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adverse reactions
6 ADVERSE REACTIONS The most common adverse reactions (≥10 % of TOBI Podhaler and TOBI patients in primary safety population) are cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 practice. TOBI Podhaler has been evaluated for safety in 425 cystic fibrosis patients exposed to at least one dose of TOBI Podhaler, including 273 patients who were exposed across three cycles (6 months) of treatment. Each cycle consisted of 28 days on-treatment (with 112 mg administered twice-daily) and 28 days off-treatment. Patients with serum creatinine ≥2 mg/dL and blood urea nitrogen (BUN) ≥40 mg/dL were excluded from clinical studies. There were 218 males and 207 females in this population, and reflecting the cystic fibrosis population in the U.S., the vast majority of patients were Caucasian. There were 221 patients ≥20 years old, 121 patients ≥13 to <20 years old, and 83 patients ≥6 to <13 years old. There were 239 patients with screening FEV 1 % predicted ≥50%, 156 patients with screening FEV 1 % predicted <50%, and 30 patients with missing FEV 1 % predicted. The primary safety population reflects patients from Study 1, an open-label study comparing TOBI Podhaler with TOBI (tobramycin inhalation solution, USP) over three cycles of 4 weeks on treatment followed by 4 weeks off treatment. Randomization, in a planned 3:2 ratio, resulted in 308 patients treated with TOBI Podhaler and 209 patients treated with TOBI. For both the TOBI Podhaler and TOBI groups, mean exposure to medication for each cycle was 28 to 29 days. The mean age for both arms was between 25 and 26 years old. The mean baseline FEV 1 % predicted for both arms was 53%. Table 1 displays adverse drug reactions reported by at least 2% of TOBI Podhaler patients in Study 1, inclusive of all cycles (on and off treatment). Adverse drug reactions are listed according to MedDRA system organ class and sorted within system organ class group in descending order of frequency. Table 1: Adverse Reactions Reported in Study 1 (Occurring in ≥2% of TOBI Podhaler Patients) Primary System Organ Class Preferred Term TOBI Podhaler N=308 % TOBI N=209 % Respiratory, thoracic, and mediastinal disorders Cough 48.4 31.1 Lung disorder This includes adverse events of pulmonary or cystic fibrosis exacerbations 33.8 30.1 Productive cough 18.2 19.6 Dyspnea 15.6 12.4 Oropharyngeal pain 14.0 10.5 Dysphonia 13.6 3.8 Hemoptysis 13.0 12.4 Nasal congestion 8.1 7.2 Rales 7.1 6.2 Wheezing 6.8 6.2 Chest discomfort 6.5 2.9 Throat irritation 4.5 1.9 Gastrointestinal disorders Nausea 7.5 9.6 Vomiting 6.2 5.7 Diarrhea 4.2 1.9 Dysgeusia 3.9 0.5 Infections and infestations Upper respiratory tract infection 6.8 8.6 Investigations Pulmonary function test decreased 6.8 8.1 Forced expiratory volume decreased 3.9 1.0 Blood glucose increased 2.9 0.5 Vascular disorders Epistaxis 2.6 1.9 Nervous system disorders Headache 11.4 12.0 General disorders and administration site conditions Pyrexia 15.6 12.4 Musculoskeletal and connective tissue disorders Musculoskeletal chest pain 4.5 4.8 Skin and subcutaneous tissue disorders Rash 2.3 2.4 Adverse drug reactions that occurred in <2% of patients treated with TOBI Podhaler in Study 1 were: bronchospasm (TOBI Podhaler 1.6%, TOBI 0.5%); deafness including deafness unilateral (reported as mild to moderate hearing loss or increased hearing loss) (TOBI Podhaler 1.0%, TOBI 0.5%); and tinnitus (TOBI Podhaler 1.9%, TOBI 2.4%). Discontinuations in Study 1 were higher in the TOBI Podhaler arm compared to TOBI (27% TOBI Podhaler versus 18% TOBI). This was driven primarily by discontinuations due to adverse events (14% TOBI Podhaler versus 8% TOBI). Higher rates of discontinuation were seen in subjects ≥20 years old and those with baseline FEV 1 % predicted <50%. Respiratory related hospitalizations occurred in 24% of the patients in the TOBI Podhaler arm and 22% of the patients in the TOBI arm. There was an increased new usage of antipseudomonal medication in the TOBI Podhaler arm (65% TOBI Podhaler versus 55% TOBI). This included oral antibiotics in 55% of TOBI Podhaler patients and 40% of TOBI patients and intravenous antibiotics in 35% of TOBI Podhaler patients and 33% of TOBI patients. Median time to first antipseudomonal usage was 89 days in the TOBI Podhaler arm and 112 