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Orkambi

Generic Name: Lumacaftor and Ivacaftor
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

Introduction

Fixed combination containing lumacaftor (cystic fibrosis transmembrane conductance regulator [CFTR] corrector) and ivacaftor (CFTR potentiator).1 4 5 6 7 8

Uses for Orkambi

Cystic Fibrosis

Lumacaftor/ivacaftor in fixed combination: Treatment of cystic fibrosis in patients homozygous for F508del mutation in the CFTR gene (designated an orphan drug by FDA for this use).1 2 3 9

Use FDA-approved cystic fibrosis mutation test to detect presence of F508del mutation on both alleles of the CFTR gene if genotype is unknown.1

Efficacy and safety not established in patients with cystic fibrosis other than those homozygous for F508del mutation.1

Orkambi Dosage and Administration

Administration

Oral Administration

Administer orally every 12 hours with fat-containing food (e.g., eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole milk dairy products) 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

Available as fixed-combination tablets containing 200 mg of lumacaftor and 125 mg of ivacaftor.1

Pediatric Patients

Cystic Fibrosis
Oral

Children ≥12 years of age: Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.1

Dosage adjustment necessary when used concomitantly with potent inhibitors of CYP3A.1 (See Interactions.)

Adults

Cystic Fibrosis
Oral

Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.1

Dosage adjustment necessary when used concomitantly with potent inhibitors of CYP3A.1 (See Interactions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Dosage adjustment not necessary.1

Moderate hepatic impairment (Child-Pugh class B): Lumacaftor 400 mg/ivacaftor 250 mg in the morning and lumacaftor 200 mg/ivacaftor 125 mg in the evening.1

Severe hepatic impairment (Child-Pugh class C): Use with caution and at a dosage of lumacaftor 200 mg/ivacaftor 125 mg twice daily (morning and evening), or less, after weighing risks and benefits of therapy.1

Renal Impairment

Mild to moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment or end-stage renal disease (ESRD): Caution advised.1

Geriatric Patients

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

Cautions for Orkambi

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Hepatic Effects

Worsening hepatic function (e.g., hepatic encephalopathy) reported in patients with advanced liver disease.1 Use with caution in patients with advanced liver disease and only if benefits expected to outweigh risks.1 If used in such patients, closely monitor after initiation of therapy and reduce dosage.1

Serious adverse effects related to elevated ALT or AST concentrations reported, sometimes associated with elevated bilirubin concentrations.1 Assess ALT, AST, and bilirubin concentrations prior to initiation of therapy, every 3 months during the first year, and annually thereafter.1 Closely monitor patients who develop increased ALT, AST, or bilirubin concentrations; continue to monitor until abnormalities resolve.1

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.1 Following resolution of ALT or AST elevations, consider benefits and risks of resuming therapy.1

Respiratory Effects

Adverse respiratory effects (e.g., chest discomfort, dyspnea, abnormal respiration) observed.1 Limited clinical experience in patients with FEV1 <40% of predicted.1 Additional monitoring of such patients recommended during initiation of therapy.1

Hypertensive Effects

Hypertensive effects reported in some patients.1 Monitor BP periodically in all patients during therapy.1

Interactions with CYP3A Substrates and Inducers

Concomitant use with CYP3A substrates may decrease systemic exposure of such substrate drugs and may decrease therapeutic effect.1 Concomitant use with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index not recommended.1

Concomitant use with hormonal contraceptives may substantially decrease systemic exposure of hormonal contraceptives resulting in reduced effectiveness.1 Incidence of menstrual abnormalities (e.g., amenorrhea, dysmenorrhea, menorrhagia, irregular menstruation) increased.1 Avoid concomitant use of hormonal contraceptives (e.g., oral, injectable, transdermal, implantable forms); not considered reliable method of contraception when used concomitantly.1

Concomitant use with potent CYP3A inducers (e.g., rifampin, St. John's wort [Hypericum perforatum]) substantially decreases systemic exposure of ivacaftor, possibly reducing efficacy of lumacaftor/ivacaftor.1 Concomitant use with potent CYP3A inducers not recommended.1 (See Interactions.)

