Kalydeco

Warnings and Precautions, Intracranial Hypertension ( 5.3 ) 09/2025 Warnings and Precautions, Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors ( 5.4 ) 03/2026

1 INDICATIONS AND USAGE KALYDECO is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 month and older 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) ] . 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. KALYDECO is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients aged 1 month and older who have at least one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. ( 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 Age Weight Dosage Administration 1 month to less than 2 months 3 kg or greater One 5.8 mg packet every 12 hours Mixed with one teaspoon (5 mL) of soft food or liquid and administered orally with fat-containing food 2 months to less than 4 months 3 kg or greater One 13.4 mg packet every 12 hours 4 months to less than 6 months 5 kg or greater One 25 mg packet every 12 hours 6 months to less than 6 years 5 kg to less than 7 kg One 25 mg packet every 12 hours 7 kg to less than 14 kg One 50 mg packet every 12 hours 14 kg or greater One 75 mg packet every 12 hours 6 years and older - One 150 mg tablet every 12 hours Taken orally with fat-containing food See full prescribing information for the recommended dosage in patients aged 6 months and older with moderate or severe hepatic impairment. ( 2.3 , 8.6 ) See full prescribing information for dosage modifications due to drug interactions with KALYDECO. ( 2.4 , 7.1 ) Not recommended in pediatric patients less than 1 month of age. ( 2.2 , 8.4 ) Not recommended in patients 1 month to less than 6 months of age with any level of hepatic impairment and/or taking concomitant moderate or strong CYP3A inhibitors. ( 2.3 , 2.4 , 8.6 ) 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 aged 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) ] . Table 1: Recommended Dosage of KALYDECO Oral Granules by Body Weight in Pediatric Patients Aged 1 Month to Less than 6 Years Age Body Weight (kg) KALYDECO Dosage 1 month to less than 2 months KALYDECO is not recommended for use in pediatric patients under 1 month of age. Use of KALYDECO in pediatric patients aged 1 to less than 6 months born at a gestational age less than 37 weeks has not been evaluated. 3 kg or greater One packet (containing 5.8 mg ivacaftor) every 12 hours 2 months to less than 4 months 3 kg or greater One packet (containing 13.4 mg ivacaftor) every 12 hours 4 months to less than 6 months 5 kg or greater One packet (containing 25 mg ivacaftor) every 12 hours 6 months to less than 6 years of age 5 kg to less than 7 kg One packet (containing 25 mg ivacaftor) every 12 hours 7 kg to less than 14 kg One packet (containing 50 mg ivacaftor) every 12 hours 14 kg or greater One packet (containing 75 mg ivacaftor) every 12 hours 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 dosage 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 aged 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 t …

3 DOSAGE FORMS AND STRENGTHS Tablets: 150 mg, light blue, film-coated, oblong-shaped tablets, with the characters "V 150" on one side and plain on the other. Oral granules: 5.8 mg, 13.4 mg, 25 mg, 50 mg, or 75 mg, white to off-white granules, in unit-dose packets. Tablets: 150 mg. ( 3 ) Oral granules: Unit-dose packets of 5.8 mg, 13.4 mg, 25 mg, 50 mg, and 75 mg. ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

