Ivacaftor

Pronunciation: EYE-va-KAF-tor
Class: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator

Trade Names

Kalydeco
- Tablets, oral 150 mg

Pharmacology

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).

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Pharmacokinetics

Absorption

Exposure increased approximately 2- to 4-fold when given with food containing fat. T _max is approximately 4 h in the fed state.

Distribution

Approximately 99% bound to plasma proteins, primarily to alpha-1 acid glycoprotein and albumin. The Vd is 353 L.

Metabolism

Extensively metabolized, primarily by CYP3A. Forms 2 major metabolites, M1 (active, one-sixth potency) and M6 (inactive).

Elimination

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 Populations

Renal 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.

Contraindications

None well documented.

Dosage and Administration

Adults 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.

General Advice

• Administer with fat-containing food (eg, eggs, butter, peanut butter, cheese pizza).
• Avoid food containing grapefruit or Seville oranges.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CYP2C9 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.

Adverse Reactions

CNS

Headache (24%); dizziness (9%); sinus headache (4% to 7%).

Dermatologic

Rash (13%); acne (4% to 7%).

EENT

Oropharyngeal pain (22%); nasal congestion (20%); nasopharyngitis (15%); pharyngeal erythema, rhinitis (4% to 7%).

GI

Abdominal pain (16%); diarrhea (13%); nausea (12%).

Hepatic

Increased AST, increased hepatic enzymes (4% to 7%).

Musculoskeletal

Arthralgia, musculoskeletal chest pain, myalgia (4% to 7%).

Respiratory

Upper respiratory tract infection (22%); pleuritic pain, sinus congestion, wheezing (4% to 7%).

Miscellaneous

Bacteria in sputum, blood glucose increased (4% to 7%).

Precautions

Monitor Assess ALT and AST prior to initiating treatment, every 3 mo during the first year of treatment, and annually thereafter.

Pregnancy

Category B.

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 6 y have not been established.

Renal Function

Use with caution in patients with severe renal impairment (CrCl 30 mL/min or less) or ESRD.

Hepatic Function

No dose adjustment is necessary for patients with mild hepatic impairment. Adjust dose in patients with moderate and severe impairment.

Hepatic effects

ALT and AST elevations have been reported.

Overdosage

Symptoms

Diarrhea, dizziness.

Patient Information

• 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.

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