Class: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
- Tablets, oral 150 mg
Potentiates epithelial cell chloride ion transport of defective (G551D mutant) cell-surface CFTR protein, improving the regulation of salt and water absorption and secretion in various tissues (eg, lung, GI tract).
Exposure increased approximately 2- to 4-fold when given with food containing fat. T max is approximately 4 h in the fed state.
Approximately 99% bound to plasma proteins, primarily to alpha-1 acid glycoprotein and albumin. The Vd is 353 L.
Extensively metabolized, primarily by CYP3A. Forms 2 major metabolites, M1 (active, one-sixth potency) and M6 (inactive).
Majority is eliminated in the feces (87.8%; 65% of dose as metabolites); minimal excretion as unchanged drug in urine. Terminal half-life is 12 h. Cl is 17.3 L/h.
Special PopulationsRenal Function Impairment
Not studied.Hepatic Function Impairment
The impact of mild hepatic impairment (Child-Pugh class A) on pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC 0-∞ is expected to be less than 2-fold. Patients with moderately impaired hepatic function (Child-Pugh class B, score 7 to 9) had similar ivacaftor C max , but an approximately 2-fold increase in ivacaftor AUC 0-∞ compared with healthy subjects. The impact of severe hepatic impairment (Child-Pugh class C, score 10 to 15) on the pharmacokinetics of ivacaftor has not been studied; however, the magnitude of increase in exposure in these patients is expected to be substantially higher than that observed in patients with moderate hepatic impairment.Gender
No dose adjustments are necessary based on gender.
Indications and Usage
For the treatment of cystic fibrosis in patients 6 y and older who have a G551D mutation in the CFTR gene.
None well documented.
Dosage and AdministrationAdults and Children 6 y and older
PO 150 mg every 12 h.Concomitant Therapy
When ivacaftor is being coadministered with strong CYP3A inhibitors (eg, ketoconazole), the dosage should be reduced to 150 mg twice a week. The dosage of ivacaftor should be reduced to 150 mg once daily when coadministered with moderate CYP3A inhibitors (eg, fluconazole).Hepatic Function Impairment
Reduce dosage to 150 mg once daily for patients with moderate hepatic impairment (Child-Pugh class B). Use with caution in patients with severe hepatic impairment (Child-Pugh class C) at a dosage of 150 mg once daily or less frequently.
- Administer with fat-containing food (eg, eggs, butter, peanut butter, cheese pizza).
- Avoid food containing grapefruit or Seville oranges.
Store between 59° and 86°F.
Drug InteractionsCYP2C9 substrates (eg, warfarin)
May increase exposure of the CYP2C9 substrate. Close monitoring is recommended.CYP3A substrates (eg, alprazolam, diazepam, midazolam, triazolam)
May increase exposure of the CYP3A substrates. Use with caution and monitor closely.Food
The exposure of ivacaftor increased approximately 2- to 4-fold when given with food containing fat; administer ivacaftor with fat-containing food. Avoid grapefruits or Seville oranges (CYP3A4 inhibitors).Moderate CYP3A inhibitors (eg, erythromycin, fluconazole)
May increase plasma levels and pharmacologic effects of ivacaftor. Reduce the dosage of ivacaftor to 150 mg once daily.P-glycoprotein substrates (eg, cyclosporine, digoxin, tacrolimus)
Ivacaftor and its M1 metabolite may inhibit P-glycoprotein (P-gp) and increase systemic exposure of drugs that are substrates of P-gp. Use with caution and monitor closely.Strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort)
May decrease plasma levels of ivacaftor, reducing the therapeutic effectiveness. Coadministration is not recommended.Strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole)
May increase plasma levels and pharmacologic effects of ivacaftor. Reduce the dosage of ivacaftor to 150 mg twice weekly.
Headache (24%); dizziness (9%); sinus headache (4% to 7%).
Rash (13%); acne (4% to 7%).
Oropharyngeal pain (22%); nasal congestion (20%); nasopharyngitis (15%); pharyngeal erythema, rhinitis (4% to 7%).
Abdominal pain (16%); diarrhea (13%); nausea (12%).
Increased AST, increased hepatic enzymes (4% to 7%).
Arthralgia, musculoskeletal chest pain, myalgia (4% to 7%).
Upper respiratory tract infection (22%); pleuritic pain, sinus congestion, wheezing (4% to 7%).
Bacteria in sputum, blood glucose increased (4% to 7%).
Assess ALT and AST prior to initiating treatment, every 3 mo during the first year of treatment, and annually thereafter.
Safety and efficacy in children younger than 6 y have not been established.
Use with caution in patients with severe renal impairment (CrCl 30 mL/min or less) or ESRD.
No dose adjustment is necessary for patients with mild hepatic impairment. Adjust dose in patients with moderate and severe impairment.
ALT and AST elevations have been reported.
- Inform patients that ivacaftor is best absorbed by the body when taken with fatty food (eg, eggs, butter, peanut butter, cheese pizza). A typical cystic fibrosis diet will satisfy this requirement.
- Advise patients to avoid food containing grapefruit or Seville oranges.
- Inform patients that elevations in LFTs have occurred during treatment with ivacaftor and that periodic evaluations of LFTs will be performed during therapy.
- Advise patients to inform their health care provider of all of all concomitant medications, vitamins, or dietary and herbal supplements.
- Advise patients that coadministration of ivacaftor with strong CYP3A inducers (eg, rifampin, St. John's wort) is not recommended, and coadministration with strong CYP3A inhibitors (eg, ketoconazole) or with moderate CYP3A inhibitors (eg, fluconazole) may require dose reduction.
Copyright © 2009 Wolters Kluwer Health.
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- Other brands: Kalydeco