Ivacaftor (Monograph)

Brand name: Kalydeco
Drug 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

Medically reviewed by Drugs.com on Nov 28, 2022. Written by ASHP.

Introduction

A cystic fibrosis transmembrane conductance regulator (CFTR) potentiator.

Uses for Ivacaftor

Cystic Fibrosis

Treatment of cystic fibrosis in patients ≥4 months of age who have one mutation in the CFTR gene that is responsive to ivacaftor based on in vitro assay and/or clinical data.

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

Designated an orphan drug by FDA for treatment of cystic fibrosis.

Guidelines from the Cystic Fibrosis Foundation give conditional recommendations for use of ivacaftor as a treatment option in adults and pediatric patients with cystic fibrosis.

The 2018 Cystic Fibrosis Foundation pulmonary guideline specifically addresses the use of CFTR modulators in patients with cystic fibrosis. For adults and children ≥6 years of age with cystic fibrosis due to gating mutations other than G551D or R117H, the guideline makes a conditional recommendation for use of ivacaftor. For patients with the R117H mutation, the guideline makes a conditional recommendation for ivacaftor use in adults ≥18 years of age and in children 6–17 years of age with an FEV₁ <90% predicted.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide recommendations for identifying patients who are eligible and could benefit from ivacaftor treatment based on CFTR genotyping. For the most recent updates, consult the Clinical Pharmacogenetics Implementation Consortium (CPIC) website at [Web]

Ivacaftor Dosage and Administration

General

Pretreatment Screening

Select patients for treatment with ivacaftor based on presence of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to ivacaftor based on clinical and/or in vitro assay data. Consult the prescribing information for full details of CFTR gene mutations that produce CFTR protein and are responsive to ivacaftor.
If a patient's genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation along with bi-directional sequencing for verification when recommended by the mutation test instructions.
A baseline ophthalmological examination is recommended in pediatric patients.

Patient Monitoring

Monitor liver function tests (ALT and AST) prior to initiating ivacaftor treatment and every 3 months during the first year of treatment, then annually thereafter as clinically indicated. For patients with a history of transaminase elevations, consider more frequent monitoring of liver function tests. Closely monitor patients who develop elevations of transaminase levels until the abnormalities resolve.
Follow-up ophthalmological examinations are recommended in pediatric patients during treatment as clinically indicated.

Administration

Oral Administration

Commercially available as tablets (for administration in adults and pediatric patients ≥6 years of age) or oral granules (for administration in pediatric patients 5 months to less than 6 years of age).

Tablets: Administer orally every 12 hours with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter, whole-milk dairy products [e.g., cheese, yogurt, whole milk, breast milk or infant formula]) to increase systemic absorption of the drug. Typical diet recommended for patients with cystic fibrosis satisfies requirement for fat-containing food.

Oral granules: Administer orally every 12 hours with age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, breast milk or infant formula, juice, water, milk, yogurt). Each dose is administered just before or after consumption of fat-containing food.

Preparation of oral granules: Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of an age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, juice) and completely consume. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for 1 hour, and therefore should be consumed during this period. Administer each dose just before or just after fat-containing food.

If a dose of ivacaftor is missed within 6 hours of time of usual administration, take the dose with fat containing food as soon as possible. If more than 6 hours have passed, missed dose should not be taken; take the dose at the next scheduled time.

Dosage

Pediatric Patients

Cystic Fibrosis

Oral

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

Oral

Pediatric patients 4 months to <6 years of age: weight-based dosing (see Table 1). Administer dose just before or after consumption of fat-containing food.

Ivacaftor is not recommended for use in patients under 4 months of age

Ivacaftor is not recommended for use in patients aged 4 months to <6 months with hepatic impairment and/or taking concomitant moderate or strong CYP3A inhibitors

Table 1: Dosage of Oral Granules by Body Weight in Pediatric Patients 4 Months to Less Than 6 Years of Age1
Age	Body Weight (kg)	Ivacaftor Dosage	Total Daily Dosage
4 months to <6 months	≥5 kg	One 25 mg packet every 12 hours	50 mg/day
≥6 months to <6 years	5 kg to <7 kg	One 25 mg packet every 12 hours	50 mg/day
≥6 months to <6 years	7 kg to <14 kg	One 50 mg packet every 12 hours	100 mg/day
≥6 months to <6 years	≥14 kg	One 75 mg packet every 12 hours	150 mg/day

Adults

Cystic Fibrosis

Oral

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

Dosage Modification for Concomitant Use of CYP3A Inhibitors in Patients ≥6 Months of Age

When coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) reduce dosage of ivacaftor to one tablet or one packet of oral granules twice weekly.

