Interactions : אינטראקציות

9     DRUG INTERACTIONS
Potential for other drugs to affect tezacaftor/ivacaftor

9.1 Inducers of CYP3A
Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced SYMDEKO efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (area under the curve [AUC]) by 89%. Tezacaftor exposures can also be expected to decrease significantly during co-administration with strong CYP3A inducers. Therefore, co-administration of SYMDEKO with strong CYP3A inducers is not recommended [see Warnings and Precautions (7.3) and Clinical Pharmacology (13.3)].

Examples of strong CYP3A inducers include:
•     rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort (Hypericum perforatum) 
9.2 Inhibitors of CYP3A
Co-administration with itraconazole, a strong CYP3A inhibitor, increased tezacaftor exposure (AUC) by 4.0-fold and ivacaftor by 15.6-fold. When co-administered with strong CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (5.4) and Clinical Pharmacology (13.3)].

Examples of strong CYP3A inhibitors include:
•     ketoconazole, itraconazole, posaconazole, and voriconazole
•     telithromycin and clarithromycin

Co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0-fold. Simulation suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2.0-fold. When co-administered with moderate CYP3A inhibitors, the dosing regimen of SYMDEKO should be adjusted [see Dosage and Administration (5.4) and Clinical Pharmacology (13.3)].

Examples of moderate CYP3A inhibitors include:
•     fluconazole
•     erythromycin

Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with SYMDEKO [see Dosage and Administration (5.4) and Clinical Pharmacology (13.3)].

9.3 Ciprofloxacin
Co-administration of SYMDEKO with ciprofloxacin had no significant effect on the exposure of tezacaftor or ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of SYMDEKO with ciprofloxacin [see Clinical Pharmacology (13.3)].

Potential for tezacaftor/ivacaftor to affect other drugs

9.4 CYP3A Substrates
Co-administration of SYMDEKO with midazolam (oral), a sensitive CYP3A substrate, did not affect midazolam exposure. No dose adjustment of CYP3A substrates is required when co-administered with SYMDEKO [see Clinical Pharmacology (13.3)].

9.5 CYP2C9 Substrates
Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co administration of SYMDEKO with warfarin is recommended. Other medicinal products for which exposure may be increased by SYMDEKO include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (13.3)].


SYMD-SPC-0923-V1                                                          Page 4 of 15 9.6 Digoxin and Other P-gp Substrates
Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold consistent with weak inhibition of P-gp by ivacaftor.
Administration of SYMDEKO may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus, and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology (13.3)].

9.7 Hormonal Contraceptives
SYMDEKO has been studied with an ethinyl estradiol/norethindrone oral contraceptive and was found to have no significant effect on the exposures of the hormonal contraceptive. SYMDEKO is not expected to modify the efficacy of hormonal contraceptives [see Clinical Pharmacology (13.3)].