days in the TOBI arm. The supportive safety population reflects patients from two studies: Study 2, a double-blind, placebo-controlled design for the first treatment cycle, followed by all patients receiving TOBI Podhaler (replaced placebo) for two additional cycles, and Study 3, a double-blind, placebo-controlled trial for one treatment cycle only. Placebo in these studies was inhaled powder without the active ingredient, tobramycin. The patient population for these studies was much younger than in Study 1 (mean age 13 years old). Adverse drug reactions reported more frequently by TOBI Podhaler patients in the placebo-controlled cycle (Cycle 1) of Study 2, which included 46 TOBI Podhaler and 49 placebo patients, were: Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain (TOBI Podhaler 10.9%, placebo 0%); dysphonia (TOBI Podhaler 4.3%, placebo 0%) Gastrointestinal disorders Dysgeusia (TOBI Podhaler 6.5%, placebo 2.0%) Adverse drug reactions reported more frequently by TOBI Podhaler patients in Study 3, which included 30 TOBI Podhaler and 32 placebo patients, were: Respiratory, thoracic, and mediastinal disorders Cough (TOBI Podhaler 10%, placebo 0%) Ear and labyrinth disorders Hypoacusis (TOBI Podhaler 10%, placebo 6.3%) Audiometric Assessment In Study 1, audiology testing was performed in a subset of approximately 25% of TOBI Podhaler (n=78) and TOBI (n=45) patients. Using the criteria for either ear of ≥10 dB loss at two consecutive frequencies, ≥20 dB loss at any frequency, or loss of response at three consecutive frequencies where responses were previously obtained, five TOBI Podhaler patients and three TOBI patients were judged to have ototoxicity, a ratio similar to the planned 3:2 randomization for this study. Audiology testing was also performed in a subset of patients in both Study 2 (n=13 from the TOBI Podhaler group and n=9 from the placebo group) and Study 3 (n=14 from the TOBI Podhaler group and n=11 from the placebo group). In Study 2, no patients reported hearing complaints but two TOBI Podhaler patients met the criteria for ototoxicity. In Study 3, three TOBI Podhaler and two placebo patients had reports of ‘hypoacusis.’ One TOBI Podhaler and two placebo patients met the criteria for ototoxicity. In some patients, ototoxicity was transient or may have been related to a conductive defect. Cough Cough is a common symptom in cystic fibrosis, reported in 42% of the patients in Study 1 at baseline. Cough was the most frequently reported adverse event in Study 1 and was more common in the TOBI Podhaler arm (48% TOBI Podhaler versus 31 % TOBI). There was a higher rate of cough adverse event reporting during the first week of active treatment with TOBI Podhaler (i.e., the first week of Cycle 1). The time to first cough event in the TOBI Podhaler and TOBI groups were similar thereafter. In some patients, cough resulted in discontinuation of TOBI Podhaler treatment. Sixteen patients (5%) receiving treatment with TOBI Podhaler discontinued study treatment due to cough events compared with 2 (1%) in the TOBI treatment group. Children and adolescents coughed more than adults when treated with TOBI Podhaler, yet the adults were more likely to discontinue: of the 16 patients on TOBI Podhaler in Study 1 who discontinued treatment due to cough events, 14 were ≥20 years of age, one patient was between the ages of 13 and <20, and one was between the ages of 6 and <13. The rates of bronchospasm (as measured by ≥20% decrease in FEV 1 % predicted post-dose) were approximately 5% in both treatment groups, and none of these patients experienced concomitant cough. In Study 2, cough was the most commonly reported adverse event during the first cycle of treatment (the double blind period of treatment) and occurred more frequently in placebo-treated patients (26.5%) than patients treated with TOBI Podhaler (13%). Similar percentages of patients in both treatment groups reported cough as a baseline symptom. In Study 3, cough events were reported by three patients in the TOBI Podhaler group (10%) and none in the placebo group (0%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TOBI Podhaler. 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. Respiratory, thoracic, and mediastinal disorders Aphonia, Sputum discolored General disorders and administration site conditions Malaise