Ivacaftor

5 WARNINGS AND PRECAUTIONS Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. In patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered. Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Interrupt dosing 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 dosing. ( 5.1 , 6 ) Hypersensitivity reactions: Anaphylaxis has been reported with KALYDECO in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.2 ) Intracranial hypertension : Intracranial hypertension (IH) has been reported in the postmarketing setting with use of drugs containing the same or similar active ingredients as KALYDECO. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt KALYDECO and refer for prompt medical evaluation. ( 5.3 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for KALYDECO or drugs containing the same or similar active ingredient. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with KALYDECO should be interrupted at the occurrence of neuropsychiatric symptoms. ( 5.4 ) Use with CYP3A inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of ivacaftor, which may diminish effectiveness. Therefore, co-administration is not recommended. ( 5.5 , 7.2 , 12.3 ) Cataracts: Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up examinations are recommended in pediatric patients initiating KALYDECO treatment. ( 5.6 ) 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 Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of drugs containing the same or similar active ingredients as KALYDECO [see Adverse Reactions (6.2) ] . Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt KALYDECO and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with KALYDECO. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk. 5.4 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking KALYDECO or drugs containing the same or similar active ingredient [see Adverse Reactions (6.2) ] . The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with KALYDECO should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement. 5.5 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) ]. 5.6 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 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: 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) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.6) ] The most common adverse drug reactions to KALYDECO (≥8% of patients with CF who have a G551D mutation in the CFTR gene) were headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, 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 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. Table 2: Incidence of Adverse Drug Reactions in ≥8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration Adverse Reaction (Preferred Term) Incidence: Pooled 48-Week Trials KALYDECO N=109 n (%) Placebo N=104 n (%) Headache 26 (24) 17 (16) Oropharyngeal pain 24 (22) 19 (18) Upper respiratory tract infection 24 (22) 14 (14) Nasal congestion 22 (20) 16 (15) Abdominal pain 17 (16) 13 (13) Nasopharyngitis 16 (15) 12 (12) Diarrhea 14 (13) 10 (10) Rash 14 (13) 7 (7) Nausea 13 (12) 11 (11) Dizziness 10 (9) 1 (1) 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). Laboratory Abnormalities Transaminase Elevations: In Trials 1, 2, and 3 the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 2%, 2%, and 6% in KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, respectively. Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 × ULN. Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo. Transaminase elevations were more common in patients with a history of transaminase elevations [ see Warnings and Precautions (5.1) ]. During the 24-week, open-label, clinical trial in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 × ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 × ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient [ see Warnings and Precautions (5.1) ]. During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3, >5, and >8 × ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ≤5 × ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (>3× ULN). In the cohort of patients aged 1 month to less than 4 months (N=7), 1 patient (14.3%) had maximum ALT or AST >3 × ULN (ALT >8 × ULN and AST of >3 to ≤5 × ULN); the patient discontinued ivacaftor treatment [see Warnings and Precautions (5.1) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of KALYDECO or drugs containing the same or similar active ingredient as 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 Nervous System Disorders : intracranial hypertension Psychiatric Disorders: anxiety, depression, suicidal ideation and behavior, insomnia

7 DRUG INTERACTIONS Potential for other drugs to affect ivacaftor CYP3A inhibitors: Reduce KALYDECO dosage in patients aged 6 months and older when co-administered with strong CYP3A inhibitors (e.g., ketoconazole) or moderate CYP3A inhibitors (e.g., fluconazole). KALYDECO is not recommended in patients aged 1 month to less than 6 months when co-administered with strong or moderate CYP3A inhibitors. Avoid food or drink containing grapefruit. ( 2.4 , 7.1 ) 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 dosage is recommended for patients aged 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 dosage is recommended for patients aged 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 (5.5) and Clinical Pharmacology (12.3) ]. 7.3 Ciprofloxacin Co-administration of KALYDECO with ciprofloxacin had no effect on the exposure of ivacaftor. Therefore, no dosage 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of KALYDECO in pregnant women. In animal reproduction studies, oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 5 (rats) and 11 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 3 times the exposures at the MRHD, respectively ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% in clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 11 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a pre- and post-natal development study, pregnant female rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. 8.2 Lactation Risk Summary There is no information regarding the presence of ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Ivacaftor is excreted into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk ( see Data ). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KALYDECO, and any potential adverse effects on the breastfed child from KALYDECO or from the underlying maternal condition. Data Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14 C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC 0-24h ) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels. 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: 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) ] . 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) ] . 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 aged 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 aged 2 years and older. Safety of KALYDECO in patients aged 1 month and older was evaluated in a 96-week, open-label study (Trial 9) in 86 patients (38 rolled over from Trial 8, and 48 KALYDECO-naïve). Adverse reactions from Trial 9 were generally similar to those reported in Trial 8. The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.1 to 0.8 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals. 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 dosage adjustment is necessary for patients aged 6 months or older [see Clinical Pharmacology (12.3) ] . Moderate Hepatic Impairment (Child-Pugh Class B): A reduced dosage 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 dosage, 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 dosage 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.

8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials and postmarketing reports on use of KALYDECO in pregnant women. In animal reproduction studies, oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse effects on fetal development at doses that produced maternal exposures up to approximately 5 (rats) and 11 (rabbits) times the exposure at the maximum recommended human dose (MRHD). No adverse developmental effects were observed after oral administration of ivacaftor to pregnant rats from organogenesis through lactation at doses that produced maternal exposures approximately 3 times the exposures at the MRHD, respectively ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage is 15% to 20% in clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation days 7-17. Ivacaftor did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 11 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a pre- and post-natal development study, pregnant female rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation day 7 through lactation day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

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: 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) ] . 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) ] . 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 aged 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 aged 2 years and older. Safety of KALYDECO in patients aged 1 month and older was evaluated in a 96-week, open-label study (Trial 9) in 86 patients (38 rolled over from Trial 8, and 48 KALYDECO-naïve). Adverse reactions from Trial 9 were generally similar to those reported in Trial 8. The safety and effectiveness of KALYDECO in pediatric patients with CF younger than 1 month of age have not been established. Juvenile Animal Toxicity Data In a juvenile toxicology study in which ivacaftor was administered to rats from postnatal days 7 to 35, cataracts were observed at all dose levels, ranging from 0.1 to 0.8 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at oral doses of 10-50 mg/kg/day). This finding has not been observed in older animals.