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Addressing Tolerability Concerns Associated With CFTR Modulators

  • Authors: Natalie E. West, MD, MHS; Christopher H. Goss, MD, MSc
  • CME Released: 10/14/2016
  • Valid for credit through: 10/14/2017, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for pulmonologists, pediatricians, and gastroenterologists.

The goal of this activity is to provide clinicians with insight on minimizing and managing reactions to the initiation of lumacaftor/ivacaftor therapy.

Upon completion of this activity, participants will have increased knowledge regarding the:

  1. Adverse events associated with the initiation of cystic fibrosis transmembrane conductance regulator (CFTR) modulators
  2. Strategies to improve provider and patient decision making in the management of adverse events that may occur with the use of CFTR modulators


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  • Natalie E. West, MD, MHS

    Assistant Professor of Medicine, Assistant Program Director, Pulmonary and Critical Care Fellowship, Johns Hopkins University Pulmonary and Critical Care Medicine, Baltimore, Maryland


    Participation by Dr. West does not constitute or imply endorsement by the Johns Hopkins University or the Johns Hopkins Hospital and Health System.

    Disclosure: Natalie E. West, MD, MHS, has disclosed no relevant financial relationships.

    Dr West does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr West does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.

  • Christopher H. Goss, MD, MSc

    Professor of Medicine and Pediatrics, Division of Pulmonary and Critical Care Medicine,  University of Washington, Seattle, Washington


    Disclosure: Christopher H. Goss, MD, MSc, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Boehringer Ingelheim Pharmaceuticals, Inc.
    Grant reviews for: Gilead Sciences, Inc.; Vertex Pharmaceuticals Incorporated

    Dr Goss does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States.

    Dr Goss does not intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States.


  • Julia Muino, MA

    Scientific Director, Medscape, LLC


    Disclosure: Julia Muino, MA, has disclosed no relevant financial relationships.

CME Reviewer

  • Amy Bernard, MS, BSN, RN-BC

    Lead Nurse Planner, Medscape, LLC


    Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

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Addressing Tolerability Concerns Associated With CFTR Modulators

Authors: Natalie E. West, MD, MHS; Christopher H. Goss, MD, MScFaculty and Disclosures

CME Released: 10/14/2016

Valid for credit through: 10/14/2017, 11:59 PM EST



  • Addressing Tolerability Issues Associated With CFTR Modulators

    • This program will cover what we have learned about tolerability related to cystic fibrosis transmembrane conductance regulator (CFTR) modulators, how to initiate the drugs, when it is appropriate to make dosage adjustments, and how to work with patients when a problem arises

  • Slide 1.

    Slide 1.

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  • Ivacaftor (Potentiator) Plus Lumacaftor (Corrector) in F508del CFTR: TRAFFIC and TRANSPORT Studies[1]

    • Ivacaftor is a potentiator that activates defective CFTR protein on the cell surface
    • Lumacaftor is a corrector that moves mutant CFTR through the cell to the cell surface, where it can be activated

  • Slide 2.

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  • Adverse Effects That Should Be Monitored/Followed and May Necessitate Stopping/Discontinuation of Lumacaftor/Ivacaftor

    • It is important to distinguish between adverse events that require stopping the drug vs events that are transient and manageable
    • Elevated liver enzymes that require drug discontinuation have not been observed at Johns Hopkins Cystic Fibrosis Center
    • Severe bronchospasm and chest tightness, as well as severe cough and, occasionally, a decrease in lung function, have been observed in patients at Johns Hopkins
    • Respiratory effects, as well as loose stools and diarrhea, have also been observed at the University of Washington Cystic Fibrosis Clinic
    • Patients with more severe disease (ppFEV1 of less than 40%) have more adverse events when initiating the drug -- typically bronchospasm and dyspnea -- than patients with mild or moderate disease

  • Slide 4.

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  • Before Initiating Lumacaftor/ivacaftor Therapy

    • At University of Washington, patients who have a ppFEV1 of less than 30% are typically hospitalized for initiation of lumacaftor/ivacaftor therapy, and started at a low dosage (eg, 1 tablet daily, increasing to 1 tablet twice a day, and then to full dosage of 2 tablets twice a day)
    • Johns Hopkins does not typically hospitalize patients with severe disease for initiation of lumacaftor/ivacaftor therapy, but may initiate therapy after a patient has finished intravenous (IV) antibiotic therapy, or has been admitted to the hospital for other reasons
    • Ensure that the patient is taking a long-acting bronchodilator
    • Ensure that the patient's airway clearance is maximized with the patient's routine therapies; this may include rhDNase, hypertonic saline, inhaled antibiotics, and augmented airway clearance with manual chest physiotherapy or other devices perceived by the patient to be effective

  • Slide 5.

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  • Adverse Events Common in CF Also Reported in TRAFFIC and TRANSPORT[1]

    • Hemoptysis was reported in 13.6% to 14.1% of patients, an adverse event that Dr Goss and Dr West agree is most likely secondary to underlying cystic fibrosis (CF), and not drug-induced
    • Although some events observed during the trials may have been caused by CF and were not necessarily drug-induced, the cough and chest tightness observed on initiation of lumacaftor/ivacaftor therapy is likely drug-induced

  • Slide 6.

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  • Managing Initiation of Lumacaftor/Ivacaftor Therapy

  • Slide 7.

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  • Drug-Drug Interactions With CFTR Modulators

  • Slide 8.

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  • Johns Hopkins University Observational Data[3]

    • If restarting lumacaftor/ivacaftor after discontinuing it because of drug-related adverse events, consider doing so after a round of IV antibiotics
    • Optimize lung function
      • Ensure patient is taking all appropriate medications
    • Consider pretreatment with prednisone

  • Slide 9.

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  • Thank you for participating in this activity

    • How we react to the real-world experience of initiating lumacaftor/ivacaftor therapy has evolved

  • Slide 10.

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  • This content has been condensed for improved clarity.

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