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3. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ivacaftor are summarized in Table 19. Only those drug-drug interactions classified as clinical significance severe or those considered life-threatening which have not yet been classified will be reviewed:

Table 19. Ivacaftor and Combination Products Drug-Drug Interactions1
Target DrugInteracting DrugInteractionRecommendationClinical Significance Level
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftorstrong CYP3A inhibitors (e.g., ketoconazole, voriconazole, posaconazole, telithromycin, clarithromycin)concurrent use significantly increased ivacaftor exposure djunctive administration may significantly increase elexacaftor, tezacaftor and ivacaftor concentrations and ↑ potential for enhanced pharmacologic/adverse effectsreduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse eventsmajor (CP)
ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftormoderate CYP3A inhibitors (e.g., fluconazole)concurrent use increased ivacaftor exposure; adjunctive administration may significantly increase tezacaftor and ivacaftor concentrations and ↑ potential for enhanced pharmacologic/adverse effectsreduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse eventsmajor (CP)
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftorstrong CYP3A inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin, St. John’s wort)concurrent use decreased ivacaftor exposure adjunctive administration may significantly reduce elexacaftor, tezacaftor and ivacaftor concentrations (CYP3A substrates) and ↓ efficacystrong CYP3A inducers should be avoided while taking ivacaftor, lumacaftor/ ivacaftor, tezacaftor/ ivacaftor, and elexacaftor/ tezacaftor/ ivacaftormajor (CP)
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftorCYP3A and/or P-glycoprotein (P-gp) substrates (e.g., midazolam, alprazolam, cyclosporine, tacrolimus)ivacaftor may be a weak CYP3A and P-gp transport inhibitoruse with caution and monitor drug- related side effects and/or monitor therapeutic levelstacrolimus and cyclosporine: major; others -moderate (CP)
lumacaftor/ivacaftorCYP3A substrates (e.g., antibiotics, antifungals, antivirals)lumacaftor is strong CYP3A inducer; concurrent use may result in reduced efficacy of CYP3A substratesconsider alternative antibiotics such as azithromycin, ciprofloxacin, or levofloxacin whenever possible; if an antifungal is required, monitor for breakthrough fungal infection; consider alternative treatment with fluconazole if possiblemajor (CP)
lumacaftor/ivacaftorhormonal contraceptivesconcurrent administration may reduce hormonal contraceptive exposure and efficacy and may increase menstruation-associated adverse events (e.g., menorrhagia)avoid concurrent use; use alternate methods of birth controlmajor (CP)
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftorwarfarinwarfarin exposure may be modified with adjunctive lumacaftor/ ivacaftor administration, as lumacaftor/ ivacaftor is a CYP3A4 inducer, the enzyme that metabolizes R-warfarin, and ivacaftor may be a weak CYP2C9 inhibitor, the primary enzyme that metabolizes S-warfarinmonitor international normalized ratio and adjust warfarin dosages as neededmoderate (CP)

Legend:

  • *CP = Clinical Pharmacology
  • AUC = area under the curve