Lumacaftor and Ivacaftor (Monograph)

Brand name: Orkambi
Drug class: Cystic Fibrosis Transmembrane Conductance Regulator Correctors
Chemical name: 3-[6-[[[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-3-methyl-2-pyridinyl]-benzoic acid
Molecular formula: C₂₄H₁₈F₂N₂O₅C₂₄H₂₈N₂O₃
CAS number: 936727-05-8

Medically reviewed by Drugs.com on Jan 31, 2023. Written by ASHP.

Introduction

Fixed combination containing lumacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] corrector) and ivacaftor (CFTR potentiator).

Uses for Lumacaftor and Ivacaftor

Cystic Fibrosis

Treatment of cystic fibrosis in patients ≥1 year of age who are homozygous for F508del mutation in the CFTR gene.

If the genotype of the patient is not known, use an FDA-approved cystic fibrosis mutation test to detect presence of F508del mutation on both alleles of the CFTR gene.

Efficacy and safety not established in patients with cystic fibrosis other than those homozygous for F508del mutation.

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

The 2018 Cystic Fibrosis Foundation pulmonary guideline specifically addresses the use of CFTR modulators in patients with cystic fibrosis. In patients with 2 copies of F508del, the guideline makes a strong recommendation for treatment with lumacaftor/ivacaftor in adults and pediatric patients ≥12 years of age with FEV₁ <90% of predicted and makes a conditional recommendation for treatment with lumacaftor/ivacaftor in adults and pediatric patients ≥12 years with FEV₁ >90% of predicted and in children 6–11 years of age.

Lumacaftor and Ivacaftor Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment with lumacaftor/ivacaftor based on whether they have 2 copies of the F508del mutation. If the patient's genotype is unknown, use an FDA-approved cystic fibrosis mutation test to detect presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions.

• Obtain baseline ALT, AST, and bilirubin concentrations.

• Baseline ophthalmologic examination recommended in pediatric patients.

Patient Monitoring

• Assess ALT, AST, and bilirubin concentrations every 3 months during the first year of treatment and annually thereafter. Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations; continue to monitor until abnormalities resolve.

• Monitor blood pressure periodically.

• Follow-up ophthalmologic examinations recommended in pediatric patients.

• Closely monitor patients with advanced liver disease after initiation of treatment and reduce dosage if necessary.

• Additional monitoring recommended during initiation of therapy in patients with FEV₁ <40% of predicted since clinical experience limited in these patients.

Administration

Oral Administration

Ivacaftor is 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).

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

Oral Granules

Mix entire contents of packet with 1 teaspoon (5 mL) of age-appropriate soft food (e.g., pureed fruits or vegetables, flavored yogurt or pudding, applesauce) or liquid (e.g., water, milk, breast milk, infant formula, juice) that is room temperature or below and consume completely within 1 hour. Each packet is for single use only.

Dosage

Available as fixed-combination tablets containing 100 mg of lumacaftor and 125 mg of ivacaftor or 200 mg of lumacaftor and 125 mg of ivacaftor.

Also available as fixed-combination granules in packets containing 75 mg of lumacaftor and 94 mg of ivacaftor, 100 mg of lumacaftor and 125 mg of ivacaftor, or 150 mg of lumacaftor and 188 mg of ivacaftor.

Pediatric Patients

Cystic Fibrosis

Oral

Children 1 to <6 years of age: Dosage based on age and weight (see Table 1).

Children 6–11 years of age: Lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

Children ≥12 years of age: Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

Dosage adjustment necessary when used concomitantly with strong inhibitors of CYP3A. (See Interactions.)

Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Oral

When initiating lumacaftor/ivacaftor tablets in children ≥12 years of age receiving a strong CYP3A inhibitor (e.g., itraconazole), the recommended dosage of the fixed combination is lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, followed by an increase in dosage to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

When initiating lumacaftor/ivacaftor tablets in children 6–11 years of age receiving a strong CYP3A inhibitor (e.g., itraconazole), the recommended dosage of the fixed combination is lumacaftor 100 mg/ivacaftor 125 mg once daily for 1 week, followed by an increase in dosage to lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

When initiating lumacaftor/ivacaftor oral granules in children 1 to <6 years of age receiving a strong CYP3A inhibitor, the recommended dosage of the fixed combination is 1 packet of lumacaftor/ivacaftor (at the recommended dose based on age and weight; see Table 1) every other day for 1 week, followed by an increase to the usual recommended daily dosage.

