sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index.sofosbuvir/velpatasvirSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of sofosbuvir/velpatasvir by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Velpatasvir is a substrate of CYP2B6, CYP2C8, and CYP3A4. Drugs that are moderate-to-potent inducers of CYP2B6, CYP2C8, or CYP3A4 may significantly decrease velpatasvir plasma concentrations, leading to potentially reduced therapeutic effect.sonidegibSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of sonidegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sonidegib with strong or moderate CYP3A4 inducers.sotorasibSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of sotorasib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.sparsentanSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of sparsentan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.St John's WortContraindicated (1)St John's Wort will decrease the level or effect of lumacaftor/ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Strong CYP3A inducers have minimal effect on lumacaftor exposure, but decreased ivacaftor exposure (AUC) by 57%. This may reduce the effectiveness of lumacaftor/ivacaftor. Therefore, coadministration is not recommended.stiripentolSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of stiripentol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If unable to avoid coadministration of stiripentol with strong CYP3A4 inducers, increase stiripentol dose.sufentanil SLMonitor Closely (1)lumacaftor/ivacaftor decreases effects of sufentanil SL by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration of CYP3A4 inducers may decrease sufentanil levels and efficacy, possibly precipitating withdrawal syndrome in patients who have developed physical dependence to sufentanil. Discontinuation of concomitantly used CYP3A4 inducers may increase sufentanil plasma concentration.sulfadiazineMonitor Closely (1)lumacaftor/ivacaftor, sulfadiazine. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .sulfisoxazoleMonitor Closely (1)lumacaftor/ivacaftor, sulfisoxazole. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .tacrolimusSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of tacrolimus by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Lumacaftor is a strong inducer of CYP3A. Avoid coadministration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index.tamoxifenMonitor Closely (1)lumacaftor/ivacaftor, tamoxifen. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .tazemetostatSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.tinidazoleMonitor Closely (1)lumacaftor/ivacaftor will decrease the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tipranavirMonitor Closely (1)tipranavir increases levels of lumacaftor/ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong CYP3A inhibitors do not impact lumacaftor exposure, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg q12hr (the approved dose of ivacaftor monotherapy). Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, reduce the dose to 1 tablet daily (lumacaftor 200 mg/ivacaftor 125 mg total daily dose) for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose. No dose adjustment is required for moderate or weak CYP3A4 inhibitors.tivozanibSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of tivozanib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.tofacitinibMonitor Closely (1)lumacaftor/ivacaftor, tofacitinib. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. .tolazamideSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of tolazamide by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Sulfonylureas are CYP2C9 substrates. Lumacaftor/ivacaftor has the potential to induce CYP2C9.tolbutamideSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of tolbutamide by affecting hepatic enzyme CYP2C9/10 metabolism. Avoid or Use Alternate Drug. Sulfonylureas are CYP2C9 substrates. Lumacaftor/ivacaftor has the potential to induce CYP2C9.torsemideMonitor Closely (1)lumacaftor/ivacaftor, torsemide. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .trabectedinSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of trabectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.triazolamSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of triazolam by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Lumacaftor is a strong inducer of CYP3A. Avoid coadministration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index.trimethoprimMonitor Closely (1)lumacaftor/ivacaftor, trimethoprim. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .trimipramineMonitor Closely (1)lumacaftor/ivacaftor, trimipramine. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. .tucatinibSerious - Use Alternative (1)lumacaftor/ivacaftor will increase the level or effect of tucatinib by Other (see comment). Avoid or Use Alternate Drug. Coadministration of tucatinib (a CYP2C8 substrate) with a strong or moderate CYP2C8 inhibitors increases tucatinib plasma concentrations and risk of toxicities.ubrogepantSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.upadacitinibSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of upadacitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid upadacitinib coadministration with strong CYP3A4 inducers.valbenazineSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of valbenazine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Concomitant use not recommended.venetoclaxSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of venetoclax with strong or moderate CYP3A inducers. Consider alternative treatment with agents that have less CYP3A induction.voclosporinSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.vonoprazanSerious - Use Alternative (1)lumacaftor/ivacaftor will decrease the level or effect of vonoprazan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.voriconazoleMonitor Closely (4)voriconazole increases levels of lumacaftor/ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong CYP3A inhibitors