of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.sertralineMonitor Closely (2)sertraline will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with moderate CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification. sertraline will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a moderate CYP3A inhibitor.silodosinMonitor Closely (1)ivacaftor increases levels of silodosin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.simvastatinMonitor Closely (1)ivacaftor increases levels of simvastatin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.siponimodSerious - Use Alternative (1)ivacaftor will increase the level or effect of siponimod by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of siponimod with a moderate or strong CYP3A4 inhibitor PLUS a moderate or strong CYP2C9 inhibitor is not recommended.sirolimusMonitor Closely (1)ivacaftor increases levels of sirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.sitagliptinMonitor Closely (1)ivacaftor increases levels of sitagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.St John's WortSerious - Use Alternative (1)St John's Wort decreases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration with strong CYP3A4 inducers; systemic exposure of ivacaftor substantially reduced (ie, ~9-fold).stiripentolMonitor Closely (2)stiripentol will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with moderate CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification. stiripentol, tezacaftor. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.sulconazoleMonitor Closely (1)sulconazole increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .tacrolimusMonitor Closely (1)ivacaftor increases levels of tacrolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.talazoparibMonitor Closely (1)ivacaftor will increase the level or effect of talazoparib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.tamoxifenMonitor Closely (1)tamoxifen increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .tazemetostatMonitor Closely (2)tazemetostat will decrease the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. tazemetostat will decrease the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.Serious - Use Alternative (1)ivacaftor will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of tazemetostat with moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce tazemetostat current dose (see drug monograph Dosage Modifications). tecovirimatMonitor Closely (2)tecovirimat will decrease the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered. tecovirimat will decrease the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.temsirolimusMonitor Closely (1)ivacaftor increases levels of temsirolimus by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.teniposideMonitor Closely (1)ivacaftor increases levels of teniposide by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.testosteroneMonitor Closely (2)ivacaftor increases levels of testosterone by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index. testosterone increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .testosterone buccal systemMonitor Closely (1)testosterone buccal system increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .testosterone topicalMonitor Closely (1)testosterone topical increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .tetracyclineMonitor Closely (1)tetracycline will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a moderate CYP3A inhibitor.tipranavirMonitor Closely (2)tipranavir will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with strong CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification. tipranavir will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a strong CYP3A inhibitor.tolvaptanMonitor Closely (1)ivacaftor increases levels of tolvaptan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.topotecanMonitor Closely (1)ivacaftor increases levels of topotecan by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.tranylcypromineMonitor Closely (1)tranylcypromine increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .tucatinibSerious - Use Alternative (2)tucatinib will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling. tucatinib will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valproic acidMonitor Closely (1)valproic acid increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .vardenafilMonitor Closely (1)ivacaftor will increase the level or effect of vardenafil by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Vardenafil dose may need to be reduced if coadministered with moderate or strong CYP3A4 inhibitors venetoclaxMonitor Closely (1)ivacaftor increases levels of venetoclax by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.verapamilMonitor Closely (3)verapamil will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with moderate CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification. verapamil will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a moderate CYP3A inhibitor. ivacaftor increases levels of verapamil by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.vinblastineMonitor Closely (1)ivacaftor increases levels of vinblastine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.vincristineMonitor Closely (1)ivacaftor increases levels of vincristine by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.vincristine liposomalMonitor Closely (1)ivacaftor increases levels of vincristine liposomal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.voclosporinMonitor Closely (1)ivacaftor will increase the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce voclosporin daily dosage to 15.8 mg PO in AM and 7.9 mg PO in PM.voriconazoleMonitor Closely (2)voriconazole will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a strong CYP3A inhibitor. voriconazole will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with strong CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification.voxelotorSerious - Use Alternative (2)voxelotor will increase the level or effect of 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. voxelotor will increase the level or effect of tezacaftor 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.zafirlukastMonitor Closely (1)zafirlukast increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors .zanubrutinibMonitor Closely (1)ivacaftor will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib dose when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib. See zanubrutinib Dosage Modifications for precise recommendation.ziprasidoneMonitor Closely (1)ziprasidone increases levels of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor when coadministered with weak CYP3A4 inhibitors . >10% Headache (17%) Upper respiratory tract infection (16%) Abdominal pain (14%) Diarrhea (13%) 1-10% Rash (10%) Increased ALT (10%) Increased AST (9%) Increased BUN (9%) Nasal congestion (9%) Rhinorrhea (8%) Rhinitis (7%) Influenza (7%) Sinusitis (5%) Increased bilirubin (5%) 2 to <5% Flatulence Abdominal distension Conjunctivitis Pharyngitis Respiratory tract infection Tonsillitis Urinary tract infection Increased C-reactive protein Hypoglycemia Dizziness Dysmenorrhea Acne Eczema Pruritus Contraindications None Cautions Noncongenital lens opacities reported with ivacaftor-containing regimens; other risk factors were present in some cases (eg, corticosteroid use, radiation exposure); a possible risk attributable to treatment with ivacaftor cannot be excluded Hormonal contraceptives may play a role in occurrence of rash; for patients taking hormonal contraceptives who develop rash, consider interrupting therapy and hormonal contraceptives; following the resolution of rash, consider resuming therapy without the hormonal contraceptives; if rash does not recur, resumption of hormonal contraceptives can be considered Elevated transaminases and hepatic injury Elevated liver transaminases and bilirubin levels observed; liver failure leading to transplantation reported in a patient with cirrhosis and portal hypertension while receiving treatment Avoid use in patients with pre-existing advanced liver disease (eg, as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless benefits expected to outweigh risks; if used in these patients, they should be closely monitored after initiation of treatment In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including patients without a history of pre-existing liver disease Measure levels before initiating, q3Months during first year, and annually thereafter;