If lumacaftor/ivacaftor is interrupted for >1 week and then reinitiated in children ≥12 years of age receiving a strong CYP3A inhibitor, reduce dosage of the fixed combination to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to the recommended daily dosage of lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor is interrupted for >1 week and then reinitiated in children 6–11 years of age receiving a strong inhibitor of CYP3A, reduce dosage of the fixed combination to lumacaftor 100 mg/ivacaftor 125 mg once daily for 1 week, then increase to the recommended daily dosage of lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor is interrupted for >1 week and reinitiated in children 1 to <6 years of age receiving a strong inhibitor of CYP3A, reduce dosage of the fixed combination granules to 1 packet of lumacaftor/ivacaftor (at the recommended dose based on age and weight; see Table 1) every other day for 1 week, followed by an increase to the usual recommended daily dosage.

Dosage adjustment not needed if a CYP3A inhibitor is initiated in patients already receiving lumacaftor/ivacaftor.

Adults

Cystic Fibrosis

Oral

Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

Dosage adjustment necessary when used concomitantly with strong inhibitors of CYP3A. (See Interactions.)

Dosage Modification for Concomitant Use of Strong CYP3A Inhibitors

Oral

When initiating lumacaftor/ivacaftor tablets in patients receiving a strong CYP3A inhibitor (e.g., itraconazole), the recommended dosage of the fixed combination is lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, followed by an increase in dosage to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor is interrupted for >1 week and then reinitiated in patients receiving a strong CYP3A inhibitor, reduce dosage of the fixed combination to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to the recommended daily dosage of lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

Dosage adjustment not needed if a CYP3A inhibitor is initiated in patients already receiving lumacaftor/ivacaftor.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.

Moderate hepatic impairment (Child-Pugh class B) in adults and children ≥12 years of age: Lumacaftor 400 mg/ivacaftor 250 mg in the morning and lumacaftor 200 mg/ivacaftor 125 mg in the evening.

Moderate hepatic impairment (Child-Pugh class B) in children 6–11 years of age: Lumacaftor 200 mg/ivacaftor 250 mg in the morning and lumacaftor 100 mg/ivacaftor 125 mg in the evening.

Severe hepatic impairment (Child-Pugh class C) in adults and children ≥12 years of age: Use with caution and at a dosage of lumacaftor 200 mg/ivacaftor 125 mg twice daily (morning and evening), or less frequently, after weighing risks and benefits of therapy.

Severe hepatic impairment (Child-Pugh class C) in children 6–11 years of age: Use with caution and at a dosage of lumacaftor 100 mg/ivacaftor 125 mg twice daily (morning and evening), or less frequently, after weighing risks and benefits of therapy.

Moderate or severe hepatic impairment in children 1 to <6 years of age: Adjust dosage based on age, weight, and severity of hepatic impairment (see Table 2).

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.

Geriatric Patients

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

Cautions for Lumacaftor and Ivacaftor

Contraindications

• None.

Warnings/Precautions

Hepatic Effects

Worsening hepatic function (e.g., hepatic encephalopathy) reported in patients with advanced liver disease. Hepatic decompensation, including liver failure leading to death, reported in patients with preexisting cirrhosis with portal hypertension. Use with caution in patients with advanced liver disease and only if benefits expected to outweigh risks. If used in such patients, closely monitor after initiation of therapy and reduce dosage.

Serious adverse effects related to elevated ALT or AST concentrations reported, sometimes associated with elevated bilirubin concentrations. Assess ALT, AST, and bilirubin concentrations prior to initiation of therapy, every 3 months during the first year, and annually thereafter. Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations; continue to monitor until abnormalities resolve.

Interrupt therapy in patients with ALT or AST elevations >5 times ULN or in patients with ALT or AST elevations >3 times ULN when associated with bilirubin elevations >2 times ULN. Following resolution of ALT or AST elevations, consider benefits and risks of resuming therapy.

Respiratory Effects

Adverse respiratory effects (e.g., chest discomfort, dyspnea, abnormal respiration) observed. Such effects resulted in drug discontinuance and can be serious, especially in patients with advanced lung disease. Limited clinical experience in patients with FEV₁ <40% of predicted. Additional monitoring of such patients recommended during initiation of therapy.

Hypertensive Effects

Hypertensive effects reported in some patients. Monitor BP periodically in all patients during therapy.

Interactions with CYP3A Substrates and Inducers

Concomitant use with CYP3A substrates may decrease systemic exposure of such substrate drugs and may decrease therapeutic effect. Concomitant use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index not recommended.

Concomitant use with hormonal contraceptives may substantially decrease systemic exposure of hormonal contraceptives resulting in reduced effectiveness. Incidence of menstrual abnormalities (e.g., amenorrhea, dysmenorrhea, menorrhagia, irregular menstruation) increased. Avoid concomitant use of hormonal contraceptives (e.g., oral, injectable, transdermal, implantable forms); not considered reliable method of contraception when used concomitantly.

Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort [Hypericum perforatum]) substantially decreases systemic exposure of ivacaftor, possibly reducing efficacy of lumacaftor/ivacaftor. Concomitant use with strong CYP3A inducers not recommended.

