n should be exercised when prescribing tobi podhaler to patients with known or suspected auditory or vestibular dysfunction. ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the tobi podhaler clinical studies [see adverse reactions (6.1) ] . tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. ototoxicity, manifested as both auditory (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. vestibular toxicity may be manifested by vertigo, ataxia or dizziness. risk of ototoxicity due to mitochondrial dna variants cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12s rrna gene ( mt-rnr1 ), particularly the m.1555a>g variant. ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. mitochondrial dna variants are present in less than 1% of the general us population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. in case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial dna variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies . 5.3 nephrotoxicity caution should be exercised when prescribing tobi podhaler to patients with known or suspected renal dysfunction. nephrotoxicity was not observed during tobi podhaler clinical studies but has been associated with aminoglycosides as a class. 5.4 neuromuscular disorders caution should be exercised when prescribing tobi podhaler to patients with known or suspected neuromuscular dysfunction. tobi podhaler should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. 5.5 embryo-fetal toxicity aminoglycosides can cause fetal harm when administered to a pregnant woman. aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. however, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see clinical pharmacology (12.3) ] . patients who use tobi podhaler during pregnancy, or become pregnant while taking tobi podhaler should be apprised of the potential hazard to the fetus [see use in specific populations (8.1) ] . 5.6 concomitant use of systemic aminoglycosides patients receiving concomitant tobi and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. serum tobramycin levels should be monitored.

en 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 )

reatment. 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

egnant women of the potential risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk cystic fibrosis may increase the risk for preterm delivery. data animal data no reproduction toxicology studies have been conducted with tobi podhaler. however, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes. doses of tobramycin ≥40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. ototoxicity was not evaluated in offspring during non-clinical reproductive toxicity studies with tobramycin. 8.2 lactation risk summary there are no data on the presence of tobramycin following administration of tobi podhaler in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. limited published data on other formulations of tobramycin in lactating women indicate that tobramycin is present in human milk. however, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see clinical pharmacology (12.3) ] . tobramycin may cause alteration in the intestinal flora of the breastfeeding infant (see clinical considerations ) . the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for tobi podhaler and any potential adverse effects on the breastfed infant from tobi podhaler or from the underlying maternal condition. clinical considerations tobramycin may cause intestinal flora alteration. advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). 8.4 pediatric use patients 6 years and older were included in the phase 3 studies with tobi podhaler; 206 patients below 20 years of age received tobi podhaler. no dosage adjustments are needed based on age. the overall pattern of adverse events in pediatric patients was similar to the adults. dysgeusia (taste disturbance) was more commonly reported in younger patients six to 19 years of age than in patients 20 years and older, 7.4% versus 2.7%, respectively. safety and effectiveness in pediatric patients below the age of 6 years have not been established. 8.5 geriatric use clinical studies of tobi podhaler did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see warnings and precautions (5.2 , 5.5) ]. 8.6 renal impairment tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure to tobramycin. the risk of adverse reactions to this drug may be greater in patients with impaired renal function. patients with serum creatinine ≥2 mg/dl and blood urea nitrogen (bun) ≥40 mg/dl have not been included in clinical studies and there are no data in this population to support a recommendation regarding dose adjustment with tobi podhaler [see warnings and precautions (5.2 , 5.5) ]. 8.7 hepatic impairment no studies have been performed in patients with hepatic impairment. as tobramycin is not metabolized, an effect of hepatic impairment on the exposure to tobramycin is not expected. 8.8 organ transplantation adequate data do not exist for the use of tobi podhaler in patients after organ transplantation.

risk to a fetus. the estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk cystic fibrosis may increase the risk for preterm delivery. data animal data no reproduction toxicology studies have been conducted with tobi podhaler. however, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes. doses of tobramycin ≥40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. ototoxicity was not evaluated in offspring during non-clinical reproductive toxicity studies with tobramycin.

