Adverse Reactions

Adverse Reactions

Pooled safety data for KALYDECO (Trials 1, 2, and 3)1

The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for patients treated with KALYDECO and 5% for patients treated with placebo.

Serious adverse reactions that occurred more frequently in patients treated with KALYDECO included abdominal pain, increased hepatic enzymes, and hypoglycemia.

The most common adverse reactions in patients treated with KALYDECO (ivacaftor) in Trials 1, 2, and 3 (N=221) were headache (17%), upper respiratory tract infection (16%), nasal congestion (16%), nausea (10%), rash (10%), rhinitis (6%), dizziness (5%), arthralgia (5%), and bacteria in sputum (5%).

Trials 1 and 21

Most Common Adverse Reactions (≥8%) in Patients With a G551D Mutation Treated With KALYDECO and Greater Than Placebo in Clinical Trials 1 and 2

Safety profile for patients with cystic fibrosis treated with KALYDECO

Trials 4, 5, and 6 safety data1

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.

Transaminase elevations (Trials 1, 2, 3, and 6)1

In Trials 1, 2, and 3, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 x ULN was 2%, 2%, and 6% in patients treated with KALYDECO and 2%, 2%, and 8% in patients treated with placebo, respectively.

  • Two patients (2%) on placebo and 1 patient (0.5%) on KALYDECO permanently discontinued treatment for elevated transaminases, all >8 x ULN
  • Two patients treated with KALYDECO were reported to have serious adverse reactions of elevated liver transaminases compared to none on placebo
  • Transaminase elevations were more common in patients with a history of transaminase elevations

During the 24-week open-label clinical study in 34 patients ages 2 to less than 6 years (Trial 6), where patients received either 50 mg (less than 14 kg) or 75 mg (14 kg or greater) ivacaftor granules twice daily, the incidence of patients experiencing transaminase elevations (ALT or AST) >3 x ULN was 14.7% (5/34). All 5 patients had maximum ALT or AST levels >8 x ULN, which returned to baseline levels following interruption of KALYDECO dosing. Transaminase elevations were more common in patients who had abnormal transaminases at baseline. KALYDECO was permanently discontinued in one patient.

ALT, alanine transaminase; AST, aspartate transaminase; ULN, upper limit of normal.

Click Here for More Information on Use of KALYDECO in Specific Populations

Important Safety
Information—
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

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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