The following adverse reaction is discussed in greater detail in other sections of the label:
- Transaminase Elevations [see WARNINGS AND PRECAUTIONS]
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 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, an 8-week crossover design trial (Trial 4) involving 39 patients with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation in the CFTR gene was conducted. Patients treated with KALYDECO in these trials were between the ages of 6 and 57 years.
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 1 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 Reaction (Preferred Term)||Incidence: Pooled 48-week Trials|
|Headache||26 (24)||17 (16)|
|Oropharyngeal pain||24 (22)||19(18)|
|Upper respiratory tract infection||24 (22)||14 (14)|
|Nasal congestion||22 (20)||16 (15)|
|Abdominal pain||17 (16)||13(13)|
|Nasopharyngitis||16 (15)||12 (12)|
|Nausea||13 (12)||11 (11)|
|Dizziness||10 (9)||1 (1)|
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
During 48-week placebo-controlled clinical studies, the incidence of maximum transaminase (ALT or AST) > 8, > 5 or > 3 x ULN was 2%, 3% 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 [see WARNINGS AND PRECAUTIONS].
The safety profile for the 39 patients with CF with a G1244E, G1349D, G178R, G551S, G970R, S1251N, S1255P, S549N, or S549R mutation enrolled in the 8-week crossover trial (Trial 4) was similar to that observed in the 48-week placebo-controlled trials (Trials 1 and 2).