Ivacaftor

Class: Cystic Fibrosis Transmembrane Conductance Regulator Potentiators
Chemical Name: N-[2,4-Bis(1,1-dimethylethyl)-5-hydroxphenyl]-4-oxo-1,4-dihydroquinoline-3-carboxamide
Molecular Formula: C₂₄H₂₈N₂O₃
CAS Number: 873054-44-5
Brands: Kalydeco

Introduction

A cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.^{1 2 4 5 8 10 11 12}

Uses for Ivacaftor

Cystic Fibrosis

Treatment of cystic fibrosis in patients with G551D mutation in the CFTR gene (designated an orphan drug by FDA for this use).^{1 2 3 4 12}

Use an FDA-approved cystic fibrosis mutation test to detect presence of G551D mutation if genotype of patient unknown.¹

Not effective in patients with cystic fibrosis homozygous for F508del mutation in the CFTR gene.^{1 5} F508del mutation in the CFTR gene is most common mutation causing cystic fibrosis; patients homozygous for this mutation account for about 50% of disease population.⁵

Not studied in other patient populations with cystic fibrosis.¹

Ivacaftor Dosage and Administration

Administration

Oral Administration

Administer orally every 12 hours with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter) to increase systemic absorption of the drug.¹ (See Food under Pharmacokinetics.) Typical diet recommended for patients with cystic fibrosis satisfies requirement for fat-containing food.¹

Dosage

Pediatric Patients

Cystic Fibrosis

Oral

Children ≥6 years of age: 150 mg every 12 hours (total daily dosage of 300 mg) with fat-containing food.¹

Dosage adjustment necessary when used in conjunction with potent and moderate inhibitors of CYP3A.¹ (See Interactions.)

Adults

Cystic Fibrosis

Oral

150 mg every 12 hours (total daily dosage of 300 mg) with fat-containing food.¹

Dosage adjustment necessary when used in conjunction with potent and moderate inhibitors of CYP3A.¹ (See Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.¹ (See Special Populations under Pharmacokinetics.)

Moderate hepatic impairment (Child-Pugh class B, score 7–9): Reduce dosage to 150 mg once daily.¹

Severe hepatic impairment (Child-Pugh class C, score 10–15): Use with caution and at a dosage of 150 mg once daily or less frequently after weighing risks and benefits of therapy.¹

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.¹ (See Renal Impairment under Cautions.)

Severe renal impairment (Cl_cr ≤30 mL/minute) or end-stage renal disease (ESRD): Use with caution.¹

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Gender

Dosage adjustment not necessary based on gender.¹

Cautions for Ivacaftor

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Hepatic Effects

Elevated ALT or AST concentrations reported.¹

Assess serum ALT and AST concentrations prior to initiation of therapy, every 3 months during first year of therapy, and annually thereafter.¹

Closely monitor patients who develop increased ALT or AST concentrations until abnormalities resolve.¹

Interrupt therapy in patients with ALT or AST elevations >5 times ULN.¹ Following resolution, consider benefits and risks of resuming therapy.¹

Interactions with CYP3A Inducers

Concomitant use with potent CYP3A inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort [Hypericum perforatum]) substantially decreases systemic exposure of ivacaftor possibly reducing efficacy of the drug.¹ Concomitant use not recommended.¹ (See Specific Drugs and Foods under Interactions.)

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; likely distributed into human milk.¹ Use with caution in nursing women.¹

Pediatric Use

Safety and efficacy established in pediatric patients 6–17 years of age with cystic fibrosis and a G551D mutation in the CFTR gene.¹

Safety and efficacy not established in pediatric patients <6 years of age.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; cystic fibrosis is generally a disease of children and young adults.¹

Hepatic Impairment

Effect of mild hepatic impairment (Child-Pugh class A) on pharmacokinetics not studied but minimal effects expected; dosage adjustment not necessary.¹ (See Special Populations under Pharmacokinetics.)

Increased AUC in patients with moderate hepatic impairment (Child-Pugh class B, score 7–9); dosage reduction recommended.¹ (See Hepatic Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Effect of severe hepatic impairment (Child-Pugh class C, score 10–15) on pharmacokinetics not studied but increased AUC expected; use with caution and at reduced dosage after weighing risks and benefits of therapy.¹

Renal Impairment

Not studied in patients with mild, moderate, or severe renal impairment or in those with ESRD.¹

Dosage adjustment not necessary in patients with mild or moderate renal impairment because of minimal urinary excretion of drug and metabolites.¹ (See Elimination Route under Pharmacokinetics.)