± 0.58 mcg/ml and median t max was 1 hour. the extent of systemic exposure (auc 0-12 ) was also similar: 4.6 ± 2.0 mcg∙h/ml following the 112 mg tobi podhaler dose and 4.8 ± 2.5 mcg∙h/ml following the 300 mg tobi dose. at the end of a 4-week dosing cycle of tobi podhaler (112 mg twice-daily), the maximum serum concentration of tobramycin 1 hour after dosing ranged from 1.48 ± 0.69 mcg/ml to 1.99 ± 0.59 mcg/ml (mean ± sd). sputum concentrations after inhalation of a 112 mg single dose (4 times 28 mg capsules) of tobi podhaler in cystic fibrosis patients, sputum c max of tobramycin was 1048 ± 1080 mcg/g (mean ± sd). in comparison, after inhalation of a single 300 mg dose of tobi, sputum c max was 737 ± 1028 mcg/g. the variability in pharmacokinetic parameters was higher in sputum as compared to serum. distribution a population pharmacokinetic analysis for tobi podhaler in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 85.1 l for a typical cystic fibrosis (cf) patient. binding of tobramycin to serum proteins is negligible. metabolism tobramycin is not metabolized and is primarily excreted unchanged in the urine. elimination tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. systemically absorbed tobramycin following tobi podhaler administration is also expected to be eliminated principally by glomerular filtration. the apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of tobi podhaler was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after tobi inhalation. a population pharmacokinetic analysis for tobi podhaler in cystic fibrosis patients aged 6 to 58 years estimated the apparent serum clearance of tobramycin to be 14.5 l/h. no clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis. 12.4 microbiology mechanism of action tobramycin is an aminoglycoside antibacterial produced by streptomyces tenebrarius . it acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death. tobramycin has in vitro activity against gram-negative bacteria including p. aeruginosa . it is bactericidal in vitro at peak concentrations equal to or slightly greater than the minimum inhibitory concentration (mic). susceptibility testing interpretive criteria for inhaled antibacterial products are not defined. the in vitro antimicrobial susceptibility test methods used to determine the susceptibility for parenteral tobramycin therapy can be used to monitor the susceptibility of p. aeruginosa isolated from cystic fibrosis patients. (1,2,3) the relationship between in vitro susceptibility test results and clinical outcome with tobi podhaler therapy is not clear. a single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of p. aeruginosa and each morphotype may require a different concentration of tobramycin to inhibit its growth in vitro. patients should be monitored for changes in tobramycin susceptibility. development of resistance in clinical studies, some increases from baseline to the end of the treatment period were observed in the tobramycin mic for p. aeruginosa morphotypes. in general, a higher percentage of patients treated with tobi podhaler had increases in tobramycin mic compared with placebo or patients treated with tobi inhalation solution. the clinical significance of changes in mics for p. aeruginosa has not been clearly established in the treatment of cystic fibrosis patients. cross-resistance some emerging resistance to aztreonam, ceftazidime, ciprofloxacin, imipenem, or meropenem were observed in the tobi podhaler clinical trials. as other anti-pseudomonal antibiotics were concomitantly utilized in many patients in the clinical trials, the association with tobi podhaler is not clear. other no trends were observed in the isolation of treatment-emergent bacterial respiratory pathogens ( burkholderia cepacia, stenotrophomonas maltophilia, staphylococcus aureus, and achromobacter xylosoxidans ).

