KALYDECO

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-If a dose is missed within 6 hours of the time it is usually taken, the dose should be taken with fat-containing food as soon as possible. If more than 6 hours have passed since the dose is usually taken, skip that dose and resume with the usual dosing schedule.
Oral Solid Formulations
-Swallow tablets whole.
-Administer each dose with fat-containing food (e.g., eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, or infant formula)).

Other Oral Formulations
Oral granules
-Mix the entire contents of packet with 5 mL of age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, juice) that is at or below room temperature.
-Administer each dose immediately before or after ingestion of fat-containing food (e.g., eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, or infant formula)).
-The mixture is stable for 1 hour and should be completely consumed within this time period.

The overall safety profile of ivacaftor is based on pooled data from 3 clinical trials of patients with cystic fibrosis (combined n = 353; age >= 6 years); ivacaftor-treated patients received 150 mg twice daily. Trial 1 (n = 161; age >= 12 years) and Trial 2 (n = 52; age 6-11 years) were double-blind, placebo-controlled, 48-week trials conducted in patients with a G551D mutation in the CFTR gene. Trial 3 (n = 140; age >= 12 years) was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial in patients homozygous for the F508del mutation. Three additional trials have been conducted. Trial 4 (n = 39; age >= 6 years) was a 8-week crossover study in patients with a G1244E, G1349D, G178R, G551S, G907R, S125IN, S1255P, S549N, or S549R mutation. Trial 5 (n = 69; age 6-68 years) was a 24-week placebo-controlled trial in patients with a R117H mutation. Trial 6 (n = 34; age 2-5 years) was a 24-week open-label trial in patients with a G551D or S549N mutation; these patients received ivacaftor granules 50 mg or 75 mg twice daily. The type and frequency of adverse reactions reported in all clinical trials were similar.

Elevated hepatic enzymes were reported in approximately 2% to 15% of patients receiving ivacaftor in clinical trials. In patients older than 6 years of age, the incidence of maximum ALT or AST more than 8, more than 5, or more than 3 times the upper limit of normal (ULN) was 2%, 2%, and 6% in patients receiving ivacaftor compared to 2%, 2%, and 8% in patients receiving placebo, respectively. One patient receiving ivacaftor and 2 patients receiving placebo permanently discontinued treatment for elevations more than 8 times ULN. Serious adverse reactions of elevated liver transaminases were reported in 2 ivacaftor-treated patients, compared to none in the placebo group. During the open-label trial in patients 2 to 5 years of age (n = 34), 15% of patients experienced maximum transaminase elevations more than 8 times ULN, which returned to baseline after interruption of therapy. Ivacaftor was permanently discontinued in 1 patient. During the open-label trial in patients 12 to 23 months of age (n = 19), the incidence of maximum ALT or AST more than 8, more than 5, or more than 3 times the ULN was 11.1%, 11.1%, and 27.8%, respectively. No patients had elevations in total bilirubin or discontinued treatment due to transaminase elevations. In patients 1 month to less than 4 months (n = 7), 1 patient had an ALT 8 times greater than the ULN and an AST of greater than 3, but less than 5 times ULN; the patient discontinued ivacaftor treatment. In most trials, transaminase elevations were more common in patients with a history of such. Monitor AST and ALT prior to initiating therapy, every 3 months during the first year of therapy, and annually thereafter. Consider more frequent monitoring in patients with a history of transaminase elevations. If transaminase elevations occur, monitor patients closely until abnormalities resolve. Temporarily discontinue ivacaftor therapy if the elevation exceeds 5 times ULN. Therapy may be resumed upon resolution of transaminase elevations, but only after careful consideration of risks and benefits of continued therapy.

Headache (17-24%) and dizziness (5-9%) occurred more frequently in patients receiving ivacaftor than placebo, respectively, during clinical trials. Sinus headache was also reported in 4-7% of ivacaftor-treated patients.

Upper respiratory tract infection (16-22% vs. 14%), nasal congestion (16-20% vs. 15%), oropharyngeal pain (22% vs. 18%), and naso-pharyngitis (15% vs. 12%) occurred more frequently in patients receiving ivacaftor than placebo, respectively, during clinical trials. Other respiratory and infectious adverse events occurring in 4-7% of patients receiving ivacaftor included bacteria in sputum, rhinitis, pharyngeal erythema, pleuritic pain, sinus congestion, and wheezing.

Abdominal pain (16% vs. 13%), nausea (10-12% vs. 11%), and diarrhea (13% vs. 10%) occurred more frequently in patients receiving ivacaftor than placebo, respectively, during clinical trials.

