Tezacaftor And Ivacaftor

1 INDICATIONS AND USAGE SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence [see Clinical Pharmacology (12.1) and Clinical Studies (14) ] . If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. SYMDEKO is a combination of tezacaftor and ivacaftor, indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence. ( 12.1 , 14 ) If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. ( 1 )

2 DOSAGE AND ADMINISTRATION Pediatric patients aged 6 to less than 12 years weighing less than 30 kg: one tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 75 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Adults and pediatric patients aged 12 years and older or pediatric patients aged 6 to less than 12 years weighing 30 kg or more: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Reduce dosage in patients with moderate and severe hepatic impairment. ( 2.3 , 8.6 , 12.3 ) See full prescribing information for dosage modifications due to drug interactions with SYMDEKO. ( 2.4 , 7.2 , 12.3 ) 2.1 General Dosage Information Swallow the tablets whole. SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats, etc. [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage in Adults, Adolescents, and Children Aged 6 Years and Older Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1. The morning and the evening doses should be taken approximately 12 hours apart. Table 1: Recommended Dosage for Patients Aged 6 Years and Older Age Morning (one tablet) Evening (one tablet) 6 to <12 years weighing <30 kg tezacaftor 50 mg/ivacaftor 75 mg ivacaftor 75 mg 6 to <12 years weighing ≥30 kg tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg ≥12 years tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg Information for Missed Doses: If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time. 2.3 Recommended Dosage for Patients with Hepatic Impairment For dosage adjustment for patients with hepatic impairment, refer to Table 2. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be higher than in patients with moderate hepatic impairment. Therefore, SYMDEKO should be used with caution at an adjusted dosage after weighing the risks and benefits of treatment in these patients [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ]. Table 2: Recommended Dosage for Patients with Hepatic Impairment Hepatic Impairment Morning Evening Patients Aged 6 to <12 Years Weighing <30 kg Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years All Patients Mild (Child-Pugh Class A) No dose adjustment No dose adjustment No dose adjustment Moderate (Child-Pugh Class B) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily No ivacaftor dose Severe (Child-Pugh Class C) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily (or less frequently) One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently) 2.4 Dosage Adjustment for Patients Taking Drugs that are CYP3A Inhibitors The dosing regimen of SYMDEKO should be adjusted when co-administered with moderate and strong CYP3A inhibitors. Moderate CYP3A inhibitors: When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin), the dosing regimen should be adjusted as in Table 3 [see Drug Interactions (7.2) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Table 3: Dosing Schedule for Concomitant Use of SYMDEKO with Moderate CYP3A Inhibitors Day 1 Day 2 Day 3 Day 4 Continue dosing with tezacaftor/ivacaftor or ivacaftor tablets on alternate days. Patients Aged 6 to <12 Years Weighing <30 kg Morning Tezacaftor 50 mg/ivacaftor 75 mg tablet ✓ - ✓ - Ivacaftor 75 mg tablet - ✓ - ✓ Evening Ivacaftor 75 mg tablet - - - - Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years Morning Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ - Ivacaftor 150 mg tablet - ✓ - ✓ Evening Ivacaftor 150 mg tablet - - - - Strong CYP3A inhibitors: When co-administered with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dosing regimen should be adjusted as in Table 4 [see Drug Interactions (7.2) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Table 4: Dosing Schedule for Concomitant Use of SYMDEKO with Strong CYP3A Inhibitors Day 1 Day 2 and Day 3 Day 4 Continue dosing with tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart. Patients Aged 6 to <12 Years Weighing <30 kg Morning Tezacaftor 50 mg/ivacaftor 75 mg tablet ✓ - ✓ Evening The evening dose of ivacaftor should not be taken on any day. Ivacaftor 75 mg tablet - - - Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years Morning Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ Evening Ivacaftor 150 mg tablet - - - Food or drink containing grapefruit should be avoided during treatment with SYMDEKO [see Drug Interactions (7.2) and Patient Counseling Information (17) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Transaminase Elevations [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial Hypertension [see Warnings and Precautions (5.3) ] Cataracts [see Warnings and Precautions (5.5) ] The most common adverse drug reactions to SYMDEKO (occurring in ≥3% of patients) were headache, nausea, sinus congestion, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The overall safety profile of SYMDEKO is based on data from 1001 patients in three double-blind, placebo-controlled, clinical trials: two parallel-group trials of 12 and 24-week duration and one cross-over design trial of 8 weeks duration. Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of SYMDEKO). In the three placebo-controlled trials (Trials 1, 2, and 3), a total of 496 patients with CF aged 12 years and older received at least one dose of SYMDEKO. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 1.6% for SYMDEKO-treated patients and 2.0% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in SYMDEKO-treated patients compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) SYMDEKO-treated patients vs. 0 placebo. There were no deaths in the placebo-controlled trials, and one death in the open-label extension study due to respiratory failure and influenza infection in a patient who had discontinued SYMDEKO seven weeks prior. The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV 1 (ppFEV 1 ), and geographic regions. Table 5 shows adverse reactions occurring in ≥3% of SYMDEKO-treated patients that also occurred at a higher rate than in the placebo-treated patients in the 12- and 24-week placebo-controlled, parallel-group trials (Trials 1 and 3). Table 5: Incidence of Adverse Drug Reactions in ≥3% of SYMDEKO-Treated Patients and Greater than Placebo Adverse Reactions (Preferred Term) SYMDEKO N=334 n (%) Placebo N=343 n (%) Headache 49 (15) 44 (13) Nausea 29 (9) 24 (7) Sinus congestion 13 (4) 6 (2) Dizziness 12 (4) 8 (2) The safety data from the following trials are similar to that observed in Trials 1 and 3: an 8-week randomized, double-blind, placebo-controlled crossover study in 244 patients with CF aged 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 2). a 24-week open-label study in 70 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor (Trial 4). Laboratory Abnormalities Transaminase elevations During the placebo-controlled trials in patients aged 12 years and older, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × the upper limit of normal (ULN) was similar between SYMDEKO-treated patients and placebo-treated patients; 0.2%, 1.0%, and 3.4% in SYMDEKO-treated patients, and 0.4%, 1.0%, and 3.4% in placebo-treated patients. One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. During the 24-week, open-label study in patients aged 6 to less than 12 years (Trial 4), the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.4%, 4.3%, and 10.0%, respectively. No SYMDEKO-treated patients experienced a transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued SYMDEKO treatment due to transaminase elevations. 6.2 Postmarketing Experience Postmarketing Adverse Reactions with SYMDEKO The following adverse reactions have been identified during post approval use of SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : anaphylaxis Skin : rash Postmarketing Adverse Reactions with Other Drugs Containing the Same or Similar Active Ingredients as SYMDEKO The following adverse reactions have been identified during post approval use of drugs containing the same or similar active ingredients as SYMDEKO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders : intracranial hypertension

12.3 Pharmacokinetics The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily. Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 7. Table 7: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF Drug C max (mcg/mL) Effective t ½ (h) AUC 0-24h or AUC 0-12h (mcg∙h/mL) AUC 0-24h for tezacaftor and AUC 0-12h for ivacaftor Tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours Tezacaftor 5.95 (1.50) 15.0 (3.44) 84.5 (27.8) Ivacaftor 1.17 (0.424) 13.7 (6.06) 11.3 (4.60) Absorption After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (t max ) of approximately 4 hours (2 to 6 hours). The median (range) t max of ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state. When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state. Distribution Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells. Elimination After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in patients with CF, the effective half-lives of tezacaftor and ivacaftor were approximately 15 (3.44) and 13.7 (6.06) hours, respectively. Metabolism Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14 C-tezacaftor to healthy male subjects, M1, M2, and M5 were the three major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor. Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 is not considered pharmacologically active. Excretion Following oral administration of 14 C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans. Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug. Specific Populations Based on population PK analyses, the PK exposure parameters of tezacaftor/ivacaftor in children and adolescents (ages 6 to <18 years) are similar to the AUCss range observed in adults when given in combination. Pediatric patients aged 6 to less than 12 years Table 8: Tezacaftor/Ivacaftor Exposure by Age Group, Mean (SD) Age Group Dose Tezacaftor AUCss mcg∙h/mL AUC 0-24h for tezacaftor and AUC 0-12h for ivacaftor Ivacaftor AUCss mcg∙h/mL 6 to <12 years Exposures in ≥ 30 kg weight range are predictions derived from the population PK model 71.3 (28.3) 8.5 (3.34) 6 to <12 years (<30 kg) tezacaftor 50 mg/ivacaftor 75 mg 56.7 (22.3) 6.92 (2.07) 6 to <12 years (≥30 kg) tezacaftor 100 mg/ivacaftor 150 mg 92.7 (21.9) 10.8 (3.52) Pediatric patients aged 12 to less than 18 years Following oral administration of SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours, the mean (±SD) AUCss for tezacaftor and ivacaftor was 97.1 (35.8) mcg∙h/mL and 11.4 (5.50) mcg∙h/mL, respectively, similar to the mean AUCss in adult patients administered SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours. Patients with Hepatic Impairment Following multiple doses of tezacaftor and ivacaftor for 10 days, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had an approximately 36% increase in AUC and a 10% increase in C max for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. In a separate study, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had similar ivacaftor C max , but an approximately 2.0-fold increase in ivacaftor AUC 0-∞ compared with healthy subjects matched for demographics. Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5-6) or severe hepatic impairment (Child-Pugh Class C, score 10-15) receiving SYMDEKO. The magnitude of increase in exposure in patients with severe hepatic impairment is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment [see Dosage and Administration (2.3) , Use in Specific Populations (8.6) , and Patient Counseling Information (17) ] . Patients with Renal Impairment SYMDEKO has not been studied in patients with moderate or severe renal impairment (creatinine clearance ≤30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug). In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in clinical trials indicated that mild renal impairment (N=147; eGFR 60 to less than 90 mL/min/1.73 m 2 ) and moderate renal impairment (N=7; eGFR 30 to less than 60 mL/min/1.73 m 2 ) did not affect the clearance of tezacaftor significantly [see Use in Specific Populations (8.7) ] . Male and Female Patients The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females. Drug Interactions Studies Drug interaction studies were performed with SYMDEKO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7) ] . Potential for Tezacaftor/Ivacaftor to Affect Other Drugs Clinical studies (with rosiglitazone and desipramine – see Table 9 ) showed that ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, ivacaftor has the potential to inhibit CYP3A and P-gp, and may also inhibit CYP2C9. In vitro , ivacaftor was not an inducer of CYP isozymes. Ivacaftor is not an inhibitor of transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3. Based on in vitro results, tezacaftor has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tezacaftor has a low potential to induce CYP3A, but it is not an inducer of CYP1A2 and CYP2B6. Tezacaftor has a low potential to inhibit transporters P-gp, BCRP, OATP1B3, OCT2, OAT1, or OAT3. Clinical studies with midazolam showed that SYMDEKO is not an inhibitor of CYP3A. Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Co-administration of SYMDEKO with an ethinyl estradiol/ norethindrone oral contraceptive had no significant effect on the exposures of the hormonal contraceptives. Co-administration of SYMDEKO with pitavastatin, an OATP1B1 substrate, had no clinically relevant effect on the exposure of pitavastatin. The effects of tezacaftor and ivacaftor (or ivacaftor alone) on the exposure of co-administered drugs are shown in Table 9 [see Drug Interactions (7) ] . Potential for Other Drugs to Affect Tezacaftor/Ivacaftor In vitro studies showed that ivacaftor and tezacaftor were substrates of CYP3A enzymes ( i.e. , CYP3A4 and CYP3A5). Exposure to ivacaftor and tezacaftor will be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors. In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp. The effects of co-administered drugs on the exposure of tezacaftor and ivacaftor (or ivacaftor alone) are shown in Table 10 [see Dosage and Administration (2.4) and Drug Interactions (7) ] . Table 9: Impact of Tezacaftor/Ivacaftor or Ivacaftor on Other Drugs Dose and Schedule Mean Ratio (90% CI) of Other Drugs No Effect=1.0 Drug Dose TEZ/IVA or IVA Effect on Drug PK AUC C max ↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics Midazolam 2 mg single oral dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Midazolam 1.12 (1.01, 1.25) 1.13 (1.01, 1.25) Digoxin 0.5 mg single dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↑ Digoxin 1.30 (1.17, 1.45) 1.32 (1.07, 1.64) Oral Contraceptive Ethinyl estradiol/ Norethindrone 0.035 mg/1.0 mg once daily TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Ethinyl estradiol 1.12 (1.03, 1.22) 1.15 (0.99, 1.33) ↔ Norethindrone 1.05 (0.98, 1.12) 1.01 (0.87, 1.19) Pitavastatin 2 mg single dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↑ Pitavastatin Effect is not clinically significant – no dosage adjustment is necessary 1.24 (1.17, 1.31) 0.977 (0.841, 1.14) Rosiglitazone 4 mg single oral dose IVA 150 mg twice daily ↔ Rosiglitazone 0.975 (0.897, 1.06) 0.928 (0.858, 1.00) Desipramine 50 mg single dose IVA 150 mg twice daily ↔ Desipramine 1.04 (0.985, 1.10) 1.00 (0.939, 1.07) Table 10: Impact of Other Drugs on Tezacaftor/Ivacaftor or Ivacaftor Dose and Schedule Mean Ratio (90% CI) of Tezacaftor and Ivacaftor No Effect = 1.0 Drug Dose TEZ/IVA or IVA Effect on TEZ/IVA PK AUC C max ↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics Itraconazole 200 mg twice a day on Day 1, followed by 200 mg once daily TEZ 25 mg + IVA 50 mg once daily ↑ Tezacaftor 4.02 (3.71, 4.63) 2.83 (2.62, 3.07) ↑ Ivacaftor 15.6 (13.4, 18.1) 8.60 (7.41, 9.98) Ciprofloxacin 750 mg twice daily TEZ 50 mg + IVA 150 mg twice daily ↔ Tezacaftor 1.08 (1.03, 1.13) 1.05 (0.99, 1.11) ↑ Ivacaftor Effect is not clinically significant – no dosage adjustment is necessary 1.17 (1.06, 1.30) 1.18 (1.06, 1.31) Oral Contraceptive Norethindrone/ethinyl estradiol 1.0 mg/0.035 mg once daily TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Tezacaftor 1.01 (0.963, 1.05) 1.01 (0.933, 1.09) ↔ Ivacaftor 1.03 (0.960, 1.11) 1.03 (0.941, 1.14) Rifampin 600 mg once daily IVA 150 mg single dose ↓ Ivacaftor 0.114 (0.097, 0.136) 0.200 (0.168, 0.239) Fluconazole 400 mg single dose on Day 1, followed by 200 mg once daily IVA 150 mg twice daily ↑ Ivacaftor 2.95 (2.27, 3.82) 2.47 (1.93, 3.17)