following the 112 mg tobi podhaler dose and 4.8 ± 2.5 mcg∙h/ml following the 300 mg tobi dose. at the end of a 4-week dosing cycle of tobi podhaler (112 mg twice-daily), the maximum serum concentration of tobramycin 1 hour after dosing ranged from 1.48 ± 0.69 mcg/ml to 1.99 ± 0.59 mcg/ml (mean ± sd). sputum concentrations after inhalation of a 112 mg single dose (4 times 28 mg capsules) of tobi podhaler in cystic fibrosis patients, sputum c max of tobramycin was 1048 ± 1080 mcg/g (mean ± sd). in comparison, after inhalation of a single 300 mg dose of tobi, sputum c max was 737 ± 1028 mcg/g. the variability in pharmacokinetic parameters was higher in sputum as compared to serum. distribution a population pharmacokinetic analysis for tobi podhaler in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 85.1 l for a typical cystic fibrosis (cf) patient. binding of tobramycin to serum proteins is negligible. metabolism tobramycin is not metabolized and is primarily excreted unchanged in the urine. elimination tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. systemically absorbed tobramycin following tobi podhaler administration is also expected to be eliminated principally by glomerular filtration. the apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of tobi podhaler was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after tobi inhalation. a population pharmacokinetic analysis for tobi podhaler in cystic fibrosis patients aged 6 to 58 years estimated the apparent serum clearance of tobramycin to be 14.5 l/h. no clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis.

l aberrations in chinese hamster ovary cells, and was negative in the mouse micronucleus test. subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.

amster ovary cells, and was negative in the mouse micronucleus test. subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.