do not impact lumacaftor exposure, but increased ivacaftor exposure by 4.3-fold. Due to the induction effect of lumacaftor on CYP3A, at steady-state the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg q12hr (the approved dose of ivacaftor monotherapy). Therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor. However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, reduce the dose to 1 tablet daily (lumacaftor 200 mg/ivacaftor 125 mg total daily dose) for the first week of treatment to allow for the steady-state induction effect of lumacaftor. Following this period, continue with the recommended daily dose. No dose adjustment is required for moderate or weak CYP3A4 inhibitors. lumacaftor/ivacaftor will decrease the level or effect of voriconazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. lumacaftor/ivacaftor, voriconazole. affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C19 substrates. . lumacaftor/ivacaftor, voriconazole. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .voxelotorSerious - Use Alternative (2)lumacaftor/ivacaftor will decrease the level or effect of voxelotor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor is primarily metabolized by CYP3A4. Avoid coadministration with moderate or strong CYP3A4 inducers. If unable to avoid coadministration, increase voxelotor dose (see Dosage Modifications). voxelotor will increase the level or effect of lumacaftor/ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.warfarinMonitor Closely (1)lumacaftor/ivacaftor will decrease the level or effect of warfarin by Other (see comment). Use Caution/Monitor. Warfarin's less potent R-enantiomer is metabolized in part by CYP3A4 (and also CYP1A2 and CYP2C19). Monitor INR more frequently if coadministered with inducers of these isoenzymes and adjust warfarin dose if needed. zafirlukastMonitor Closely (1)lumacaftor/ivacaftor, zafirlukast. affecting hepatic enzyme CYP2C9/10 metabolism. Use Caution/Monitor. In vitro studies suggest that lumacaftor may induce and ivacaftor may inhibit CYP2C9 substrates. .zanubrutinibMonitor Closely (1)lumacaftor/ivacaftor will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib (a CYP3A4 substrate) to 80 mg PO BID to when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib. >10% Dyspnea (13%) Nasopharyngitis (13%) Nausea (13%) Diarrhea (12%) 1-10% Menstrual abnormalities (10%) Upper respiratory tract infection (10%) Fatigue (9%) Abnormal respiration (9%) Increased blood CPK (7%) Rash (7%) Flatulence (7%) Rhinorrhea (6%) <1% Increased ALT or AST Increased bilirubin Hepatic encephalopathy Contraindications None Cautions Worsening liver function, including hepatic encephalopathy, in patients with advanced liver disease reported Liver function decompensation, including liver failure leading to death, has been reported in cystic fibrosis patients with pre-existing cirrhosis with portal hypertension Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of therapy compared to those who received placebo; these events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40); clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended Elevated transaminases associated with elevated bilirubin in some patients; measure transaminases and bilirubin before initiating therapy, every 3 months during first year of treatment, and annually thereafter; elevated transaminases may require therapy interruption (see Dosage Modifications) Chest discomfort, including dyspnea, and abnormal respiration reported during initiation; clinical experience in patients with percent predicted FEV1 <40 is limited; additional monitoring recommended during initiation of therapy Increase in blood pressure reported in some patients; monitor blood pressure periodically Cases of noncongenital lens opacities have been reported in pediatric patients treated with ivacaftor Use in transplanted patients not recommended due to potential drug-drug interactions Safety and efficacy in patients < 12 years, with cystic fibrosis, not established; cases of noncongenital lens opacities reported in pediatric patients treated with ivacaftor; although other risk factors present, direct cause cannot be excluded Drug interaction overview Ivacaftor: CYP3A substrate (major); CYP2C9 inhibitor (in vitro); CYP3A4 inhibitor (weak); P-gp inhibitor (weak) Lumacaftor: CYP3A inducer (strong); in vitro induction of CYP2B6, CYP2C8, CYP2C9, and CYP2C19; in vitro inhibition of CYP2C8 and CYP2C9; inhibits and induces P-gp Strong CYP3A inhibitors Coadministration of lumacaftor/ivacaftor with a strong CYP3A inhibitor (ie, itraconazole), did not impact on lumacaftor exposure, but increased ivacaftor exposure by 4.3-fold; owing to the induction effect of lumacaftor on CYP3A, at steady-state, the net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg q12hr (ie, approved dose of ivacaftor monotherapy); therefore, no dose adjustment is necessary when CYP3A inhibitors are initiated in patients currently taking lumacaftor/ivacaftor However, when initiating lumacaftor/ivacaftor in patients taking strong CYP3A inhibitors, reduce lumacaftor/ivacaftor dose to 1 tablet daily or 1 packet of oral granules every other day (children aged 2 through 5 yr) for the first week of treatment to allow for the steady-state induction effect of lumacaftor Following this period, continue with the recommended daily dose Strong CYP3A inducers Coadministration of lumacaftor/ivacaftor with a strong CYP3A inducer (ie, rifampin), had minimal effect on lumacaftor exposure, but decreased ivacaftor exposure (AUC) by 57% This may reduce lumacaftor/ivacaftor; therefore, coadministration with strong CYP3A inducers is not recommended CYP3A substrates Lumacaftor is a strong inducer of CYP3A; coadministration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by ~80% Administration of lumacaftor/ivacaftor may decrease systemic exposure of CYP3A substrates, resulting in reduced therapeutic effect Coadministration with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index is not