KALYDECO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KALYDECO (KALYDECO).
Potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein; increases the probability of CFTR channel opening by binding to the nucleotide-binding domain, thereby enhancing chloride transport in cells with defective CFTR gating mutations.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5; minor pathways include CYP2C8, CYP2C9, and CYP2C19. |
| Excretion | Primarily hepatic metabolism (CYP3A4), then biliary/fecal elimination; 88% in feces, <1% in urine as unchanged drug. |
| Half-life | 12 hours (terminal); supports twice-daily dosing; steady-state reached in 2-3 days. |
| Protein binding | 99% bound primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 2.5 L/kg; extensive distribution into tissues. |
| Bioavailability | Oral: Approximately 80% (taken with fat-containing food increases AUC by approximately 2-3-fold). |
| Onset of Action | Oral: Improvements in lung function (FEV1) and sweat chloride within 15 days. |
| Duration of Action | Twice-daily dosing maintains therapeutic effect; sustained improvement in lung function observed over 48 weeks. |
150 mg orally every 12 hours with fat-containing food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). For severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease, use with caution; reduce dose to 150 mg once daily. |
| Liver impairment | Child-Pugh Class A (mild): no dose adjustment. Child-Pugh Class B (moderate): reduce dose to 150 mg once daily. Child-Pugh Class C (severe): not recommended. |
| Pediatric use | Approved for children aged 6 months and older with certain CFTR mutations. Weight-based dosing: <5 kg: 25 mg every 12 hours; 5 to <8 kg: 25 mg every 12 hours; 8 to <10 kg: 50 mg every 12 hours; 10 to <14 kg: 75 mg every 12 hours; 14 to <25 kg: 100 mg every 12 hours; ≥25 kg: 150 mg every 12 hours. |
| Geriatric use | No specific geriatric dose adjustments; use caution due to age-related renal and hepatic function decline. Monitor renal function and consider renal adjustment if eGFR <30 mL/min/1.73 m². |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KALYDECO (KALYDECO).
| Breastfeeding | It is not known whether ivacaftor is excreted in human milk. In lactating rats, ivacaftor was present in milk; however, the clinical significance is unknown. The M/P ratio has not been determined in humans. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. |
| Teratogenic Risk | Kalydeco (ivacaftor) is classified as Pregnancy Category B. Animal studies at doses up to 5 times the human exposure showed no fetal harm. There are no adequate and well-controlled studies in pregnant women. However, because animal reproduction studies are not always predictive of human response, Kalydeco should be used during pregnancy only if clearly needed. Available postmarketing data do not suggest a drug-associated risk of major birth defects or miscarriage when used in the first trimester; risks in the second and third trimesters are unknown due to limited data. |
■ FDA Black Box Warning
None
| Serious Effects |
["Use with strong CYP3A inducers (e.g., rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort)."]
| Precautions | ["Hepatic adverse reactions including transaminase elevations; monitor ALT, AST, and bilirubin at baseline and every 3 months during first year, then annually.","Use with caution in patients with moderate to severe hepatic impairment (Child-Pugh class B or C); dose adjustment is recommended.","Risk of cataracts in pediatric patients; baseline and follow-up ophthalmological examinations are recommended.","QT interval prolongation with high doses or when coadministered with CYP3A inhibitors; monitor ECG and electrolytes.","Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) reduces exposure and is not recommended.","Use in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) is not recommended."] |
| Food/Dietary | Take with fat-containing food (e.g., eggs, butter, peanut butter, cheese) to enhance absorption. Avoid grapefruit juice and Seville oranges (e.g., in marmalade) as they are CYP3A inhibitors that can increase ivacaftor levels. |
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| Fetal Monitoring | No specific maternal fetal monitoring requirements have been established. However, standard prenatal care and monitoring for potential adverse effects, including liver function tests (ALT, AST) as recommended for all patients, should be continued. Regular monitoring of pulmonary function and infection status is advised due to underlying cystic fibrosis. |
| Fertility Effects | No human data on the effect of ivacaftor on fertility are available. In animal studies, ivacaftor did not affect fertility in male or female rats at doses up to 5 times the human exposure. However, fertility may be affected by underlying cystic fibrosis, which can cause reduced fertility in both men and women. |
| Clinical Pearls | Ivacaftor (KALYDECO) is a CFTR potentiator indicated for cystic fibrosis patients with G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutations. Monitor liver function tests (ALT, AST) at baseline, every 3 months for the first year, then annually; for patients with R117H, monitor LFTs every 6 months. Adjust dose for moderate hepatic impairment (Child-Pugh Class B): 150 mg once daily. Avoid use with strong CYP3A inducers (e.g., rifampin, St. John’s wort). Dose reduction to 150 mg once daily required with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin). Monitor for cataracts in pediatric patients. |
| Patient Advice | Take KALYDECO with fat-containing food (e.g., eggs, butter, peanut butter, cheese) to improve absorption. · Do not crush or chew the tablet; swallow whole. · If you have moderate liver problems, your dose may be reduced to one tablet daily. Take it with a fat-containing meal. · Avoid grapefruit or Seville oranges (e.g., in marmalade) while taking this medicine as they can increase drug levels. · Tell your doctor about all other medications, including over-the-counter drugs and herbal supplements. |