2.1 Recommended Dosage in Adults and Pediatric Patients Aged 6 Years and Older

The recommended dosage of KALYDECO for adults and pediatric patients aged 6 years and older is 150 mg orally every 12 hours (300 mg total daily dose) with fat-containing food [see Dosage and Administration (2.5)].

2.2 Recommended Dosage in Pediatric Patients Aged 1 Month to Less than 6 Years

The recommended dosage of KALYDECO (oral granules) for pediatric patients ages 1 month to less than 6 years is weight-based provided in Table 1. Take KALYDECO orally with fat-containing food [see Dosage and Administration (2.5)].

2.3 Recommended Dosage for Patients with Hepatic Impairment

KALYDECO is not recommended in patients less than 6 months of age with any level of hepatic impairment. The following is the recommended dosage of KALYDECO taken with fat-containing food [see Dosage and Administration (2.5)] for patients aged 6 months and older with hepatic impairment:

• Mild Hepatic Impairment (Child-Pugh Class A):
  • Less than 6 months of age: KALYDECO is not recommended.
  • No dose adjustment is necessary for patients aged 6 months or older [see Clinical Pharmacology (12.3)].
• Moderate Hepatic Impairment (Child-Pugh Class B):
  • Less than 6 months of age: KALYDECO is not recommended.
  • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily based on dosing recommended for age and weight in Table 1 [see Dosage and Administration (2.2)].
  • 6 years of age and older: 150 mg orally once daily.
• Severe Hepatic Impairment (Child-Pugh Class C): Should not be used in patients less than 6 months of age. In patients 6 months and older should be used with caution. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dose, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology (12.3)].
  • Less than 6 months of age: KALYDECO is not recommended.
  • 6 months to less than 6 years of age: one packet (containing 25 mg, 50 mg, or 75 mg ivacaftor) of oral granules once daily or less frequently based on dosing recommended for age and weight in Table 1 [see Dosage and Administration (2.2)].
  • 6 years of age and older: 150 mg orally once daily or less frequently.

2.4 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

Concomitant use of moderate or strong CYP3A inhibitors is not recommended in patients below 6 months of age. Food or drink containing grapefruit should be avoided [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Take KALYDECO with fat-containing food [see Dosage and Administration (2.5)].

2.5 Administration Information

Administer KALYDECO tablets or oral granules with fat-containing food. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, or infant formula), etc. [see Clinical Pharmacology (12.3)].

5.1 Transaminase (ALT or AST) Elevations

Elevated transaminases have been reported in patients with CF receiving KALYDECO. ALT and AST should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO [see Adverse Reactions (6) and Use in Specific Populations (8.6)].

5.2 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue KALYDECO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO.

5.3 Concomitant Use with CYP3A Inducers

Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Therefore, co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

5.4 Cataracts

Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Although other risk factors were present in some cases (such as corticosteroid use and/or exposure to radiation), a possible risk attributable to KALYDECO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment.

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 KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted [see Clinical Pharmacology (12) and Clinical Studies (14)]:

• An 8-week, crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene.
• A 24-week, placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene.
• A 24-week, open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.
• An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor. A total of 156 patients were randomized to and received KALYDECO.
• A 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8) including a cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, a cohort of 6 patients aged 4 months to less than 6 months, and a cohort of 7 patients aged 1 month to less than 4 months. Patients with a gating mutation or R117H mutation were eligible for the first three cohorts of this study. Patients with any ivacaftor-responsive mutation were eligible for the cohort aged 1 to less than 4 months.

Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo for 16 to 48 weeks.

The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients, included abdominal pain, increased hepatic enzymes, and hypoglycemia.

The most common adverse reactions in the 221 patients treated with KALYDECO were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%).

The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in ≥8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.

