Interactions : אינטראקציות

9    DRUG INTERACTIONS
Potential for other drugs to affect elexacaftor/tezacaftor/ivacaftor
9.1 Inducers of CYP3A
Elexacaftor, 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 Trikafta efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during co-administration with strong CYP3A inducers. Therefore, co- administration of Trikafta 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 elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0 to 4.5-fold. When co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dosage of Trikafta should be reduced when co-administered with strong CYP3A inhibitors [see Dosage and Administration (5.3), Warnings and Precautions (7.4) and Clinical Pharmacology (13.3)].

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

Simulations indicated that co-administration with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9 to 2.3-fold and 2.1- fold, respectively. Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold. The dosage of Trikafta should be reduced when co-administered with moderate CYP3A inhibitors [see Dosage and Administration (5.3), Warnings and Precautions (7.4) and Clinical Pharmacology (13.3)].

Examples of moderate CYP3A inhibitors include:
•     fluconazole
•     erythromycin

Co-administration of Trikafta with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with Trikafta [see Dosage and Administration (5.3)].

9.3    Ciprofloxacin
Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor. Therefore, no dose adjustment is necessary during concomitant administration of Trikafta with ciprofloxacin [see Clinical Pharmacology (13.3)].


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

9.5     Transporters
Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P- gp by ivacaftor. Administration of Trikafta 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)].

Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Co-administration of Trikafta may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (13.3)]. Bilirubin is an OATP1B1 and OATP1B3 substrate.

9.6    Hormonal Contraceptives
Trikafta has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. Trikafta is not expected to have an impact on the efficacy of oral contraceptives.