Kalydeco
(ivacaftor)Dosage & 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 |
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Kalydeco Prescribing Information
KALYDECO is indicated for the treatment of cystic fibrosis (CF) in patients age 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.
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)].
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)].
| Age | Body Weight (kg) | KALYDECO Dosage |
|---|---|---|
| ||
| 1 month to less than 2 months * † | 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 | |
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.
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)].
Dosage modification for patients 6 months of age and older taking CYP3A inhibitors:
- Moderate CYP3A inhibitors:
- 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.
- Strong CYP3A inhibitors:
- 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 twice a week 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 twice weekly.
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)].
Instruction for Administration of Tablets
Swallow tablets whole.
Instruction for Administration of Oral Granules
Administer each dose of KALYDECO oral granules immediately before or after ingestion of fat-containing food. Mix the entire contents of each packet of oral granules with one teaspoon (5 mL) of age-appropriate soft food or liquid that is at or below room temperature. Some examples of soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice. Food or liquid should be at or below room temperature. Once mixed, the product should be completely consumed within one hour.
Tablets: 150 mg, light blue, film-coated, capsule 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.
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 in pregnant rats dosed during the period of organogenesis from gestation days 7-17, ivacaftor was not teratogenic and 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). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 7-19, ivacaftor was not teratogenic and 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). In a pre- and post-natal development study in pregnant female rats dosed 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.
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 14C-ivacaftor administered 9 to 10 days postpartum to lactating mothers (dams). Exposure (AUC0-24h) values for ivacaftor in milk were approximately 1.5 times higher than plasma levels.
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.
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.
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.
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)].
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.
None.
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)].
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.
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)].
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.