Ocular Effects

Noncongenital lens opacities reported in pediatric patients receiving lumacaftor/ivacaftor or ivacaftor monotherapy. Baseline and follow-up ophthalmologic examinations recommended in pediatric patients receiving lumacaftor/ivacaftor.

Specific Populations

Pregnancy

Limited data available regarding use of lumacaftor/ivacaftor in fixed combination or its individual components in pregnant women. Evidence of teratogenicity or adverse effects on fetal development not observed in animals receiving lumacaftor or ivacaftor. No animal data available with concomitant use of lumacaftor and ivacaftor.

Placental transfer of lumacaftor or ivacaftor observed in pregnant rats and rabbits.

Use during pregnancy only when clearly needed.

Lactation

Distributed into milk in rats; not known whether distributed into human milk.

Consider developmental and health benefits of breast-feeding and clinical importance of therapy to the woman when deciding whether to use caution or discontinue nursing. Effects of lumacaftor/ivacaftor in fixed combination on nursing infants or milk production unknown.

Pediatric Use

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

Efficacy in patients 1–11 years of age extrapolated from efficacy results in patients ≥12 years of age with support from population pharmacokinetic analyses demonstrating similar drug exposures in patients 1–11 years of age and those ≥12 years of age. Safety profile in patients 1–11 years of age similar to that observed in patients ≥12 years 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

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied; dosage adjustment not necessary.

Moderate hepatic impairment (Child-Pugh class B): Increased exposure; dosage reduction recommended.

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied, but increased exposure 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.

Mild or moderate renal impairment: Dosage adjustment not necessary.

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

Common Adverse Effects

Adverse effects (≥5%): Dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, abnormal respiration, increased CPK concentrations, rash, flatulence, rhinorrhea, influenza.

Drug Interactions

Lumacaftor is a strong inducer of CYP3A; has potential to induce CYP2B6, 2C8, 2C9, and 2C19; and may inhibit CYP2C8 and 2C9. Has potential to inhibit and induce P-glycoprotein (P-gp).

Ivacaftor is a CYP3A4 and 3A5 substrate, may inhibit CYP2C9, and is a weak inhibitor of P-gp.

Net effect of lumacaftor/ivacaftor in fixed combination is strong CYP3A induction.

CYP Substrates

CYP3A substrate: Possible pharmacokinetic interaction (decreased exposure and efficacy of substrate drug). Concomitant use with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index not recommended.

CYP2B6, 2C8, 2C9, and 2C19 substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).

Strong CYP3A Inhibitors

Pharmacokinetic interaction (possible increased ivacaftor exposure). Because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation. Concomitant use not recommended; consider alternative therapy.

If concomitant use required, dosage adjustment not necessary if strong CYP3A inhibitor initiated in patient already receiving lumacaftor/ivacaftor.

If lumacaftor/ivacaftor initiated in children 1 to <6 years of age already receiving a strong CYP3A inhibitor, reduce dosage to 1 packet of lumacaftor/ivacaftor (at the recommended dose based on age and weight; see Table 1) every other day for 1 week, then increase to the usual recommended daily dosage.

If lumacaftor/ivacaftor initiated in children 6–11 years of age already receiving a strong CYP3A inhibitor, reduce dosage to lumacaftor 100 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor initiated in adults and children ≥12 years of age already receiving a strong CYP3A inhibitor, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in children 1 to <6 years of age receiving a strong CYP3A inhibitor, reduce dosage to 1 packet of lumacaftor/ivacaftor (at the recommended dose based on age and weight; see Table 1) every other day for 1 week, then increase to the usual recommended daily dosage.

If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in children 6–11 years of age receiving a strong CYP3A inhibitor, reduce dosage to lumacaftor 100 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.

If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in adults and children ≥12 years of age receiving a strong CYP3A inhibitor, reduce dosage to lumacaftor 200 mg/ivacaftor 125 mg once daily for 1 week, then increase to lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.

CYP3A Inducers

Strong CYP3A inducers: Pharmacokinetic interaction (decreased ivacaftor exposure; may reduce efficacy of lumacaftor/ivacaftor). Concomitant use not recommended.

Moderate or weak CYP3A inducers: Dosage adjustment not necessary.

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).

Specific Drugs

Lumacaftor and Ivacaftor Pharmacokinetics

Absorption

Bioavailability

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

Steady-state concentrations achieved approximately 7 days after twice-daily oral administration.

Lumacaftor: Systemic exposure increases with accumulation ratio of approximately 1.9.

Ivacaftor: Steady-state exposure lower than that observed on first day of administration resulting from CYP3A induction by lumacaftor.

Food

Administration of single dose with food containing fat resulted in systemic exposures of lumacaftor and ivacaftor approximately twofold and threefold higher, respectively, when compared with administration in fasting state.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied.

