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:
Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
---|---|---|---|---|
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | strong 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 effects | reduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse events | major (CP) |
ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | moderate 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 effects | reduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse events | major (CP) |
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | strong 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 ↓ efficacy | strong CYP3A inducers should be avoided while taking ivacaftor, lumacaftor/ ivacaftor, tezacaftor/ ivacaftor, and elexacaftor/ tezacaftor/ ivacaftor | major (CP) |
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | CYP3A and/or P-glycoprotein (P-gp) substrates (e.g., midazolam, alprazolam, cyclosporine, tacrolimus) | ivacaftor may be a weak CYP3A and P-gp transport inhibitor | use with caution and monitor drug- related side effects and/or monitor therapeutic levels | tacrolimus and cyclosporine: major; others -moderate (CP) |
lumacaftor/ivacaftor | CYP3A substrates (e.g., antibiotics, antifungals, antivirals) | lumacaftor is strong CYP3A inducer; concurrent use may result in reduced efficacy of CYP3A substrates | consider 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 possible | major (CP) |
lumacaftor/ivacaftor | hormonal contraceptives | concurrent 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 control | major (CP) |
ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | warfarin | warfarin 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-warfarin | monitor international normalized ratio and adjust warfarin dosages as needed | moderate (CP) |
Legend:
- *CP = Clinical Pharmacology
- AUC = area under the curve