Use with caution in patients with severe renal impairment (Cl_cr ≤30 mL/minute) or in those with ESRD.¹

Common Adverse Effects

Headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, dizziness.¹

Interactions for Ivacaftor

Principally metabolized by CYP3A.¹

Ivacaftor and its M1 metabolite are substrates of CYP3A (i.e., 3A4, 3A5).¹

Ivacaftor is a weak inhibitor of CYP3A, has potential to inhibit P-glycoprotein (P-gp) at therapeutic concentrations, and may inhibit CYP2C8 and 2C9.¹ M1 metabolite (but not M6), has potential to inhibit CYP3A and P-gp.¹

Ivacaftor and its M1 and M6 metabolites are not CYP inducers.¹

Drugs or Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Pharmacokinetic interaction (substantially increased systemic exposure [i.e., AUC] of ivacaftor).¹ If used concomitantly, reduce dosage of ivacaftor to 150 mg twice weekly.¹

Moderate CYP3A inhibitors: Pharmacokinetic interaction (increased systemic exposure [i.e., AUC] of ivacaftor).^{1 7} If used concomitantly, reduce dosage of ivacaftor to 150 mg once daily.¹

Potent CYP3A inducers: Pharmacokinetic interaction (substantially decreased systemic exposure [i.e., AUC] and possible reduced efficacy of ivacaftor).¹ Concomitant use not recommended.¹

Drugs Metabolized by Hepatic Microsomal Enzymes and/or P-glycoprotein (P-gp) Transport System

Substrates of CYP3A and/or P-gp: Potential pharmacokinetic interaction (increased systemic exposure; possible increased or prolonged therapeutic and adverse effects of substrate).¹ Use with caution and appropriate monitoring.^{1 7}

Substrates of CYP2C9: Potential pharmacokinetic interaction (increased systemic exposure; possible increased or prolonged therapeutic and adverse effects of substrate).^{1 7} Appropriate monitoring recommended.^{1 7}

Specific Drugs and Foods

Ivacaftor Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved at approximately 4 hours following oral administration in the fed state.¹

Steady-state plasma concentrations attained within 3–5 days.¹

Food

Systemic exposure increased approximately twofold to fourfold when administered with food containing fat.¹ (See Administration under Dosage and Administration.)

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied; increase in AUC expected to be less than twofold.¹

Moderate hepatic impairment (Child-Pugh class B, score 7–9): Similar peak plasma concentrations, but an approximately twofold increase in AUC, compared with healthy individuals matched for demographics.¹

Severe hepatic impairment (Child-Pugh class C, score 10–15): Effect on pharmacokinetics not studied; magnitude of increase in systemic exposure unknown, but expected to be substantially higher than that observed in patients with moderate hepatic impairment.¹ (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with mild, moderate, or severe renal impairment or in those with ESRD.¹ (See Renal Impairment under Cautions.)

Distribution

Extent

Distributed into milk in rats; likely distributed into human milk.¹

Plasma Protein Binding

Approximately 99% (mainly α1-acid glycoprotein, albumin).¹

Does not bind to human RBCs.¹

Elimination

Metabolism

Extensively metabolized in humans, principally by CYP3A.¹

Two major metabolites are M1 and M6.¹ M1 considered pharmacologically active (approximately one-sixth the potency of ivacaftor).¹ M6 not considered pharmacologically active (<one-fiftieth the potency of ivacaftor).¹

Ivacaftor and its M1 metabolite are substrates of CYP3A (i.e., 3A4, 3A5).¹ Ivacaftor is a weak inhibitor of CYP3A, has potential to inhibit P-gp at therapeutic concentrations, and may inhibit CYP2C8 and 2C9.¹ M1 metabolite (but not M6) has potential to inhibit CYP3A and P-gp.¹

Ivacaftor and its M1 and M6 metabolites are not CYP inducers.¹

Elimination Route

Mainly excreted in feces (87.8%) after metabolic conversion.¹ Approximately 65% of total dose excreted as M1 (22%) and M6 (43%) metabolites.¹

Ivacaftor and metabolites minimally excreted in urine (6.6% of total radioactivity recovered); negligible amounts of unchanged drug excreted in urine.¹

Half-life

Apparent terminal half-life: Approximately 12 hours.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

• Potentiator of CFTR protein, a chloride channel present at epithelial cell surface in multiple organs involved in salt and fluid transport.^{1 2 4 5 8 9 10 11 12}

• Mutations in the gene encoding the CFTR protein affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.^{2 4 8 9 10 11}

• G551D mutation causes mutated CFTR protein to reach the cell surface but not to activate normally resulting in low probability of channel opening and defective chloride transport.^{2 11}

• Ivacaftor facilitates increased chloride transport by potentiating probability of channel opening (or gating) of the G551D-CFTR protein.¹

Advice to Patients

• Importance of advising patients to read manufacturer's patient information before beginning treatment and each time prescription is refilled.¹

• Importance of taking ivacaftor with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter) to increase systemic absorption of the drug.¹

• Importance of advising patients to avoid grapefruit juice or food containing grapefruit or Seville oranges (e.g., orange marmalade) during ivacaftor therapy.^{1 13}

• Risk of elevated hepatic function tests.¹ Importance of monitoring hepatic function tests prior to initiation of ivacaftor therapy, every 3 months during first year of therapy, and annually thereafter.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.