When co-administered with moderate CYP3A inhibitors (e.g., fluconazole), reduced dosage of ivacaftor to one tablet or one packet of granules once daily.

Concomitant use of moderate or strong CYP3A inhibitors not recommended in patients <6 months of age.

Dosage Modification for Toxicity

Hepatic Toxicity

Interrupt ivacaftor dosing if elevation in serum ALT or AST concentrations exceeding 5 times the ULN occurs. Consider benefits versus risk of resuming ivacaftor after resolution of transaminase levels to baseline.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A) in patients ≥6 months of age: Dosage adjustment not necessary.

Moderate hepatic impairment (Child-Pugh class B) in patients ≥6 months of age: Reduce dosage to one tablet or one packet of oral granules once daily.

Severe hepatic impairment (Child-Pugh class C) in patients ≥6 months of age: Use with caution and at a reduced dosage (one tablet or one packet of oral granules once daily or less frequently) after weighing risks and benefits of therapy.

Ivacaftor treatment is not recommended in patients <6 months of age with hepatic impairment.

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.

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

Geriatric Patients

No specific dosage recommendations.

Cautions for Ivacaftor

Contraindications

Manufacturer states none known.

Warnings/Precautions

Hepatic Effects

Elevated ALT or AST concentrations reported.

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

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

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

Concomitant Use with CYP3A Inducers

Concomitant use with strong 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. Concomitant use not recommended.

Cataracts

Non-congenital lens opacities and cataracts reported in pediatric patients.

Ophthalmological examinations recommended in pediatric patients at baseline and follow-up during treatment as clinically indicated.

Specific Populations

Pregnancy

Limited human data from clinical trials and postmarketing reports of ivacaftor use in pregnant women.

Ivacaftor administration in animal studies did not have teratogenicity or adverse effects on fetal development.

Lactation

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

Pediatric Use

Safety and efficacy established in pediatric patients 4 months to 17 years of age with cystic fibrosis and one mutation in the CFTR gene that is responsive to ivacaftor based on clinical and/or in vitro assay data.

Safety and efficacy not established in pediatric patients <4 months of age.

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.

Hepatic Impairment

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

Increased AUC in patients with moderate hepatic impairment (Child-Pugh class B); dosage reduction recommended.

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

Renal Impairment

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

Dosage adjustment not necessary in patients with mild or moderate renal impairment because of minimal urinary excretion of drug and metabolites.

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

Common Adverse Effects

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

Interactions for Ivacaftor

Principally metabolized by CYP3A.

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

Ivacaftor is a weak inhibitor of CYP3A, has potential to inhibit P-glycoprotein (P-gp) at therapeutic concentrations, and may inhibit CYP2C9. M1 metabolite (but not M6), has potential to inhibit CYP3A and P-gp.

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes or Transport Proteins

Strong CYP3A inhibitors: Pharmacokinetic interaction (substantially increased AUC of ivacaftor). If used concomitantly, reduce dosage of ivacaftor.

Moderate CYP3A inhibitors: Pharmacokinetic interaction (increased AUC of ivacaftor). If used concomitantly, reduce dosage of ivacaftor.

Strong CYP3A inducers: Pharmacokinetic interaction (substantially decreased AUC and possible reduced efficacy of ivacaftor). Concomitant use not recommended.