Ocular Effects

Noncongenital lens opacities reported in pediatric patients receiving ivacaftor monotherapy.1 Baseline and follow-up ophthalmologic examinations recommended in pediatric patients receiving lumacaftor/ivacaftor.1

Specific Populations

Pregnancy

Limited data available regarding use of lumacaftor/ivacaftor in fixed combination or its individual components in pregnant women.1 Evidence of teratogenicity or adverse effects on fetal development not observed in animals receiving lumacaftor or ivacaftor.1 No animal data available with concomitant use of lumacaftor and ivacaftor.1 Placental transfer of lumacaftor or ivacaftor observed in pregnant rats and rabbits.1 Use during pregnancy only when clearly needed.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 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.1 Effects of lumacaftor/ivacaftor in fixed combination on nursing infants or milk production unknown.1

Pediatric Use

Safety and efficacy not established in pediatric patients <12 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

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied; dosage adjustment not necessary.1 (See Special Populations under Pharmacokinetics.)

Moderate hepatic impairment (Child-Pugh class B): Increased exposure; dosage reduction recommended.1 (See Hepatic Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Severe hepatic impairment (Child-Pugh class C): Effect on pharmacokinetics not studied, but increased exposure expected;1 use with caution and at reduced dosage after weighing risks and benefits of therapy.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

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

Mild or moderate renal impairment: Dosage adjustment not necessary.1

Severe renal impairment (Clcr ≤30 mL/minute) or ESRD: Use with caution.1

Common Adverse Effects

Dyspnea,1 3 nasopharyngitis,1 3 nausea,1 3 diarrhea,1 3 upper respiratory tract infection,1 3 fatigue,1 abnormal respiration,1 3 increased CPK concentrations,1 rash,1 flatulence,1 rhinorrhea,1 influenza.1

Interactions for Orkambi

Lumacaftor is a potent inducer of CYP3A;1 has potential to induce CYP2B6, 2C8, 2C9, and 2C19; and may inhibit CYP2C8 and 2C9.1 Has potential to inhibit and induce P-glycoprotein (P-gp).1

Ivacaftor is a CYP3A4 and 3A5 substrate, may inhibit CYP2C9, and is a weak inhibitor of P-gp.1

Net effect of lumacaftor/ivacaftor in fixed combination is potent CYP3A induction.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A substrate: Possible pharmacokinetic interaction (decreased exposure and efficacy of substrate drug).1 Concomitant use with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index not recommended.1

Potent CYP3A inhibitors: Pharmacokinetic interaction (possible increased ivacaftor exposure).1 Because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation.1 Concomitant use not recommended; consider alternative therapy.1 If concomitant use required, dosage adjustment not necessary if potent CYP3A inhibitor initiated in patient already receiving lumacaftor/ivacaftor.1 However, if lumacaftor/ivacaftor initiated in patient already receiving a potent CYP3A inhibitor or if lumacaftor/ivacaftor interrupted for >1 week and then reinitiated in patient receiving a potent 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 hours1

Potent CYP3A inducers: Pharmacokinetic interaction (decreased ivacaftor exposure; may reduce efficacy of lumacaftor/ivacaftor).1 Concomitant use not recommended.1

Moderate or weak CYP3A inducers: Dosage adjustment not necessary.1

CYP2B6, 2C8, 2C9, and 2C19 substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).1

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Possible pharmacokinetic interaction (altered exposure of substrate drug).1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased AUC of ivacaftor and reduced efficacy of lumacaftor/ivacaftor1

Concomitant use not recommended1

Antifungals, azoles (itraconazole, ketoconazole, posaconazole, voriconazole)

Itraconazole: Possible decreased exposure and efficacy of itraconazole;1 ivacaftor exposure increased by 4.3-fold;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Ketoconazole, posaconazole, voriconazole: Possible decreased exposure and efficacy of such azole antifungals;1 possible increased ivacaftor exposure;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Itraconazole, ketoconazole, posaconazole, voriconazole: Concomitant use not recommended;1 consider alternative azole antifungal (e.g., fluconazole);1 if concomitant use required, monitor for breakthrough fungal infections1

Dosage adjustment not necessary if such azole antifungals initiated in patient already receiving lumacaftor/ivacaftor1

If lumacaftor/ivacaftor initiated in patients already receiving such azole antifungals, 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 hours1

If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in patient receiving such azole antifungals, 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 hours1

Antimuscarinics (ipratropium, tiotropium)

Dosage adjustment not necessary1

Antimycobacterials (rifabutin, rifampin)

Rifabutin, rifampin: Possible decreased ivacaftor exposure and reduced efficacy of lumacaftor/ivacaftor1

Rifampin decreased ivacaftor exposure by 57%; minimal effect on lumacaftor exposure1

Concomitant use not recommended1

Azithromycin

Dosage adjustment not necessary1

Aztreonam

Dosage adjustment not necessary1

Benzodiazepines (midazolam, triazolam)