ed with tobi podhaler, 37% were males and 63% were females. thirty-six patients were between 6 and 12 years of age, and 40 patients were between 13 and 21 years of age. patients had a mean baseline fev 1 of 56% of predicted normal value. in both studies, >90% of patients received concomitant therapies for cystic fibrosis-related indications. the most frequently used other antibacterial drugs (any route of administration) were azithromycin, ciprofloxacin, and ceftazidime. consistent with the population of cystic fibrosis patients, the most frequently used concomitant medications included oral pancreatic enzyme preparations, mucolytics (especially dornase alfa), and selective β 2 -adrenoreceptor agonists. study 2 study 2 was a randomized, 3-cycle, 2-arm trial. each cycle comprised of 28 days on treatment followed by 28 days off treatment. the first cycle was double-blind, placebo-controlled with eligible patients randomized 1:1 to tobi podhaler (4 times 28 mg capsules twice-daily) or placebo. upon completion of the first cycle, patients who were randomized to the placebo treatment group received tobi podhaler for cycles 2 and 3. the total treatment period was 24 weeks. a total of 95 patients were randomized into study 2 and received tobi podhaler (n=46) or placebo (n=49) in cycle 1. all patients were less than 22 years of age (mean age 13.3 years) and had not received inhaled antipseudomonal antibiotics within four months prior to screening; 56% were female and 84% were caucasian. this study was stopped early for demonstrated benefit and the primary analysis used the set of patients included in the interim analysis (n=79); 16 patients did not have data on the primary endpoint at that time. of the 79 patients included in the interim analysis, 18 patients were excluded due to a failure to meet spirometry quality review criteria as determined by an external review panel. this resulted in a total of 61 patients, 29 in the tobi podhaler arm and 32 in the placebo arm, who were included in the primary analysis. in the primary analysis, tobi podhaler significantly improved lung function compared with placebo as measured by the relative change in fev 1 % predicted from baseline to the end of cycle 1 dosing. this analysis adjusted for the covariates of baseline fev 1 % predicted, age, and region, and imputed for missing data. treatment with tobi podhaler and placebo resulted in relative increases in fev 1 % predicted of 12.54% and 0.09%, respectively (ls mean difference = 12.44%; 95% ci: 4.89, 20.00; p=0.002). analysis of absolute changes in fev 1 % predicted showed ls means of 6.38% for tobi podhaler and -0.52% for placebo with a difference of 6.90% (95% ci: 2.40, 11.40). improvements in lung function were achieved during the subsequent cycles of treatment with tobi podhaler, although the magnitude was reduced (figure 1). the percentage of patients using new antipseudomonal antibiotics in cycle 1 was greater in the placebo treatment group (18.4%) compared with the tobi podhaler treatment group (13.1%). during the first cycle, 8.7% of tobi podhaler patients and 10.2% of placebo patients were treated with parenteral antipseudomonal antibiotics. in cycle 1, two patients (4.4%) in the tobi podhaler treatment group required respiratory-related hospitalizations, compared with six patients (12.2%) in the placebo treatment group. figure 1 – study 2: mean relative change in fev1 % predicted from baseline in cycles 1 to 3 by treatment group study 3 study 3 was a randomized, double-blind, placebo-controlled trial, similar in design to study 2. eligible patients were randomized 1:1 to receive tobi podhaler (4 times 28 mg capsules twice-daily) or placebo for one cycle (28 days on-treatment and 28 days off-treatment). a total of 62 patients were randomized into study 3 and allocated to tobi podhaler (n=32) or placebo (n=30). all patients were less than 22 years of age (mean age 12.9 years) and had not received inhaled antipseudomonal antibiotics within 4 months prior to screening; 64.5% were female and 98.4% were caucasian. in this study, the results were not statistically significant for the primary lung function endpoint when adjusting for the covariates of age (<13 years, ≥13 years) and fev 1 % predicted at screening (<50%, ≥50%) and imputing for missing data. improvement in lung function for tobi podhaler compared with placebo was evaluated using the relative change in fev 1 % predicted from baseline to the end of cycle 1 dosing. treatment with tobi podhaler (8.19%) compared to placebo (2.27%) failed to achieve statistical significance in relative change in fev 1 % predicted (ls mean difference = 5.91%; 95% ci: -2.54, 14.37; p=0.167). analyses of absolute changes in fev 1 % predicted showed ls means of 4.86% for tobi podhaler and 0.48% for placebo with a difference of 4.38% (95% ci:-0.17, 8.94). study 1 study 1 was a randomized, open-label, active-controlled parallel arm trial. eligible patients were randomized 3:2 to tobi podhaler (4 times 28 mg capsules twice-daily) or tobi (300 mg/5 ml twice-daily). treatment was administered for 28 days, followed by 28 days off therapy (one cycle) for three cycles. the total treatment period was 24 weeks. the time to administer a dose of tobi podhaler (10 th to 90 th percentiles) ranged from 2 to 7 minutes at the end of the dosing period for cycle 1, and 2 to 6 minutes at the end of the dosing period for cycle 3. a total of 517 patients were randomized in study 1 and received tobi podhaler (n=308) or tobi (n=209). patients were predominantly 20 years of age or older (mean age 25.6 years) with no inhaled antipseudomonal antibiotic use within 28 days prior to study drug administration; 45% were female and 91% were caucasian. the primary purpose of study 1 was to evaluate safety. interpretation of efficacy results in study 1 is limited by several factors including open-label design, testing of multiple secondary endpoints, and missing values for the outcome of fev 1 % predicted. the number (%) of patients with missing values for fev 1 % predicted at weeks 5 and 25 in the tobi podhaler treated group were 40 (13.0%) and 86 (27.9%) compared to 15 (7.2%) and 40 (19.1%) in the tobi treated group. using imputation of the missing data, the mean differences (tobi podhaler minus tobi) in the percent relative change from baseline in fev 1 % predicted at weeks 5 and 25 were -0.87 (95% ci: -3.80, 2.07) and 1.62 (95% ci: -0.90, 4.14), respectively. figure 1 – study 2: mean relative change in fev1 % predicted from baseline in cycles 1 to 3 by treatment group

rmitted to 15°c to 30°c (59°f to 86°f) protect tobi podhaler from moisture. • tobi podhaler capsules should be used with the podhaler device only. the podhaler device should not be used with any other capsules. • capsules should always be stored in the blister and each capsule should only be removed immediately before use. • always use the new podhaler device provided with each weekly pack. keep this and all drugs out of the reach of children.

