KALYDECO SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Transaminase Elevations
• Cataracts

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The overall safety profile of KALYDECO is based on pooled data from three placebo-controlled clinical trials conducted in 353 patients 6 years of age and older with CF who had a G551D mutation in the CFTR gene (Trials 1 and 2) or were homozygous for the F508del mutation (Trial 3). In addition, the following clinical trials have also been conducted:

• An 8-week, crossover design trial (Trial 4) involving 39 patients between the ages of 6 and 57 years with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene.
• A 24-week, placebo-controlled trial (Trial 5) involving 69 patients between the ages of 6 and 68 years with an R117H mutation in the CFTR gene.
• A 24-week, open-label trial (Trial 6) in 34 patients 2 to less than 6 years of age. Patients eligible for Trial 6 were those with the G551D, G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene. Of 34 patients enrolled, 32 had the G551D mutation and 2 had the S549N mutation.
• An 8-week, crossover design trial (Trial 7) involving patients between the ages of 12 and 72 years who were heterozygous for the F508del mutation and a second CFTR mutation predicted to be responsive to ivacaftor. A total of 156 patients were randomized to and received KALYDECO.
• A cohort of 19 patients aged 12 months to less than 24 months, a cohort of 11 patients aged 6 months to less than 12 months, and a cohort of 6 patients aged 4 months to less than 6 months in a 24-week open-label clinical trial in patients with CF aged less than 24 months (Trial 8).

Of the 353 patients included in the pooled analyses of patients with CF who had either a G551D mutation or were homozygous for the F508del mutation in the CFTR gene, 50% of patients were female and 97% were Caucasian; 221 received KALYDECO, and 132 received placebo from 16 to 48 weeks.

The proportion of patients who prematurely discontinued study drug due to adverse reactions was 2% for KALYDECO-treated patients and 5% for placebo-treated patients. Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in KALYDECO-treated patients included abdominal pain, increased hepatic enzymes, and hypoglycemia.

The most common adverse reactions in the 221 patients treated with KALYDECO 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%).

The incidence of adverse reactions below is based upon two double-blind, placebo-controlled, 48-week clinical trials (Trials 1 and 2) in a total of 213 patients with CF ages 6 to 53 who have a G551D mutation in the CFTR gene and who were treated with KALYDECO 150 mg orally or placebo twice daily. Table 2 shows adverse reactions occurring in ≥8% of KALYDECO-treated patients with CF who have a G551D mutation in the CFTR gene that also occurred at a higher rate than in the placebo-treated patients in the two double-blind, placebo-controlled trials.

Table 1: Incidence of Adverse Drug Reactions in ≥8% of KALYDECO-Treated Patients with a G551D Mutation in the CFTR Gene and Greater than Placebo in 2 Placebo-Controlled Phase 3 Clinical Trials of 48 Weeks Duration

Adverse reactions in the 48-week clinical trials that occurred in the KALYDECO group at a frequency of 4 to 7% where rates exceeded that in the placebo group include:

Infections and infestations: rhinitis

Investigations: aspartate aminotransferase increased, bacteria in sputum, blood glucose increased, hepatic enzyme increased

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal chest pain, myalgia

Nervous system disorders: sinus headache

Respiratory, thoracic and mediastinal disorders: pharyngeal erythema, pleuritic pain, sinus congestion, wheezing

Skin and subcutaneous tissue disorders: acne

The safety profile for the CF patients enrolled in the other clinical trials (Trials 3-8) was similar to that observed in the 48-week, placebo-controlled trials (Trials 1 and 2).

Laboratory Abnormalities

Transaminase Elevations

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 KALYDECO-treated patients and 2%, 2%, and 8% in placebo-treated patients, 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 trial 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.

During the 24-week, open-label, clinical trial in patients aged less than 24 months (Trial 8), the incidence of patients experiencing transaminase elevations (ALT or AST) >3 , >5 , and >8 x ULN in the cohort of patients aged 12 months to less than 24 months (N=19) was 27.8% (5/18), 11.1% (2/18) and 11.1% (2/18), respectively. In the cohort of patients aged 6 months to less than 12 months (N=11) one patient (9.1%) had elevated ALT of >3 to ≤5 x ULN. In the cohort of patients aged 4 months to less than 6 months (N=6), no patients had elevated ALT or AST (> 3x ULN). No patients had elevations in total bilirubin, or discontinued ivacaftor treatment due to transaminase elevations in any cohort.