Possible decreased exposure and efficacy of the benzodiazepine1

Concomitant use not recommended; consider alternatives to midazolam and triazolam1

Calcium carbonate

Dosage adjustment not necessary1

Ceftazidime

Dosage adjustment not necessary1

Cetirizine

Dosage adjustment not necessary1

Colistin (commercially available in US as colistimethate sodium)

Dosage adjustment not necessary1

Corticosteroids (budesonide, fluticasone, methylprednisolone, prednisone)

Methylprednisolone, prednisone: Possible decreased exposure and efficacy of the corticosteroid1

Methylprednisolone, prednisone: Increased dosage of corticosteroid may be needed to obtain desired clinical effect1

Budesonide, fluticasone: Dosage adjustment not necessary1

Co-trimoxazole

Dosage adjustment not necessary1

Digestive enzymes (pancreatin, pancrelipase)

Dosage adjustment not necessary1

Digoxin

Possible altered digoxin concentrations1

Monitor serum digoxin concentrations and titrate digoxin dosage to obtain desired clinical effect1

Dornase alfa

Dosage adjustment not necessary1

Estrogens and progestins (oral, injectable, transdermal, implantable contraceptives)

Possible decreased exposure and efficacy of the contraceptive1

Avoid concomitant use;1 not considered reliable method of contraception when used concomitantly1

Fluoroquinolones (ciprofloxacin, levofloxacin)

Dosage adjustment not necessary1

Ibuprofen

Possible decreased exposure and efficacy of ibuprofen1

Increased dosage of ibuprofen may be required to obtain desired therapeutic effect1

Immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus)

Possible decreased exposure and efficacy of the immunosuppressant1

Data not available in patients with cystic fibrosis and organ transplants, but potential for drug interaction exists1

Concomitant use not recommended1

Avoid concomitant use in patients with cystic fibrosis and organ transplants1

Macrolides (clarithromycin, erythromycin, telithromycin)

Clarithromycin, erythromycin, telithromycin: Possible decreased exposure and efficacy of such macrolide antibiotics1

Clarithromycin, telithromycin: Possible increased ivacaftor exposure;1 because of lumacaftor induction of CYP3A, net steady-state exposure of ivacaftor not expected to exceed exposure of ivacaftor single-entity preparation1

Clarithromycin, erythromycin, telithromycin: Consider alternative antibiotic (e.g., azithromycin, ciprofloxacin, levofloxacin)1

Clarithromycin, telithromycin: If concomitant use with such macrolides required, dosage adjustment not needed if macrolide initiated in patients already receiving lumacaftor/ivacaftor1

Clarithromycin, telithromycin: If lumacaftor/ivacaftor initiated in patients already receiving such macrolides, 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 hours1

Clarithromycin, telithromycin: If lumacaftor/ivacaftor interrupted for >1 week and reinitiated in patients already receiving such macrolides, 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 hours1

Metformin

Dosage adjustment not necessary1

Montelukast

Possible decreased exposure and efficacy of montelukast1

Dosage adjustment not necessary; clinically monitor patient1

Proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole)

Possible decreased exposure and efficacy of the proton-pump inhibitor1

Dosage adjustment of the proton-pump inhibitor may be required to obtain desired therapeutic effect1

Ranitidine

Possible decreased ranitidine exposure and efficacy1

Ranitidine dosage adjustment may be required to obtain desired therapeutic effect1

Repaglinide

Possible decreased repaglinide exposure and efficacy1

Repaglinide dosage adjustment may be required to obtain desired therapeutic effect1

Selective β2-adrenergic agonists (albuterol, salmeterol)

Dosage adjustment not necessary1

SSRIs (citalopram, escitalopram, sertraline)

Possible decreased exposure and efficacy of the SSRI1

Increased SSRI dosage may be required to obtain desired therapeutic effect1

St. John’s wort (Hypericum perforatum)

Possible decreased AUC of ivacaftor and reduced efficacy of lumacaftor/ivacaftor1

Concomitant use not recommended1

Tobramycin

Dosage adjustment not necessary1

Warfarin

Possible altered warfarin exposure1

Monitor INR1

Orkambi Pharmacokinetics

Absorption

Bioavailability

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

Steady-state concentrations achieved approximately 7 days after twice-daily oral administration.1

Lumacaftor: Systemic exposure increases with accumulation ratio of approximately 1.9.1

Ivacaftor: Steady-state exposure lower than that observed on first day of administration resulting from CYP3A induction by lumacaftor.1

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.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): Effect on pharmacokinetics not studied.1

