Dosing and uses of Kalydeco (ivacaftor)
Adult dosage forms and strengths
tablet
- 150mg
oral granules
- 50mg/unit dose packet
- 75mg/unit dose packet
Cystic Fibrosis
Indicated for the treatment of cystic fibrosis in adults and children ≥2 years who have R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations in the CFTR gene; not effective if homozygous for the F508del mutation in the CFTR gene
150 mg PO q12hr with fat-containing food
Dosage modification
Coadministration with strong CYP3A inhibitors: Reduce dose to 150 mg PO twice-a-week
Coadministration with moderate CYP3A inhibitors: Reduce dose to 150 mg PO qDay
Renal & Hepatic Impairment
Renal impairment
- Has not been studied in patients with renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe (CrCl <30 mL/min) or end stage renal disease: Caution advised
Hepatic impairment
- Mild (Child-Pugh Class A): No dosage adjustment required
- Moderate (Child-Pugh Class B): Reduce dose to 150 mg PO qDay
- Severe (Child-Pugh Class C): Has not been studied, but exposure is expected to be higher; use with caution at reduced dose of 150 mg PO qDay or less frequently
Dosing Considerations
Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene
Pediatric dosage forms and strengths
tablet
- 150mg
oral granules
- 50mg/unit dose packet
- 75mg/unit dose packet
Cystic Fibrosis
Indicated for the treatment of cystic fibrosis in adults and children ≥2 years who have R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations in the CFTR gene; not effective if homozygous for the F508del mutation in the CFTR gene
<2 years: Safety and efficacy not established
2-5 years, <14 kg: 50 mg granules PO q12hr
2-5 years, ≥14 kg: 75 mg granules PO q12hr
6-17 years: 150 mg PO q12hr
Take just before or after eating fat-containing food
Dosage modification
Coadministration with strong CYP3A inhibitors: Reduce dose to 150 mg PO twice-a-week
Coadministration with moderate CYP3A inhibitors: Reduce dose to 150 mg PO qDay
Renal & Hepatic Impairment
Renal impairment
- Has not been studied in patients with renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe (CrCl <30 mL/min) or end stage renal disease: Caution advised
Hepatic impairment
- Mild (Child-Pugh Class A): No dosage adjustment required
- Moderate (Child-Pugh Class B): Reduce dose to 150 mg PO qDay
- Severe (Child-Pugh Class C): Has not been studied, but exposure is expected to be higher; use with caution at reduced dose of 150 mg PO qDay or less frequently
Dosing Considerations
Not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene
Kalydeco (ivacaftor) adverse (side) effects
>10%
Headache (24%)
Oropharyngeal pain (22%)
Upper respiratory tract injection (22%)
Nasal congestion (20%)
Abdominal pain (16%)
Nasopharyngitis (15%)
Rash (13%)
Diarrhea (13%)
Nausea (12%)
1-10%
Dizziness (9%)
Rhinitis (6%)
Arthralgia (5%)
Bacteria in sputum (5%)
Warnings
Contraindications
None
Cautions
Elevated transaminases (ALT or AST); evaluate liver enzymes before initiating and every 3 months for the first year of treatment, and then annually thereafter; consider more frequent monitoring for patients with a history of transaminase elevations; interrupt dose if ALT or AST increases to >5 times ULn
Coadministration with CYP3A inhibitors require dose reduction (see Dosage modification)
Avoid eating grapefruit juice, grapefruit, or Seville oranges during treatment with ivacaftor; these fruits contain 1 or more components that moderately inhibit CYP3A
Avoid coadministration with strong CYP3A inducers (eg, rifampin); systemic exposure of ivacaftor substantially decreased (~9-fold), which may reduce therapeutic effect
Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; caution when coadministration with CYP3A and/or P-gp substrates
Cases of noncongenital lens opacities/cataracts have been reported in pediatric patients up to age 12 yr; although other risk factors were present in some cases (eg, corticosteroid use and/or exposure to radiation), a possible risk attributable to ivacaftor cannot be excluded; cataracts were seen in juvenile rats dosed with ivacaftor at dose levels of 10 mg/kg/day; baseline and follow-up ophthalmological examinations are recommended in pediatric patients
Pregnancy and lactation
Pregnancy category: B
Lactation: Probably excreted in human breast milk (based on studies in rats); caution advised
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Kalydeco (ivacaftor)
Mechanism of action
Potentiates the cystic fibrosis transmembrane conductance regulator (CFTR)
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 the G551D-CFTR protein
In addition to G551D-CFTR, ivacaftor potentiated gating of other mutant CFTR genes (ie, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R); it also potentiated channel-opening of R117H-CFTR, which has low gating and reduced channel amplitude compared to normal CFTr
Absorption
Peak Plasma Time: 4 hr (with high fat food)
Peak Plasma Concentration: 768 ng/mL
AUC: 10,600 ng•hr/mL
Distribution
Protein Bound: 99% (primarily albumin and alpha 1-acid glycoprotein)
Does not bind to red blood cells Vd: 353 L
Metabolism
Metabolized by CYP3A
Metabolites: M1 and M6 are the 2 major metabolites; M1 has 1/6 the potency of ivacaftor and is considered pharmacologically active; whereas, M6 has <1/50 the potency of ivacaftor and is not considered pharmacologically active
Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp
Elimination
Half-life: 12 hr
Total body clearance: 17.3 L/hr
Excretion: feces 87.8% (M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6); urine (negligible)
Pharmacogenomics
G551D mutation in the CFTR gene
- In 2 studies of patients with the G551D mutation, treatment with ivacaftor resulted in a significant improvement in FEV1
- The treatment difference between ivacaftor and placebo for the mean absolute change in percent predicted FEV1 from baseline through Week 24 was 10.6 percentage points (P < 0.0001) in Trial 1 and 12.5 percentage points (P < 0.0001) in Trial 2
- These changes persisted through 48 weeks
Homozygous for the F508del mutation in the CFTR gene
- Should not be used in patients homozygous for the F508del mutation in the CFTR gene
- Efficacy results from a double-blind, placebo-controlled trial in patients with CF who are homozygous for the F508del mutation in the CFTR gene showed no statistically significant difference in forced expiratory volume exhaled in one second (FEV1) over 16 weeks of ivacaftor treatment compared to placebo
Administration
Oral Tablets
Take with fat-containing food (eg, eggs, butter, peanut butter, cheese pizza)
Oral Granules
The entire contents of each packet of oral granules should be mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and completely consumed
Food or liquid should be at or below room temperature
Once mixed, the product has been shown to be stable for 1 hour, and therefore should be consumed during this period
Some examples of soft foods or liquids may include puréed fruits or vegetables, yogurt, applesauce, water, milk, or juice
Each dose should be administered just before or just after eating fat-containing food (eg, eggs, butter, peanut butter, cheese pizza)