Adverse reactions in the 48-week clinical trials that occurred in the KALYDECO group at a frequency of 4 to 7% where rates exceeded that in the placebo group include:

Infections and infestations: rhinitis

Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia

Nervous system disorders: sinus headache

Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing

Skin and subcutaneous tissue disorders: acne

The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of KALYDECO. 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

7.1 Inhibitors of CYP3A

Ivacaftor is a sensitive CYP3A substrate. Co-administration with ketoconazole, a strong CYP3A inhibitor, significantly increased ivacaftor exposure [measured as area under the curve (AUC)] by 8.5-fold. Based on simulations of these results, a reduction of the KALYDECO dose is recommended for patients 6 months and older taking concomitant strong CYP3A inhibitors, such as ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin. KALYDECO is not recommended for patients less than 6 months of age taking strong CYP3A inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dose is recommended for patients 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin. KALYDECO is not recommended for patients less than 6 months of age taking moderate CYP3A inhibitors [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

Co-administration of KALYDECO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of ivacaftor. Therefore, avoid food or drink containing grapefruit during treatment with KALYDECO [see Clinical Pharmacology (12.3)].

7.2 Inducers of CYP3A

Co-administration with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor exposure (AUC) by approximately 9-fold. Therefore, co-administration with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John's wort is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

7.3 Ciprofloxacin

Co-administration of KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dose adjustment is necessary during concomitant administration of KALYDECO with ciprofloxacin [see Clinical Pharmacology (12.3)].

Potential for ivacaftor to affect other drugs

7.4 CYP2C9 Substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of KALYDECO with warfarin is recommended. Other therapeutic products for which exposure may be increased by KALYDECO include glimepiride and glipizide; these therapeutic products should be used with caution [see Clinical Pharmacology (12.3)].

7.5 CYP3A and/or P-gp Substrates

Ivacaftor and its M1 metabolite have the potential to inhibit CYP3A and P-gp. Co-administration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor. Co-administration with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of KALYDECO may increase systemic exposure of drugs that are substrates of CYP3A and/or P-gp, which may increase or prolong their therapeutic effect and adverse events. Therefore, caution and appropriate monitoring are recommended when co-administering KALYDECO with sensitive CYP3A and/or P-gp substrates, such as digoxin, cyclosporine, and tacrolimus [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of KALYDECO for the treatment of CF have been established in pediatric patients 1 month to 17 years of age who have at least one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data [see Clinical Pharmacology (12.1) and Clinical Studies (14)].

The use of KALYDECO for this indication is supported by evidence from placebo-controlled clinical trials in the following pediatric patients with CF:

• 6 to 17 years of age with a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation in the CFTR gene [see Adverse Reactions (6) and Clinical Studies (14)].
• 12 to 17 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].

The effectiveness of KALYDECO in patients aged 2 to less than 6 years was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and pediatric patients 2 to less than 6 years of age [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a 24-week, open-label clinical trial in 34 patients ages 2 to less than 6 years (mean age 3 years) administered either 50 mg or 75 mg of ivacaftor granules twice daily (Trial 6). The type and frequency of adverse reactions in this trial were similar to those in patients 6 years and older. Transaminase elevations were more common in patients who had abnormal transaminases at baseline [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

The effectiveness of KALYDECO in patients aged 1 month to less than 24 months was extrapolated from patients 6 years of age and older with support from population pharmacokinetic analyses showing that the exposure of ivacaftor in pediatric patients 1 month to less than 24 months of age is within the range of exposure in adults and pediatric patients 6 years of age and older [see Clinical Pharmacology (12.3)]. Safety of KALYDECO in this population was derived from a cohort of 7 patients aged 1 month to less than 4 months (mean age 1.9 months at baseline), a cohort of 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline), a cohort of 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline), and a cohort of 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline) in a 24-week, open-label clinical trial, administered 5.8 mg, 11.4 mg, 17.1 mg, 22.8 mg, 25 mg, 50 mg, or 75 mg (11.4 mg, 17.1 mg, and 22.8 mg are not recommended dosages) of ivacaftor granules twice daily (Trial 8). The safety profile of patients in this trial was similar to that observed in patients 2 years and older.

The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established.

8.5 Geriatric Use

CF is largely a disease of children and young adults. Clinical trials of KALYDECO did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

• Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is necessary for patients aged 6 months or older [see Clinical Pharmacology (12.3)].
• Moderate Hepatic Impairment (Child-Pugh Class B): A reduced dose is recommended in patients aged 6 months or older [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
• Severe Hepatic Impairment (Child-Pugh Class C): Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dose, in patients aged 6 months or older with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Due to variability in maturation of cytochrome (CYP) enzymes involved in ivacaftor metabolism, treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any level of hepatic impairment [see Dosage and Administration (2.3)].

