Indications

Cystic Fibrosis with Homozygous F508del (Phe508del) Mutation (see Cystic Fibrosis, [[Cystic Fibrosis]])

• General Information
  • FDA-Approved for this Indication in 7/15
  • F508del is present in 68% of CF Cases
  • The F508del Mutation Interferes with CFTR Protein Folding and Channel Gating Activity
  • Lumacaftor + Ivacaftor is Indicated for Patients at Least 12 y/o
• Clinical Efficacy
  • TRAFFIC and TRANSPORT Trials (NEJM, 2015) [MEDLINE]
    • Lumacaftor + Ivacaftor Improved FEV1
    • Lumacaftor + Ivacaftor Decreased Pulmonary Exacerbations
    • Lumacaftor + Ivacaftor Decreased Antibiotic Use and Rate of Hospitalizations

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Pharmacology

• Lumacaftor Partially Corrects CFTR Protein Folding, While Ivacaftor Improves CFTR Gating Activity: neither drug (lumacaftor or ivacaftor) is efficacious when used alone in CF patients with the F508del mutation
  • Lumacaftor: CFTR potentiator -> lumacaftor (VX-809) partially corrects CFTR misfolding
  • Ivacaftor (see Ivacaftor, [[Ivacaftor]]): CFTR corrector -> restores function of the mutant ion channel

Metabolism

• Hepatic

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Administration

• PO: 2 tablets (200 mg lumacaftor/125 mg ivacaftor) q12hrs
  • Take with Fat-Containing Foods

Monitor Liver Function Tests (LFT’s)

• Check LFT’s Prior to Ivacaftor Administration
• Check LFT’s q3 mo x 1 yr
• Check LFT’s Annually Thereafter

Dose Adjustment

• Hepatic: dose reduce with patients with hepatic impairment
• Renal: none

Drug Interactions

• P4503A (CYP3A)-Inhibitors (itraconazole, clarithromycin, fluconazole): it is recommended to dose-reduce ivacaftor, since these agents may increase ivacaftor concentration
• P4503A (CYP3A)-Inducers (rifampin, phenobarbital, carbamazepine, phenytoin, St. John’s wort): use of ivacaftor with these agents is contraindicated, since these agents significantly decrease ivacaftor concentration
• Lumacaftor + Ivacaftor May Induce CYP3A and Decrease Concentration of Other Medications Which are CYP3A Substrates
  • Lumacaftor + Ivacaftor May Decrease the Concentration of Azole Anti-Fungals, Except Fluconazole: lumacaftor + ivacaftor should not be used in this setting
  • Lumacaftor + Ivacaftor May Decrease the Concentration of Cyclosoporine A/Everolimus/Sirolimus/Tacrolimus: lumacaftor + ivacaftor should not be used in this setting
  • Lumacaftor + Ivacaftor May Decrease the Effectiveness of Oral Contraceptives

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Adverse Effects

Pulmonary Adverse Effects

• Chest Discomfort/Dyspnea (see Dyspnea, [[Dyspnea]]): occurred particularly in CF patients with worse baseline lung function

Reproductive Adverse Effects

• Menstrual Irregularities: occurred particularly in women taking oral contraceptives

Other Adverse Effects

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References

• Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul;373(3):220-31. Epub 2015 May 17 [MEDLINE]