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.1

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.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; not known whether distributed into human milk.1

Plasma Protein Binding

Lumacaftor: Approximately 99% (mainly albumin).1

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

Elimination

Metabolism

Lumacaftor: Not extensively metabolized in humans; principally metabolized by oxidation and glucuronidation.1

Ivacaftor: Extensively metabolized in humans, principally by CYP3A.1 Two major metabolites are M1 and M6.1

Elimination Route

Lumacaftor: Mainly excreted unchanged in feces (51%).1 Lumacaftor and metabolites minimally excreted in urine (8.6%).1

Ivacaftor: Mainly excreted in feces (87.8%) after metabolic conversion.1 Ivacaftor and metabolites minimally excreted in urine (6.6%).1

Half-life

Lumacaftor: Approximately 26 hours in patients with cystic fibrosis.1

Ivacaftor: Approximately 9 hours in healthy individuals.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

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.1 4 5 7 8 Lumacaftor is a CFTR corrector; ivacaftor is a CFTR potentiator.1 4 5 8

  • Mutations in the gene encoding CFTR affect quantity or function of this protein at the cell surface resulting in cystic fibrosis.4 5 7 8

  • 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.1 4 5 6 7 Small amount of F508del-CFTR reaching cell surface is less stable and has low probability of channel opening (defective gating activity).1 4 6

  • Lumacaftor improves conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to cell surface.1 4 6 7

  • Ivacaftor facilitates increased chloride transport by potentiating the probability of channel opening (or gating) of the CFTR protein at cell surface.1 4 6

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information.1

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

  • If a dose of lumacaftor/ivacaftor is missed by <6 hours, take the dose with fat-containing food as soon as it is remembered.1 If a dose is missed by >6 hours, omit the dose and take the next dose at the regularly scheduled time.1 Do not take a double dose to make up for a missed dose.1

  • Risk of worsening hepatic function in patients with advanced liver disease.1 Importance of dosage reduction and close monitoring in such patients after initiation of lumacaftor/ivacaftor.1

  • Importance of dosage reduction in patients with moderate hepatic impairment (Child-Pugh class B).1 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.1

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

  • Risk of chest discomfort, dyspnea, and abnormal respiration.1 Importance of additional monitoring during initiation of lumacaftor/ivacaftor in patients with FEV1 <40% of predicted.1

  • Risk of increased BP.1 Importance of informing patients that periodic monitoring of BP during therapy is recommended.1

  • Ocular abnormalities (i.e., cataracts) observed in pediatric patients receiving ivacaftor monotherapy.1 Importance of baseline and follow-up ophthalmologic examination in pediatric patients receiving lumacaftor/ivacaftor.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 Concomitant use of lumacaftor/ivacaftor with sensitive CYP3A substrates, inhibitors, and inducers requires particular attention.1 (See Interactions.)

  • Risk of menstrual abnormalities; avoid concomitant use of hormonal contraceptives.1 Hormonal contraceptives not considered a reliable method of contraception when used concomitantly.1 Importance of advising patients to use alternative methods of contraception.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.

Lumacaftor and Ivacaftor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Lumacaftor 200 mg and Ivacaftor 125 mg

Orkambi

Vertex

AHFS DI Essentials. © Copyright 2017, Selected Revisions April 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Vertex Pharmaceuticals Incorporated. Orkambi (lumacaftor and ivacaftor) tablets prescribing information. Boston, MA; 2016 May.

2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2016 March 28

3. Wainwright CE, Elborn JS, Ramsey BW et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015; 373:220-31. [PubMed 25981758]

4. Kopeikin Z, Yuksek Z, Yang HY et al. Combined effects of VX-770 and VX-809 on several functional abnormalities of F508del-CFTR channels. J Cyst Fibros. 2014; 13:508-14. [PubMed 24796242]

5. Cholon DM, Quinney NL, Fulcher ML et al. Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci Transl Med. 2014; 6:246ra96. [PubMed 25101886]

6. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 206038Orig1s000: Summary review. From FDA website. Accessed 2016 Mar 1.

7. Ren HY, Grove DE, De La Rosa O et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell. 2013; 24:3016-24. [PubMed 23924900]

8. Kuk K, Taylor-Cousar JL. Lumacaftor and ivacaftor in the management of patients with cystic fibrosis: current evidence and future prospects. Ther Adv Respir Dis. 2015; 9:313-26. [PubMed 26416827]

9. Boyle MP, Bell SC, Konstan MW et al. A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014; 2:527-38. [PubMed 24973281]

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