8.7 Renal Impairment

KALYDECO has not been studied in patients with mild, moderate, or severe renal impairment or in patients with end-stage renal disease. No dose adjustment is necessary for patients with mild to moderate renal impairment; however, caution is recommended while using KALYDECO in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.

12.1 Mechanism of Action

Ivacaftor is a potentiator of the CFTR protein. The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel open probability (or gating) of CFTR protein located at the cell surface. The overall level of ivacaftor-mediated CFTR chloride transport is dependent on the amount of CFTR protein at the cell surface and how responsive a particular mutant CFTR protein is to ivacaftor potentiation.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF.

After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively.

After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year studies were conducted in CD-1 mice and Sprague-Dawley rats to assess carcinogenic potential of KALYDECO. No evidence of tumorigenicity was observed in mice or rats at ivacaftor oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equal to 1 and 4 times the MRHD based on summed AUCs of ivacaftor and its metabolites).

Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus test.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, the MRHD based on summed AUCs of ivacaftor and its major metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations, and viable embryos in rats at 200 mg/kg/day (approximately 5 times the MRHD based on summed AUCs of ivacaftor and its major metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (yielding exposures approximately 6 and 3 times, respectively, the MRHD based on summed AUCs of ivacaftor and its major metabolites).

14.1 Trials in Patients with CF who have a G551D Mutation in the CFTR Gene

14.2 Trial in Patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R Mutation in the CFTR Gene

The efficacy and safety of KALYDECO in patients with CF who have a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene were evaluated in a two-part, randomized, double-blind, placebo-controlled, crossover design clinical trial in 39 patients with CF (Trial 4). Patients who completed Part 1 of this trial continued into the 16-week open-label Part 2 of the study. The mutations studied were G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D. See Clinical Studies (14.1) for efficacy in patients with a G551D mutation.

Patients were 6 years of age or older (mean age 23 years) with FEV1 ≥40% at screening [mean FEV1 at baseline 78% predicted (range: 43% to 119%)]. Patients with evidence of colonization with Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN at screening were excluded.

Patients were randomized 1:1 to receive either 150 mg of KALYDECO or placebo every 12 hours with fat-containing food for 8 weeks in addition to their prescribed CF therapies during the first treatment period and crossed over to the other treatment for the second 8 weeks. The two 8-week treatment periods were separated by a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted.

The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 8 weeks of treatment. Other efficacy variables included absolute change from baseline in sweat chloride through 8 weeks of treatment [see Clinical Pharmacology (12.2)], absolute change from baseline in body mass index (BMI) at 8 weeks of treatment (including body weight at 8 weeks), and improvement in CFQ-R respiratory domain score through 8 weeks of treatment. For the overall population of the 9 mutations studied, treatment with KALYDECO compared to placebo resulted in significant improvement in percent predicted FEV1 [10.7 through Week 8 (P<0.0001)], BMI [0.66 kg/m2 at Week 8 (P<0.0001)], and CFQ-R respiratory domain score [9.6 through Week 8 (P=0.0004)]; however, there was a high degree of variability of efficacy responses among the 9 mutations (Table 6).

14.3 Trial in Patients with CF who have an R117H Mutation in the CFTR Gene

The efficacy and safety of KALYDECO in patients with CF who have an R117H mutation in the CFTR gene were evaluated in a randomized, double-blind, placebo-controlled, parallel-group clinical trial (Trial 5). Fifty-nine of 69 patients completed 24 weeks of treatment. Two patients discontinued and 8 patients did not complete treatment due to study termination. Trial 5 evaluated 69 clinically stable patients with CF who were 6 years of age or older (mean age 31 years). Patients who were 12 years and older had FEV1 at screening between 40-90% predicted, and patients who were 6-11 years of age had FEV1 at screening between 40-105% predicted. The overall mean FEV1 was 73% predicted at baseline (range: 33% to 106%). The patients had well preserved BMIs (mean overall: 23.76 kg/m2) and a high proportion were pancreatic sufficient as assessed by a low rate of pancreatic enzyme replacement therapy use (pancreatin: 11.6%; pancrelipase: 5.8%). Patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening, and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN, were excluded.