ey are feeling better. 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. patients should be advised that if they have been prescribed a 7-day pack of tobi podhaler either immediately before or during a 28-day treatment with tobi podhaler, then they must count each day of use toward the 28 day on-treatment part of their cycle. patients should only take a total of 28 consecutive days of treatment during a cycle. similarly, patients should be advised that if they have been prescribed a 1-day pack of tobi podhaler either immediately before or during a 28-day treatment with tobi podhaler, then they must count each day of use toward the 28 day on-treatment part of their cycle. patients should only take a total of 28 consecutive days of treatment during a cycle. it is important for patients to understand how to correctly administer tobi podhaler capsules using the podhaler device. it is recommended that caregivers and patients be adequately trained in the proper use of the tobi podhaler prior to use. [see instructions for use at the end of the patient information leaflet.] caregivers should provide assistance to children using tobi podhaler (including preparing the dose for inhalation) particularly for those aged 10 years or younger, and should continue to supervise them until they are able to use the podhaler device properly without help. for patients taking several different inhaled medications and/or performing chest physiotherapy, advise the patient regarding the order in which they should take the therapies. it is recommended that tobi podhaler be taken last. difficulty breathing : advise patients to inform their physicians if they experience shortness of breath or wheezing after administration of tobi podhaler. tobi podhaler can cause a narrowing of the airway [see warnings and precautions (5.1) ]. hearing loss : advise patients to inform their physician if they experience ringing in the ears, dizziness, or any changes in hearing because tobi podhaler has been associated with hearing loss [see warnings and precautions (5.2) ]. kidney damage : advise patients to inform their physician if they have any history of kidney problems because tobi podhaler is in a class of drugs that have caused kidney damage [see warnings and precautions (5.3) ] . embryo-fetal toxicity: advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to a pregnant woman [see warnings and precautions (5.5) and use in specific populations (8.1) ]. lactation: advise a woman to monitor their breastfed infants for diarrhea and/or bloody stools [see use in specific populations (8.2) ] . cough: inform patients that cough was reported with the use of tobi podhaler in clinical trials. if coughing that may be experienced with tobi podhaler becomes bothersome or cannot be tolerated, advise patients that tobramycin inhalation solution or alternative therapeutic options may be considered.

