Homozygous F508del Mutation

Trial 3: Patients Homozygous for the F508del Mutation

KALYDECO (ivacaftor) is not effective in patients with CF who are homozygous for the F508del mutation1

  • Trial 3 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial in 140 patients with CF 12 years of age and older (mean age: 23 years; FEV1 at screening: greater than or equal to 40% predicted) who were homozygous for the F508del mutation
  • Patients received either KALYDECO 150 mg (n=112) or placebo (n=28) every
    12 hours in addition to their prescribed CF therapies. The use of inhaled hypertonic saline was not permitted
    • Patients with persistent infections (Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus) or abnormal liver function were excluded from the trial
  • The primary endpoint was improvement in lung function as determined by the mean absolute change from baseline in percent predicted FEV1 through Week 16 of treatment
    • Mean absolute change in percent predicted FEV1 from baseline was
      1.5 percentage points for KALYDECO and -0.2 percentage points for placebo through Week 16 (P=0.15)
  • No meaningful differences between patients treated with KALYDECO compared to placebo for secondary endpoints (i.e., change in CF symptoms, change in weight, and change in sweat chloride concentration)

Important Safety Information—
Concomitant Use with CYP3A Inducers

  • Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Co-administration of KALYDECO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort is not recommended

Please click here for additional Important Safety Information.

Indications and Usage

KALYDECO (ivacaftor) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R.

KALYDECO is indicated for the treatment of CF in patients age 2 years and older who have an R117H mutation in the CFTR gene.

If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Limitation of Use:

KALYDECO is not effective in patients with CF who are homozygous for the F508del mutation in the CFTR gene.

Important Safety Information

Transaminase (ALT or AST) Elevations

  • Elevated transaminases have been reported in patients with CF receiving KALYDECO. Transaminase elevations were more common in patients with a history of transaminase elevations or in patients who had abnormal transaminases at baseline. It is recommended that ALT and AST be assessed prior to initiating KALYDECO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring of liver function tests should be considered
  • Patients who develop increased transaminase levels should be closely monitored until the abnormalities resolve. Dosing should be interrupted in patients with ALT or AST of greater than 5 times the upper limit of normal (ULN). Following resolution of transaminase elevations, consider the benefits and risks of resuming KALYDECO dosing

Concomitant Use with CYP3A Inducers

  • Use of KALYDECO with strong CYP3A inducers, such as rifampin, substantially decreases the exposure of ivacaftor, which may reduce the therapeutic effectiveness of KALYDECO. Co-administration of KALYDECO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort is not recommended

Cataracts

  • Cases of non-congenital lens opacities/cataracts have been reported in pediatric patients treated with KALYDECO. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating KALYDECO treatment

Pediatric Use

  • The safety and efficacy of KALYDECO in patients with CF younger than 2 years of age have not been studied. The use of KALYDECO in children under the age of 2 years is not recommended

Serious Adverse Reactions

  • Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in patients treated with KALYDECO included abdominal pain, increased hepatic enzymes, and hypoglycemia

Adverse Reactions

  • The most common adverse reactions in patients with a G551D mutation in the CFTR gene (Trials 1 and 2) with an incidence of ≥8% and at a higher incidence for patients treated with KALYDECO (N=109) than for placebo (N=104) were headache (24% vs 16%), oropharyngeal pain (22% vs 18%), upper respiratory tract infection (22% vs 14%), nasal congestion (20% vs 15%), abdominal pain (16% vs 13%), nasopharyngitis (15% vs 12%), diarrhea (13% vs 10%), rash (13% vs 7%), nausea (12% vs 11%), and dizziness (9% vs 1%)
  • The safety profiles for patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation enrolled in Trial 4, for patients with an R117H mutation enrolled in Trial 5, and for patients ages 2 to less than 6 years enrolled in
    Trial 6 were similar to that observed in Trials 1 and 2

Click here to access full Prescribing Information for KALYDECO (ivacaftor).

References: 1. KALYDECO (ivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; March 2015. 2. Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672. 3. Davies JC, Wainwright CE, Canny GJ, et al; VX08-770-103 (ENVISION) Study Group. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013;187(11):1219-1225. 4. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133. 5. Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis: membrane transport disorders. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw-Hill Companies, Inc; 2004:part 21, chap 201. http://www.ommbid.com. Accessed February 25, 2016. 6. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254. 7. Orenstein DM, Spahr JE, Weiner DJ. Cystic Fribrosis: A Guide for Patient and Family. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. 8. Yu H, Burton B, Huang C-J, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cyst Fibros. 2012;11(3):237-245.
9. US CF Foundation, Johns Hopkins University. The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). http://www.cftr2.org/index.php. Accessed February 25, 2016. 10. Berwouts S, Morris MA, Girodon E, Schwarz M, Stuhrmann M, Dequeker E. Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme. Hum Mutat. 2011;32(11):1197-1203. 11. US Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory Web site. ndb.nal.usda.gov/. Accessed February 25, 2016.

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