Patients were randomized 1:1 to receive either 150 mg of KALYDECO (n=34) or placebo (n=35) every 12 hours with fat-containing food for 24 weeks in addition to their prescribed CF therapies.

The primary efficacy endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment. The treatment difference for absolute change in percent predicted FEV1 through Week 24 was 2.1 percentage points (analysis conducted with the full analysis set which included all 69 patients) and did not reach statistical significance (Table 7).

Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 24, improvement in cystic fibrosis respiratory symptoms through Week 24 as assessed by the CFQ-R respiratory domain score (Table 7), absolute change in body mass index (BMI) at Week 24, and time to first pulmonary exacerbation. The overall treatment difference for the absolute change from baseline in BMI at Week 24 was 0.3 kg/m2 and the calculated hazard ratio for time to first pulmonary exacerbation was 0.93, which were not statistically significant.

Statistically significant improvements in clinical efficacy (FEV1, CFQ-R respiratory domain score) were seen in several subgroup analyses and decreases in sweat chloride were observed in all subgroups. The mean baseline sweat chloride for all patients was 70 mmol/L. Subgroups analyzed included those based on age, lung function, and poly-T status (Table 7).

14.4 Trial in Patients with CF Heterozygous for the F508del Mutation and a Second Mutation Predicted to be Responsive to ivacaftor

The efficacy and safety of KALYDECO and an ivacaftor-containing combination product in 246 patients with CF was evaluated in a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover design clinical trial (Trial 7). Mutations predicted to be responsive to ivacaftor were selected for the study based on the clinical phenotype (pancreatic sufficiency), biomarker data (sweat chloride), and in vitro responsiveness to ivacaftor.

Eligible patients were heterozygous for the F508del mutation with a second mutation predicted to be responsive to ivacaftor. Of the 244 patients included in the efficacy analysis, who were randomized and dosed, 146 patients had a splice mutation and 98 patients had a missense mutation, as the second allele. 156 patients received KALYDECO and 161 patients received placebo. Patients were aged 12 years and older (mean age 35 years [range 12-72]) and had a percent predicted FEV1 at screening between 40-90 [mean ppFEV1 at study baseline 62 (range: 35 to 94)]. Patients with evidence of colonization with organisms associated with a more rapid decline in pulmonary status (e.g., Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus) and those with abnormal liver function at screening were excluded. Abnormal liver function was defined as 2 or more liver function tests (ALT, AST, ALP, GGT) ≥3 times the ULN or total bilirubin ≥2 times the ULN, or a single increase in ALT/AST ≥5 times the ULN.

The primary efficacy endpoint was the mean absolute change from study baseline in percent predicted FEV1 averaged at Weeks 4 and 8 of treatment. The key secondary efficacy endpoint was absolute change in CFQ-R respiratory domain score from study baseline averaged at Weeks 4 and 8 of treatment. For the overall population, treatment with KALYDECO compared to placebo resulted in significant improvement in ppFEV1 [4.7 percent points from study baseline to average of Week 4 and Week 8 (P<0.0001)] and CFQ-R respiratory domain score [9.7 points from study baseline to average of Week 4 and Week 8 (P<0.0001)]. Statistically significant improvements compared to placebo were also observed in the subgroup of patients with splice mutations and missense mutations (Table 8).

In an analysis of BMI at Week 8, an exploratory endpoint, patients treated with KALYDECO had a mean improvement of 0.28 kg/m2 [95% CI (0.14, 0.43)], 0.24 kg/m2 [95% CI (0.06, 0.43)], and 0.35 kg/m2 [95% CI (0.12, 0.58)] versus placebo for the overall, splice, and missense mutation populations of patients, respectively.

14.5 Trial in Patients Homozygous for the F508del Mutation in the CFTR Gene

Trial 3 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥40% predicted. Patients were randomized 4:1 to receive KALYDECO 150 mg (n=112) every 12 hours or placebo (n=28) in addition to their prescribed CF therapies. The mean age of patients enrolled was 23 years and the mean baseline FEV1 was 79% predicted (range 40% to 129%). As in Trials 1 and 2, patients who had persistent Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus isolated from sputum at screening and those with abnormal liver function defined as 3 or more liver function tests (ALT, AST, AP, GGT, total bilirubin) ≥3 times the ULN were excluded. The use of inhaled hypertonic saline was not permitted.