Rash (unspecified) (10-13%) and acne vulgaris (4-7%) occurred more frequently in ivacaftor-treated patients than placebo-treated patients during clinical trials.

Arthralgia, myalgia, and musculoskeletal pain (chest) occurred in 4-7% of ivacaftor-treated patients during clinical trials.

Hyperglycemia occurred in 4-7% of ivacaftor-treated patients during clinical trials. Hypoglycemia was also reported as a serious event in ivacaftor-treated patients; however, incidence was unspecified and causality not established.

Cases of non-congenital lens opacities/cataracts have been reported in children and adolescents treated with ivacaftor. Although other risk factors (e.g., corticosteroid use, radiation exposure) were present in some cases, a possible risk attributable to ivacaftor cannot be excluded. Cataracts were also noted in juvenile rats receiving ivacaftor 10 mg/kg/day or greater from postnatal day 7-35; this finding was not observed in older animals. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating ivacaftor treatment.

Hypersensitivity reactions, including anaphylaxis or anaphylactoid reactions, have been reported during postmarketing experience. Discontinue ivacaftor and administer appropriate therapy if signs or symptoms of serious hypersensitivity reactions develop during treatment. Consider the benefits and risks when deciding whether to resume therapy.

Ivacaftor is not effective in patients with cystic fibrosis (CF) who are homozygous for the F508del mutation in the CFTR gene. Results from a double-blind, placebo-controlled trial in patients with CF who were homozygous for the F508del mutation showed no statistically significant difference in forced expiratory volume exhaled in 1 second (FEV-1) over 16 weeks of treatment compared to placebo. If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed.

Use ivacaftor with caution in patients 6 months and older with hepatic disease. Ivacaftor is not recommended in patients younger than 6 months of age with hepatic impairment due to immature cytochrome enzymes involved in ivacaftor metabolism. A dose reduction is required in patients 6 months and older with moderate or severe (Child-Pugh Class B or C) hepatic disease. Ivacaftor can cause elevated transaminases in patients with cystic fibrosis, and it is recommended that patients have AST and ALT assessed prior to initiating therapy, every 3 months during the first year of therapy, and annually thereafter. Consider more frequent monitoring in patients with a history of transaminase elevations. Closely monitor patients who develop increased transaminases until the abnormalities resolve. Temporarily discontinue ivacaftor in patients with an ALT or AST greater than 5 times the upper limit of normal. Upon resolution, ivacaftor therapy may be resumed after careful consideration of the benefits and risks of therapy.

Use ivacaftor with caution in patients with severe renal impairment (CrCl 30 mL/minute or less) or end stage renal disease (renal failure). Ivacaftor has not been studied in patients with any degree of renal impairment or renal disease.

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

Description: Ivacaftor is an orally bioavailable cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients who have one mutation in the CFTR gene that is responsive to ivacaftor. Ion channel modulators, such as ivacaftor, aim to correct the underlying cellular defect (chloride ion transport) responsible for CF instead of the severity of symptoms. Of note, ivacaftor monotherapy is not effective in patients who are homozygous for the F508del mutation, the most frequent genotype in patients with CF; approximately half of CF patients are homozygous for this allele. However, in patients with an indicated mutation, ivacaftor therapy has been associated with improved forced expiratory volume in 1 second (FEV1), decreased risk of pulmonary exacerbation, increased quality of life, improved nutrition, and a large correction of elevated sweat chloride concentrations. The Cystic Fibrosis Pulmonary Guidelines strongly recommend chronic use of ivacaftor to improve lung function and quality of life and reduce exacerbations in patients with a qualifying mutation. In clinical trials of CF patients with at least one G551D-CFTR mutation (n = 213), mean improvement in FEV1 ranged from 10.6% to 12.5% in patients treated with ivacaftor (p less than 0.001). Effects on pulmonary function were evident by 2 weeks, and significant effects were maintained throughout the 48-week trial period. The change in sweat chloride, a measure of CFTR activity, with ivacaftor ranged from -48 to -54 mmol/L (p less than 0.001). The risk of pulmonary exacerbations was 55% lower in those treated with ivacaftor compared to placebo in patients 12 years and older (n = 161); the risk was low but did not differ between active- and placebo-treated groups in children 6 to 11 years (n = 52). Serious adverse reactions related to elevated liver transaminases and, in pediatric patients, the development of cataracts have been associated with ivacaftor. Hence, liver function test monitoring and eye exams are required at baseline and periodically throughout therapy. Ivacaftor is FDA-approved for use in pediatric patients 1 month of age and older.