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

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

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Potential decreased AUC and efficacy of ivacaftor	Concomitant use not recommended
Azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)	Concomitant administration with ketoconazole, a potent CYP3A inhibitor, substantially increased AUC of ivacaftor Concomitant administration with fluconazole, a moderate CYP3A inhibitor, also increased AUC of ivacaftor, but a lesser extent	Reduce dosage of ivacaftor when used concomitantly
Benzodiazepines (alprazolam, diazepam, midazolam, triazolam)	Concomitant administration of ivacaftor with midazolam, a sensitive CYP3A substrate, increased systemic exposure of midazolam	Caution and adequate monitoring for benzodiazepine-related adverse effects (e.g., prolonged or increased sedation or respiratory depression) is recommended when ivacaftor is used concomitantly with alprazolam, diazepam, midazolam, or triazolam
Ciprofloxacin	No effect on ivacaftor exposure	No dose adjustment is necessary
Cyclosporine	Possible increased systemic exposure of cyclosporine	Caution advised with concomitant use; appropriate monitoring recommended
Digoxin	Possible increased systemic exposure of digoxin	Caution advised with concomitant use; appropriate monitoring recommended
Glimepiride	Possible increased systemic exposure of glimepiride	Use concomitantly with caution
Glipizide	Possible increased systemic exposure of glipizide	Use concomitantly with caution
Grapefruit juice	Possible increased systemic exposure of ivacaftor	Avoid use of grapefruit juice or foods containing grapefruit
Macrolide antibiotics (clarithromycin, erythromycin)	Potential for substantially increased AUC of ivacaftor	Reduce dosage of ivacaftor when used concomitantly
Oral contraceptives	Concomitant administration with an oral contraceptive containing ethinyl estradiol and norethindrone did not affect systemic exposures of ivacaftor or its metabolites, ethinyl estradiol, or norethindrone	Dosage adjustment of ivacaftor or oral contraceptives not necessary
Rifabutin	Potential decreased AUC and efficacy of ivacaftor	Concomitant use not recommended
Rifampin	Concomitant administration with rifampin, a potent CYP3A inducer, substantially decreased AUC of ivacaftor; potential reduced efficacy of ivacaftor	Concomitant use not recommended
St. John's wort (Hypericum perforatum)	Potential decreased AUC and efficacy of ivacaftor	Concomitant use not recommended
Tacrolimus	Possible increased systemic exposure of tacrolimus	Caution advised with concomitant use; appropriate monitoring recommended
Telithromycin	Potential for substantially increased AUC of ivacaftor	Reduce dosage of ivacaftor when used concomitantly
Warfarin	Concomitant administration with warfarin, a CYP2C9 substrate, may increase systemic exposure of warfarin	Use concomitantly with caution with INR monitoring

Ivacaftor Pharmacokinetics

Absorption

Bioavailability

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

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

Food

Systemic exposure increased approximately twofold to fourfold when administered with food containing fat. Effect of food is similar for tablets and granules.

Special Populations

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

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

Severe hepatic impairment (Child-Pugh class C): 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.

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

Distribution

Extent

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

Plasma Protein Binding

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

Does not bind to human RBCs.

Elimination

Metabolism

Extensively metabolized in humans, principally by CYP3A.

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

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

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

Elimination Route

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

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

Half-life

Apparent terminal half-life: Approximately 12 hours.

Stability

Storage

Oral

Tablets

Store at 20–25°C (excursions permitted between 15–30°C).

Actions

Potentiator of CFTR protein, a chloride channel present at epithelial cell surface in multiple organs involved in salt and fluid transport.
Mutations in the gene encoding the CFTR protein affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.
CFTR 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.
Ivacaftor facilitates increased chloride transport by potentiating probability of channel opening (or gating) of the CFTR protein.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (patient information.
Inform patients that ivacaftor tablets are best absorbed when taken with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter). A typical cystic fibrosis diet will satisfy this requirement.
Inform patients and caregivers that ivacaftor oral granules should be mixed with one teaspoon (5 mL) of age-appropriate soft food or liquid (e.g., pureed fruits or vegetables, yogurt, applesauce, water, breast milk, infant formula, milk, or juice) and completely consumed to ensure delivery of the entire dose. Food or liquid should be at or below room temperature. Once mixed, the product has been shown to be stable for 1 hour, and therefore should be consumed during this period. Inform patients that ivacaftor is best absorbed when taken with food that contains fat; therefore, the oral granules should be taken just before or just after consuming food that contains fat (e.g., eggs, butter, peanut butter, cheese pizza, whole-milk dairy products). A typical cystic fibrosis diet will satisfy this requirement.
Inform patients that if a dose of ivacaftor is missed within 6 hours of the time it is usually taken, to take the prescribed dose with fat-containing food as soon as possible. If more than 6 hours have passed, the missed dose should NOT be taken, and the patient should resume the usual dosing schedule.
Advise patients of important drug interactions with CYP3A inducers and inhibitors. Treatment with ivacaftor is not recommended in patients 4 months to less than 6 months of age who are taking concomitant moderate or strong CYP3A inhibitors. Advise patients to avoid grapefruit juice or food containing grapefruit during ivacaftor therapy.
Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving ivacaftor. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating the drug.
Assess whether patients have liver impairment. Dosage adjustment or avoidance of treatment may be required based on the degree of impairment.
Inform patients of the risk of elevated hepatic function tests and the importance of monitoring hepatic function tests prior to initiation of ivacaftor therapy, every 3 months during the first year of therapy, and annually thereafter. More frequent monitoring of liver function tests should be considered in patients with a history of transaminase elevations.
Advise patients to inform their clinician 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).
Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Advise patients of other important precautionary information. (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 is available only from designated specialty distributors and pharmacies. The manufacturer should be contacted for additional information.