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

Drug or Food	Interaction	Comments
Benzodiazepines (e.g., alprazolam, diazepam, midazolam, triazolam)	Midazolam: Increased midazolam AUC consistent with weak inhibition of CYP3A by ivacaftor1 7	Use with caution; monitor for adverse effects (e.g., prolonged or increased sedation, respiratory depression)1 7
Carbamazepine	Potential for substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Clarithromycin	Potential for substantially increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Cyclosporine	Possible increased cyclosporine systemic exposure; may increase or prolong effects of cyclosporine1	Use with caution; monitor appropriately (e.g., prolonged or increased immunosuppression)1 7
Desipramine	No effect on desipramine systemic exposure7	Dosage adjustment of desipramine not recommended1 7
Digoxin	Possible increased digoxin systemic exposure; may increase or prolong effects of digoxin1	Use with caution; monitor appropriately (e.g., digoxin concentrations)1 7
Erythromycin	Possible increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg once daily1
Fluconazole	Increased ivacaftor AUC1 7	Reduce dosage of ivacaftor to 150 mg once daily1
Grapefruit juice or food containing grapefruit or Seville oranges (e.g., orange marmalade)1 13	Possible increased ivacaftor systemic exposure1	Avoid grapefruit juice or food containing grapefruit or Seville oranges1 13
Itraconazole	Potential for substantially increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Ketoconazole	Substantially increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Oral contraceptives	No effect on systemic exposure of ivacaftor or its M1 or M6 metabolites, ethinyl estradiol, or norethindrone7	Dosage adjustment of ivacaftor or oral contraceptives not recommended1 7
Phenobarbital	Potential for substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Phenytoin	Potential for substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Posaconazole	Potential for substantially increased ivacaftor systemic exposure AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Rifabutin	Potential for substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Rifampin	Substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Rosiglitazone	No substantial effect on rosiglitazone systemic exposure7	Dosage adjustment of rosiglitazone not recommended1 7
St. John’s wort (Hypericum perforatum)	Potential for substantially decreased ivacaftor AUC; may reduce efficacy of ivacaftor1	Concomitant use not recommended1
Tacrolimus	Possible increased tacrolimus systemic exposure; may increase or prolong effects of tacrolimus1	Use with caution; monitor appropriately (e.g., prolonged or increased immunosuppression)1 7
Telithromycin	Potential for substantially increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Voriconazole	Potential for substantially increased ivacaftor AUC1	Reduce dosage of ivacaftor to 150 mg twice weekly1
Warfarin	Possible increased warfarin systemic exposure from ivacaftor's potential to inhibit CYP2C91 7	If concomitant use required, monitoring recommended (e.g., INR)1 7

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.

Ivacaftor

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	150 mg	Kalydeco	Vertex