General dosing information:
-Ivacaftor is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene. If a patient's genotype is unknown, an FDA-cleared CF mutation test should be performed to detect the presence of a CFTR mutation; some tests may require verification with bi-directional sequencing.

For the treatment of cystic fibrosis in persons who have 1 mutation in the CFTR gene that is responsive to ivacaftor:
NOTE: If a patient's genotype is unknown, an FDA-cleared cystic fibrosis (CF) mutation test should be performed; some tests may require verification with bi-directional sequencing.
Oral dosage:
Infants 1 month weighing 3 kg or more: 5.8 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.
Infants 2 to 3 months weighing 3 kg or more: 13.4 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.
Infants 4 to 5 months weighing 5 kg or more: 25 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided; review drug interactions.
Infants and Children 6 months to 5 years weighing 5 to 6 kg: 25 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants and Children 6 months to 5 years weighing 7 to 13 kg: 50 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Infants and Children 6 months to 5 years weighing 14 kg or more: 75 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 6 to 17 years: 150 mg PO every 12 hours. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Younger than 1 month: Safety and efficacy have not been established.
1 month weighing 3 kg or more: 11.6 mg/day PO.
2 to 3 months weighing 3 kg or more: 26.8 mg/day PO.
4 to 5 months weighing 5 kg or more: 50 mg/day PO.
6 to 11 months weighing 5 to 6 kg: 50 mg/day PO.
6 to 11 months weighing 7 to 13 kg: 100 mg/day PO.
6 to 11 months weighing 14 kg or more: 150 mg/day PO.
-Children
1 to 5 years weighing 5 to 6 kg: 50 mg/day PO.
1 to 5 years weighing 7 to 13 kg: 100 mg/day PO.
1 to 5 years weighing 14 kg or more: 150 mg/day PO.
6 to 12 years: 300 mg/day PO.
-Adolescents
300 mg/day PO.

Patients with Hepatic Impairment Dosing
Use is NOT recommended in patients younger than 6 months of age with hepatic impairment.
In patients 6 months of age and older:
Mild impairment (Child-Pugh Class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh Class B): Administer the usual recommended dose, but reduce the frequency to once daily (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg once daily).
Severe impairment (Child-Pugh Class C): Administer the usual recommended dose, but reduce the frequency to once daily or less frequently after weighing the risks and benefits of treatment. Use with caution; ivacaftor has not been studied in patients with severe hepatic impairment.

Patients with Renal Impairment Dosing
CrCl more than 30 mL/minute: No dosage adjustment necessary.
CrCl 30 mL/minute or less: Use with caution; specific guidelines for dosage adjustments are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Ivacaftor is a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel present at the surface of epithelial cells in multiple organs. Patients with cystic fibrosis (CF) have a mutation in the CFTR gene that encodes the protein. These mutations affect chloride channel function and disrupt the regulation of salt and water absorption and secretion. In the lungs, this results in thick mucus, impaired mucociliary transport, mucus stasis, airway obstruction, and pathogen-induced inflammation. In addition, impairment of CFTR-mediated reabsorption of chloride in the sweat gland results in salty sweat, a diagnostic sign of CF. Ivacaftor increases chloride transport by potentiating the channel-opening probability of the CFTR protein. Patients with the G551D, G1244E, G1349D, G178R, G551S, S125IN, S1255P, S549N, S549R, or R117H mutations in the CFTR gene who received ivacaftor in clinical trials had statistically significant reductions in sweat chloride concentrations, a determinant of increased CFTR activity. Evidence of clinical efficacy exists for other mutations in the CFTR gene that are responsive to ivacaftor, including some splice mutations. Because ivacaftor targets the underlying protein defect, it may help to maintain adequate airway hydration and modify disease progression.

Pharmacokinetics: Ivacaftor is administered orally. It is approximately 99% bound to proteins, primarily alpha1-acid glycoprotein and albumin. Mean apparent Vd is 353 +/- 122 L at steady state. Ivacaftor is extensively metabolized, primarily by CYP3A, to the major metabolites M1 (pharmacologically active; one-sixth the potency of parent drug) and M6 (pharmacologically inactive). Ivacaftor is primarily eliminated in the feces (88%), with M1 and M6 accounting for approximately 65% of the total dose eliminated; negligible amounts of the parent drug are eliminated in the urine. Mean clearance is 17 +/- 8 L/hour with a terminal half-life of approximately 12 hours.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C9, and P-gp
Ivacaftor is metabolized by the cytochrome P450 (CYP450) enzyme group, primarily CYP3A. Dosage adjustments are recommended when ivacaftor is co-administered with moderate or strong CYP3A inhibitors; concurrent use with strong CYP3A inducers is not recommended. Ivacaftor and the M1 metabolite are considered weak inhibitors of CYP3A, CYP2C9, and P-glycoprotein (P-gp) transport. Increased monitoring is recommended when ivacaftor is administered concurrently with CYP3A, CYP2C9, or P-gp substrates.