The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline through Week 16 in percent predicted FEV1. The treatment difference from placebo for the mean absolute change in percent predicted FEV1 through Week 16 in patients with CF homozygous for the F508del mutation in the CFTR gene was 1.72 percentage points (1.5% and -0.2% for patients in the KALYDECO and placebo-treated groups, respectively) and did not reach statistical significance (Table 9).

Other efficacy variables that were analyzed included absolute change in sweat chloride from baseline through Week 16, change in cystic fibrosis respiratory symptoms through Week 16 as assessed by the CFQ-R respiratory domain score (Table 9), change in weight through Week 16, and rate of pulmonary exacerbation. The overall treatment difference for change from baseline in weight through Week 16 was -0.16 kg (95% CI -1.06, 0.74); the rate ratio for pulmonary exacerbation was 0.677 (95% CI 0.33, 1.37).

Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

Transaminase (ALT or AST) Elevations and Monitoring

Inform patients that elevation in liver tests have occurred in patients treated with KALYDECO. Liver function tests will be performed prior to initiating KALYDECO, every 3 months during the first year of treatment and annually thereafter. More frequent monitoring of liver function tests should be considered in patients with a history of transaminase elevations [see Warnings and Precautions (5.1)].

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis are possible with use of KALYDECO. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of KALYDECO immediately and contact their physician or go to the emergency department if these symptoms occur.

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of KALYDECO with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended, as they may reduce the therapeutic effectiveness of KALYDECO. Dose reduction is recommended when patients aged 6 months and older are taking concomitant strong CYP3A inhibitors, such as ketoconazole, or moderate CYP3A inhibitors, such as fluconazole [see Dosage and Administration (2.4), Drug Interactions (7.1)]. Treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months who are taking concomitant moderate or strong CYP3A inhibitors. Food or drink containing grapefruit should be avoided [see Drug Interactions (7.1, 7.2) and Clinical Pharmacology (12.3)].

Use in Patients with Hepatic Impairment

Inquire and/or assess whether patients have liver impairment. Reduce the dose of KALYDECO in patients aged 6 months and older with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) to one tablet or one packet of granules once daily. KALYDECO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15); however, exposure is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients aged 6 months and older with severe hepatic impairment at a reduced dose [see Dosage and Administration (2.3)]. Treatment with KALYDECO is not recommended in patients aged 1 month to less than 6 months with any signs of hepatic impairment. No dose adjustment is recommended for patients 6 months and older with mild hepatic impairment (Child-Pugh Class A, score 5-6) [see Use in Specific Populations (8.6)].

Driving and Operating Machinery

Dizziness has been reported in patients receiving KALYDECO, which could influence the ability to drive or operate machines [see Adverse Reactions (6.1)]. Advise patients not to drive or operate machines if they experience dizziness until symptoms abate.

Administration

KALYDECO (ivacaftor) tablets 150 mg

Inform patients that KALYDECO tablet is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, and yogurt), etc.

KALYDECO (ivacaftor) oral granules 5.8 mg, 13.4 mg, 25 mg, 50 mg, or 75 mg

Inform patients and caregivers that KALYDECO oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for one hour, and therefore should be consumed during this period. Some examples of appropriate soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice.

Inform patients and caregivers that KALYDECO is best absorbed by the body when taken with food that contains fat; therefore, KALYDECO oral granules should be taken just before or just after consuming food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, and infant formula), etc.

Patients should be informed about what to do in the event they miss a dose of KALYDECO:

• In case a dose of KALYDECO is missed within 6 hours of the time it is usually taken, patients should be instructed to take the prescribed dose of KALYDECO with fat-containing food as soon as possible.
• If more than 6 hours have passed since KALYDECO is usually taken, the missed dose should NOT be taken, and the patient should resume the usual dosing schedule.
• Patients should be advised to contact their healthcare provider if they have questions.

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving KALYDECO. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating KALYDECO treatment [see Warnings and Precautions (5.4)].