Moderate hepatic impairment (Child-Pugh class B): AUCs and peak plasma concentrations of lumacaftor and ivacaftor increased by 50 and 30%, respectively, for both drugs when compared with healthy individuals.

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; not known whether distributed into human milk.

Plasma Protein Binding

Lumacaftor: Approximately 99% (mainly albumin).

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

Elimination

Metabolism

Lumacaftor: Not extensively metabolized in humans; principally metabolized by oxidation and glucuronidation.

Ivacaftor: Extensively metabolized in humans, principally by CYP3A. Two major metabolites are M1 and M6.

Elimination Route

Lumacaftor: Mainly excreted unchanged in feces (51%). Lumacaftor and metabolites minimally excreted in urine (8.6%).

Ivacaftor: Mainly excreted in feces (87.8%) after metabolic conversion. Ivacaftor and metabolites minimally excreted in urine (6.6%).

Half-life

Lumacaftor: Approximately 26 hours in patients with cystic fibrosis.

Ivacaftor: Approximately 9 hours in healthy individuals.

Stability

Storage

Oral

Granules

20–25°C (may be exposed to 15–30°C).

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Lumacaftor/ivacaftor in fixed combination contains 2 drugs acting directly on CFTR protein, a chloride channel present at epithelial cell surface in multiple organs involved in salt and fluid transport. Lumacaftor is a CFTR corrector; ivacaftor is a CFTR potentiator.

• Mutations in the gene encoding CFTR affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.

• F508del mutation causes CFTR protein misfolding resulting in defective cellular processing and trafficking, which targets CFTR for degradation and reduces quantity of CFTR at cell surface. Small amount of F508del-CFTR reaching cell surface is less stable and has low probability of channel opening (defective gating activity).

• Lumacaftor improves conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to cell surface.

• Ivacaftor facilitates increased chloride transport by potentiating the probability of channel opening (or gating) of the CFTR protein at cell surface.

Advice to Patients

• Importance of advising patients to read the manufacturer's patient information.

• Importance of taking lumacaftor/ivacaftor with fat-containing food (e.g., butter, cheese pizza, eggs, peanut butter).

• Importance of advising patients to administer oral granules by mixing entire contents of packet with 1 teaspoon (5 mL) of age-appropriate soft food (e.g., pureed fruits or vegetables, flavored yogurt or pudding, applesauce) or liquid (e.g., water, milk, breast milk, infant formula, juice) that is room temperature or below and consuming completely within 1 hour.

• If a dose of lumacaftor/ivacaftor is missed by <6 hours, take the dose with fat-containing food as soon as it is remembered. If a dose is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time. Do not take a double dose to make up for a missed dose.

• Importance of advising patients to avoid grapefruit products during the first week after initiation of lumacaftor/ivacaftor therapy.

• Risk of worsening hepatic function in patients with advanced liver disease. Importance of dosage reduction and close monitoring in such patients after initiation of lumacaftor/ivacaftor.

• Importance of dosage reduction in patients with moderate hepatic impairment (Child-Pugh class B). Importance of considering risks and benefits of lumacaftor/ivacaftor in patients with severe hepatic impairment (Child-Pugh class C) prior to initiating therapy; importance of dosage reduction in such patients.

• Risk of elevated liver function tests. Importance of monitoring liver function tests prior to initiation of lumacaftor/ivacaftor, every 3 months during the first year of therapy, and annually thereafter. Importance of advising patients to contact clinician if symptoms of hepatotoxicity occur.

• Risk of chest discomfort, dyspnea, and abnormal respiration, especially in patients with advanced lung disease; importance of contacting clinician if such symptoms occur. Importance of additional monitoring during initiation of lumacaftor/ivacaftor in patients with FEV₁ <40% of predicted.

• Risk of increased BP. Importance of informing patients that periodic monitoring of BP during therapy is recommended. Importance of contacting clinician if hypertension develops or worsens.

• Ocular abnormalities (i.e., cataracts) observed in pediatric patients receiving lumacaftor/ivacaftor. Importance of baseline and follow-up ophthalmologic examination in pediatric patients receiving lumacaftor/ivacaftor. Importance of advising pediatric patients and their caregivers to contact clinician if visual changes occur.

• 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). Concomitant use of lumacaftor/ivacaftor with sensitive CYP3A substrates, inhibitors, and inducers requires particular attention. (See Interactions.)

• Risk of menstrual abnormalities; avoid concomitant use of hormonal contraceptives. Hormonal contraceptives not considered a reliable method of contraception when used concomitantly. Importance of advising patients to use alternative methods of contraception.

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

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

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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Frequently asked questions

• How do you take Orkambi?
• What is the difference between Symdeko and Orkambi?

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