TOBI PODHALER

TOBI Podhaler consists of a dry powder formulation of tobramycin for oral inhalation only with the Podhaler device. The inhalation powder is filled into clear, colorless hypromellose capsules. Each clear, colorless hypromellose capsule contains a spray dried powder of 28 mg of tobramycin active ingredient with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride, and sulfuric acid (for pH adjustment). The active component of TOBI Podhaler is tobramycin. Tobramycin is an aminoglycoside antibiotic. Its chemical name is O -3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)- O -[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine; its structural formula is: Tobramycin has a molecular weight of 467.52, and its empirical formula is C 18 H 37 N 5 O 9 . Tobramycin is a white to almost white powder; visually free from any foreign contaminants. Tobramycin is freely soluble in water, very slightly soluble in ethanol, and practically insoluble in chloroform and ether. The Podhaler device is a plastic device used to inhale the dry powder contained in the TOBI Podhaler capsule. Under standardized in vitro testing at a fixed flow rate of 60 L/min and volume of 2 L for 2 seconds, the Podhaler device has a target delivered dose of 102 mg of tobramycin from the mouthpiece (4 capsules per dose). Peak inspiratory flow rate and inhaled volumes were explored in 96 cystic fibrosis patients aged 6 years and older. Older patients with significant disease progression and associated decreases in forced expiratory volume (FEV 1 ) and younger patients with inhaled volumes <1 L were able to generate inspiratory flow rates and volumes required to receive their medication when following the instructions for use. However, no pediatric patients aged 6 to 10 years with FEV 1 less than 40% predicted were evaluated. Tobramycin structural formula

TOBI Podhaler is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa . Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) <25% or >80% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ] . TOBI Podhaler is an aminoglycoside antibacterial indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa . Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) <25% or >80%, or patients colonized with Burkholderia cepacia ( 1 )

DO NOT SWALLOW TOBI PODHALER CAPSULES FOR USE WITH THE PODHALER DEVICE ONLY FOR ORAL INHALATION ONLY TOBI Podhaler capsules must not be swallowed as the intended effects in the lungs will not be obtained. The contents of TOBI Podhaler capsules are only for oral inhalation and should only be used with the Podhaler device. The recommended dosage of TOBI Podhaler for both adults and pediatric patients 6 years of age and older is the inhalation of the contents of four 28 mg TOBI Podhaler capsules twice-daily for 28 days using the Podhaler device. Refer to the Instructions For Use (IFU) for full administration information. Dosage is not adjusted by weight. Each dose of four capsules should be taken as close to 12 hours apart as possible; each dose should not be taken less than 6 hours apart. TOBI Podhaler is administered twice-daily in alternating periods of 28 days. After 28 days of therapy, patients should stop TOBI Podhaler therapy for the next 28 days, and then resume therapy for the next 28-day on and 28-day off cycle. TOBI Podhaler capsules should always be stored in the blister and each capsule should only be removed IMMEDIATELY BEFORE USE. For patients taking several different inhaled medications and/or performing chest physiotherapy, the order of therapies should follow the physician’s recommendation. It is recommended that TOBI Podhaler is taken last. • DO NOT swallow TOBI Podhaler capsules ( 2 ) • For use with the Podhaler device only ( 2 ) • For oral inhalation only ( 2 ) • The recommended dosage is the inhalation of four 28 mg capsules twice-daily for 28 days ( 2 )

TOBI Podhaler is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside ( 4 )

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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

No clinical drug interaction studies have been performed with TOBI Podhaler. In clinical studies, patients receiving TOBI Podhaler continued to take dornase alfa, bronchodilators, inhaled corticosteroids, and macrolides. No clinical signs of drug interactions with these medicines were identified. Concurrent and/or sequential use of TOBI Podhaler with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI Podhaler should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and TOBI Podhaler has not been evaluated. Concurrent and/or sequential use of TOBI Podhaler with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided ( 7 )