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%), …

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 CF …

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. CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) cells expressing mutant CFTR The chloride transport response of mutant CFTR protein to ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface. The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response. A patient must have at least one CFTR mutation responsive to ivacaftor to be indicated. Note that splice site mutations cannot be studied in the FRT assay. Evidence of clinical efficacy exists for non-canonical splice mutations 2789+5G→A , 3272-26A→G , 3849+10kbC→T , 711+3A→G and E831X and these are listed in Table 3 below [see also Clinical Studies (14.4) ] . The G970R mutation causes a splicing defect resulting in little-to-no CFTR protein at the cell surface that can be potentiated by ivacaftor [see Clinical Studies (14.2) ] . Ivacaftor also increased chloride transport in cultured human bronchial epithelial (HBE) cells derived from CF patients who carried F508del on one CFTR allele and either G551D or R117H-5T on the second CFTR allele. Table 3 lists mutations that are responsive to ivacaftor based on 1) a positive clinical response and/or 2) in vitro data in FRT cells indicating that ivacaftor increases chloride transport to at least 10% over baseline (% of normal). Table 3: List of CFTR Gene Mutations that Produce CFTR Protein and are Responsive to KALYDECO 711+3A→G Clinical data exist for these mutations [see Clinical Studies (14) ] . F311del I148T R75Q S589N 2789+5G→A F311L I175V R117C S737F 3272-26A→G F508C I807M R117G S945L 3849+10kbC→T F508C;S1251N Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. I1027T R117H S977F A120T F1052V I1139V R117L S1159F A234D F1074L K1060T R117P S1159P A349V G178E L206W R170H S1251N A455E G178R L320V R347H S1255P A1067T G194R L967S R347L T338I D110E G314E L997F R352Q T1053I D110H G551D L1480P R553Q V232D D192G G551S M152V R668C V562I D579G G576A M952I R792G V754M D924N G970D M952T R933G V1293G D1152H G1069R P67L R1070Q W1282R D1270N G1244E Q237E R1070W Y1014C E56K G1249R Q237H R1162L Y1032C E193K G1349D Q359R R1283M E822K H939R Q1291R S549N E831X H1375P R74W S549R

11 DESCRIPTION The active ingredient in KALYDECO tablets and oral granules is ivacaftor, a cystic fibrosis transmembrane conductance regulator potentiator, which has the following chemical name: N -(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Its molecular formula is C 24 H 28 N 2 O 3 and its molecular weight is 392.49. Ivacaftor has the following structural formula: Ivacaftor is a white to off-white powder that is practically insoluble in water (<0.05 microgram/mL). KALYDECO is available as a light blue, oblong-shaped, film-coated tablet for oral administration containing 150 mg of ivacaftor. Each KALYDECO tablet contains 150 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. KALYDECO is also available as white to off-white granules for oral administration (sweetened but unflavored) and enclosed in a unit-dose packet containing 5.8 mg of ivacaftor, 13.4 mg of ivacaftor, 25 mg of ivacaftor, 50 mg of ivacaftor, or 75 mg of ivacaftor. Each unit-dose packet of KALYDECO oral granules contains 5.8 mg of ivacaftor, 13.4 mg of ivacaftor, 25 mg of ivacaftor, 50 mg of ivacaftor, or 75 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sucralose, and sodium lauryl sulfate. Chemical Structure

10 OVERDOSAGE There have been no reports of overdose with KALYDECO. No specific antidote is available for overdose with KALYDECO. Treatment of overdose with KALYDECO consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

16 HOW SUPPLIED/STORAGE AND HANDLING KALYDECO (ivacaftor) tablets are supplied as light blue, film-coated, oblong-shaped tablets containing 150 mg of ivacaftor. Each tablet is printed with the characters "V 150" on one side and plain on the other, and is packaged as follows: 56-count carton (contains 4 individual blister cards of 14 tablets per card) NDC 51167-200-01 60-count bottle NDC 51167-200-02 KALYDECO (ivacaftor) oral granules are supplied as small, white to off-white granules and enclosed in unit-dose packets as follows: 56-count carton (contains 56 unit-dose packets of 5.8 mg ivacaftor per packet) NDC 51167-785-01 56-count carton (contains 56 unit-dose packets of 13.4 mg ivacaftor per packet) NDC 51167-770-01 56-count carton (contains 56 unit-dose packets of 25 mg ivacaftor per packet) NDC 51167-600-01 56-count carton (contains 56 unit-dose packets of 50 mg ivacaftor per packet) NDC 51167-300-01 56-count carton (contains 56 unit-dose packets of 75 mg ivacaftor per packet) NDC 51167-400-01 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].