ess than 25% or greater than 80% predicted • in people who are colonized with a bacterium called burkholderia cepacia who should not use tobi podhaler? do not use tobi podhaler if you are allergic to tobramycin, any of the ingredients in tobi podhaler, or to any other aminoglycoside antibacterial medicines. what should i tell my healthcare provider before using tobi podhaler? before using tobi podhaler, tell your healthcare provider about all of your medical conditions, including if you: • have or have had hearing problems (including noises in your ears such as ringing or hissing), hearing loss, or your mother has had hearing problems after taking an aminoglycoside. • have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from your mother. • have dizziness. • have or have had kidney problems. • have or have had problems with muscle weakness such as myasthenia gravis or parkinson’s disease. • have or have had breathing problems such as wheezing, coughing, or chest tightness. • have had an organ transplant. • are pregnant or plan to become pregnant. tobi podhaler contains a medicine that can harm your unborn baby. see “ what are the possible side effects of tobi podhaler? ” for more information. • are breastfeeding or plan to breastfeed. it is not known if the medicine in tobi podhaler (tobramycin inhalation powder) passes into your breast milk. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. using tobi podhaler with certain other medicines can cause serious side effects. ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. know the medicines you take. keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. if you are using tobi podhaler, you should discuss with your healthcare provider if you should take: • other medicines that may harm your nervous system, kidneys, or hearing • “water pills” (diuretics) such as edecrin (ethacrynic acid), lasix (furosemide), or intravenous mannitol • urea how should i use tobi podhaler? • see the step-by-step instructions for use at the end of this patient information leaflet about the right way to use tobi podhaler. do not use tobi podhaler unless your healthcare provider has taught you how to use it the right way. • use tobi podhaler exactly as your healthcare provider tells you to use it. ask your healthcare provider or pharmacist if you are not sure. • the usual dose for adults and children over 6 years of age is: • the contents of 4 tobi podhaler capsules inhaled by mouth in the morning using your podhaler device and the contents of 4 tobi podhaler capsules inhaled by mouth in the evening using your podhaler device. • check to see that each capsule is empty after inhaling. if powder remains in the capsule, repeat inhalation until the capsule is empty. • each dose of 4 tobi podhaler capsules should be taken as close to 12 hours apart as possible. • you should not take your dose of 4 tobi podhaler capsules less than 6 hours apart. • after using tobi podhaler for 28 days, you should stop using it and wait 28 days. after you have stopped using tobi podhaler for 28 days, you should start using tobi podhaler again for 28 days. complete the full 28-day course even if you are feeling better. it is important that you keep to the 28-day on, 28-day off cycle (see figure a). (figure a) • if you have been prescribed a 7-day pack of tobi podhaler either immediately before or during a 28-day treatment with tobi podhaler, then you must count each day of use toward the 28-day on-treatment part of the cycle. you should only take a total of 28 consecutive days of treatment during a cycle. • if you have been prescribed a 1-day pack of tobi podhaler either immediately before or during a 28-day treatment with tobi podhaler, then you must count each day of use toward the 28-day on-treatment part of the cycle. you should only take a total of 28 consecutive days of treatment during a cycle. • if you are taking other medicines inhaled through your mouth, your healthcare provider will tell you how to take your medicines the right way. • if you are doing therapies for cystic fibrosis (chest physiotherapy), you should use tobi podhaler after your other therapies are done. • if you inhale too much tobi podhaler, tell your healthcare provider right away. • if you accidentally swallow tobi podhaler capsules, tell your healthcare provider right away. • use a new tobi podhaler device every 7 days. • caregivers should help children who are 10 years of age and younger use tobi podhaler, and keep watching them use their tobi podhaler until they are able to use it the right way without help. • tell your doctor if your symptoms worsen while using your tobi podhaler. what are the possible side effects of tobi podhaler? tobi podhaler can cause serious side effects, including: • severe breathing problems (bronchospasm) . tell your healthcare provider right away if you get any of these symptoms of bronchospasm while using tobi podhaler: • shortness of breath with wheezing • coughing and chest tightness • hearing loss or ringing in the ears (ototoxicity) . tell your healthcare provider right away if you have hearing loss or hear noises in your ears such as ringing or hissing, or if you develop vertigo, difficulty with balance or dizziness. • worsening kidney problems (nephrotoxicity) . tobi podhaler is in a class of medicines which may cause worsening kidney problems, especially in people with known or suspected kidney problems. your healthcare provider may do a blood test to check how your kidneys are working while you are using tobi podhaler. • worsening muscle weakness . tobi podhaler is in a class of medicines which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or parkinson’s disease). • the medicine in tobi podhaler is in a class of medicines which may cause harm to an unborn baby . the most common side effects of tobi podhaler include: • cough • worsening of lung problems or cystic fibrosis • productive cough • shortness of breath • fever • sore throat • changes in your voice (hoarseness) • coughing up blood • headache let your healthcare provider know if your symptoms get worse. some patients may not be able to continue using tobi podhaler and need to consider other treatments. tell your healthcare provider about any side effect that bothers you enough to stop treatment or that does not go away. these are not all of the possible side effects of tobi podhaler. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. general information about the safe and effective use of tobi podhaler. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use tobi podhaler for a condition for which it was not prescribed. do not give tobi podhaler to other people, even if they have the same problem you have. it may harm them. you can ask your healthcare provider or pharmacist for information about tobi podhaler that was written for healthcare professionals. for more information, go to www.tobipodhaler.com or call 1-877-999-tobi (8624). what are the ingredients in tobi podhaler? active ingredient : tobramycin inactive ingredients : 1,2-distearoyl-sn-glycero-3-phosphocholine (dspc), calcium chloride, and sulfuric acid (for ph adjustment) patient information leaflet figure a