Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to BETHKIS in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving BETHKIS ranged in age from 6 to 31 years.
In Study 1, an eight week study, 29 patients received BETHKIS versus 30 patients who received placebo for a total of four weeks on drug and four weeks off drug. All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. 52.5% of patients were 6 to 12 years of age while 30.5% of patients were 13-17 years old. Only 16.5% of patients were adults ( > 17 years old). Eighty percent (80%) of patients were chronically colonized with Pseudomonas aeruginosa while 20.3% of patients were initially or intermittently colonized with Pseudomonas aeruginosa during the study.
More patients in the placebo group discontinued/dropped out of Study 1 than in the BETHKIS group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the BETHKIS group discontinued/dropped out because of treatment-emergent adverse events (TEAEs) such as pulmonary exacerbations and respiratory disorders.
In Study 2, a 24 week study, 161 patients received BETHKIS versus 85 patients who received placebo in alternating four week on-off cycles for three cycles. All patients were ≤ 46 years of age (mean age 14.8 years) and 45% were females. 41% of patients were 612 years old while 29% of patients were 13-17 years old. Only 30% were adults ( > 17 years). Eighty-seven percent (87%) of patients were chronically colonized with P. aeruginosa. Only 13% were either initially or intermittently colonized with P. aeruginosa during the study.
More patients in the placebo group discontinued/dropped out of Study 2 than in the BETHKIS group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the BETHKIS group (1.9%) compared to 2 patients in the placebo group (2.4%) withdrew due to a TEAE. The most common TEAEs causing patients to discontinue from the study drug are respiratory, thoracic, and mediastinal disorders.
The most common adverse experiences reported were respiratory disorders, consistent with the underlying disease in the patient population being evaluated and these were similarly distributed between both BETHKIS-and placebo-treated patients. The following adverse reactions were more commonly reported in ≥ 2% of the BETHKIS-treated patients compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1).
Table 1: Patients with Selected Treatment-Emergent Adverse Reactions Occurring in ≥ 2% of BETHKIS Patients
|Forced expiratory volume decreased||59 (31%)||33 (29%)|
|Rales||36 (19%)||18 (16%)|
|Red blood cell sedimentation rate increased||16 (8%)||6 (5%)|
|Dysphonia||11 (6%)||2 (2%)|
|Wheezing||10 (5%)||4 (4%)|
|Pharyngolaryngeal pain||5 (3%)||2 (2%)|
|Bronchitis||5 (3%)||1 (1%)|
|Diarrhea||3 (2%)||1 (1%)|
|Immunoglobulins increased||3 (2%)||0|
In postmarketing experience, some patients receiving inhaled tobramycin have reported hearing loss. Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus (see WARNINGS AND PRECAUTIONS, Ototoxicity).
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.