-Route-Specific Pharmacokinetics
Oral Route
Peak plasma concentrations (768 +/- 233 ng/mL) were obtained approximately 4 hours (range: 3 to 6 hours) after oral administration of a single 150-mg dose (fed state) during clinical trials. Under these same conditions, AUC was 10,600 +/- 5,260 ng x hour/mL. In adult patients receiving one 150-mg tablet every 12 hours, mean AUC at steady state was 10,700 +/- 4,100 ng x hour/mL, which was similar to exposure achieved in most pediatric populations studied. After every 12-hour dosing, steady state plasma concentrations were obtained within 3 to 5 days. Administration of ivacaftor with fat-containing foods increased exposure by 2 to 4 fold during clinical studies; hence, administration with fat-containing foods is recommended. The bioavailability of ivacaftor tablets and granules is similar.


-Special Populations
Pediatrics
In pharmacokinetic studies of ivacaftor use in children 1 month to 17 years, mean exposures were similar to exposures seen in adults administered ivacaftor tablets 150 mg every 12 hours (mean steady state AUC 10,700 +/- 4,100 ng x hour/mL), except for children 6 to 11 years in whom exposures were higher.
-Infants 1 month weighing 3 kg or more: After oral administration of ivacaftor granules 5.8 mg every 12 hours, the mean steady state AUC was 5,490 +/- 1,310 ng x hour/mL.
-Infants 2 to 3 months weighing 3 kg or more: After oral administration of ivacaftor granules 13.4 mg every 12 hours, the mean steady state AUC was 6,730 +/- 3.650 ng x hour/mL.
-Infants 4 to 6 months weighing 5 kg or more: After oral administration of ivacaftor granules 25 mg every 12 hours, the mean steady state AUC was 6,480 +/- 2,520 ng x hour/mL.
-Infants 6 to 11 months weighing 5 to less than 7 kg: After oral administration of ivacaftor granules 25 mg every 12 hours, the mean steady state AUC was 5,360 ng x hour/mL.
-Infants 6 to 11 months weighing 7 to less than 14 kg: After oral administration of ivacaftor granules 50 mg every 12 hours, the mean steady state AUC was 9,390 +/- 3,120 ng x hour/mL.
-Children 12 to 23 months weighing less than 14 kg: After oral administration of ivacaftor granules 50 mg every 12 hours, the mean steady state AUC was 9,050 +/- 3,050 ng x hour/mL.
-Children 12 to 23 months weighing 14 kg or more: After oral administration of ivacaftor granules 75 mg every 12 hours, the mean steady state AUC was 9,600 +/- 1,800 ng x hour/mL.
-Children 2 to 5 years weighing less than 14 kg: After oral administration of ivacaftor granules 50 mg every 12 hours, the mean steady state AUC was 10,500 +/- 4,260 ng x hour/mL.
-Children 2 to 5 years weighing 14 kg or more: After oral administration of ivacaftor granules 75 mg every 12 hours, the mean steady state AUC was 11,300 +/- 3,820 ng x hour/mL.
-Children 6 to 11 years: After oral administration of ivacaftor tablets 150 mg every 12 hours, the mean steady state AUC was 20,000 +/- 8,330 ng x hour/mL.
-Children and Adolescents 12 to 17 years: After oral administration of ivacaftor tablets 150 mg every 12 hours, the mean steady state AUC was 9,240 +/- 3,420 ng x hour/mL.

Hepatic Impairment
Adult patients with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) had an approximately 2-fold increase in AUC but a similar Cmax after ivacaftor administration compared to healthy subjects. The pharmacokinetics of ivacaftor in patients with mild (Child-Pugh Class A) or severe (Child-Pugh Class C, score 10 to 15) hepatic impairment have not been studied.

Renal Impairment
The pharmacokinetics of ivacaftor have not been studied in patients with any degree of renal impairment. Ivacaftor and its metabolites have negligible renal elimination; only 6.6% of total radioactivity was recovered in the urine during human studies.