotein transporter.
Simvastatin, lovastatin: Ticagrelor will result in higher serum concentrations of simvastatin and lovastatin because these drugs are metabolized by CYP3A4. Avoid simvastatin and lovastatin doses greater than 40 mg.
Digoxin: Because of inhibition of the P-glycoprotein transporter, monitor digoxin levels with initiation of or any change in ticagrelor therapy.
Other concomitant therapy: Ticagrelor can be administered with unfractionated or low-molecular-weight heparin, GPIIb/IIIa inhibitors, proton pump inhibitors, beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers.
Ciclosporin (P-gp and CYP3A inhibitor): Coadministration of ciclosporin (600 mg) with ticagrelor increased ticagrelor Cmax and AUC equal to 2.3 fold and 2.8 fold, respectively. The AUC of the active metabolite was increased by 32% and Cmax was decreased by 15% in the presence of ciclosporin. No data are available on concomitant use of ticagrelor with other active substances that also are potent P-gp inhibitors and moderate CYP3A4 inhibitors (e.g., verapamil, quinidine) that also may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution.
Oral contraceptives: Coadministration of ticagrelor and levonorgestrel and ethinyl estradiol increased ethinyl estradiol exposure approximately 20% but did not alter the pharmacokinetics of levonorgestrel. No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are coadministered with ticagrelor.
Medicinal products known to induce bradycardia: Due to observations of mostly asymptomatic ventricular pauses and bradycardia, caution should be exercised when administering ticagrelor concomitantly with medicinal products known to induce bradycardia. However, no evidence of clinically significant adverse reactions was observed after concomitant administration with one or more medicinal products known to induce bradycardia (e.g., 96% beta blockers, 33% calcium channel blockers diltiazem and verapamil, and 4% digoxin).
Others: Coadministration of ticagrelor with heparin, enoxaparin, and acetylsalicylic acid or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or the active metabolite or on ADP induced platelet aggregation compared with ticagrelor alone. If clinically indicated, medicinal products that alter hemostasis should be used with caution in combination with ticagrelor. A 2 fold increase of ticagrelor exposure was observed after daily consumption of large quantities of grapefruit juice (3 x 200 ml). This magnitude of increased exposure is not expected to be clinically relevant to most patients.