TOBI PODHALER- tobramycin_capsule
Function and Efficacy
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.
CLINICAL PHARMACOLOGY
Tobramycin is an aminoglycoside antibacterial [see Clinical Pharmacology (12. 4) TOBI Podhaler contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. TOBI Podhaler is specifically formulated for administration by oral inhalation. The systemic exposure to tobramycin after inhalation of TOBI Podhaler is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as tobramycin and is not absorbed to any appreciable extent when administered via the oral route. After inhalation of a 112 mg single dose (4 times 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, the maximum serum concentration (C max max max max 0-12 After inhalation of a 112 mg single dose (4 times 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, sputum C max max 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. Tobramycin is not metabolized and is primarily excreted unchanged in the urine. 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. No clinically relevant covariates that were predictive of tobramycin clearance were identified from this analysis. Tobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius Tobramycin has in vitro activity against Gram-negative bacteria including P. aeruginosa 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 (1,2,3) P. aeruginosa In clinical studies, some increases from baseline to the end of the treatment period were observed in the tobramycin MIC for P. aeruginosa The clinical significance of changes in MICs for P. aeruginosa 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. No trends were observed in the isolation of treatment-emergent bacterial respiratory pathogens ( Burkholderia cepacia, Stenotrophomonas maltophilia, Staphylococcus aureus, Achromobacter xylosoxidans.
Serum Concentrations
After inhalation of a 112 mg single dose (4 times 28 mg capsules) of TOBI Podhaler in cystic fibrosis patients, the maximum serum concentration (C max max max max 0-12
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 max
Indication
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 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 Burkholderia cepacia 1.
Usage and Dosage
DOSAGE AND ADMINISTRATION
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. 2 2 2 2.
INSTRUCTIONS FOR USE
TOBI (TOH-bee) Podhaler (POD-hay-ler) Your healthcare provider should show you or a caregiver how to use TOBI Podhaler the right way before you use it for the first time. 4 capsules inhaled by mouth 2 times each day 4 capsules for inhalation in the morning 4 capsules for inhalation in the evening. You must inhale all of the powdered medicine from all 4 TOBI Podhaler capsules to get the full dose. o 2 (See Figure S) ▪ is throw it away ▪ is not see the section “What to do with a capsule that has not been emptied” You or a caregiver should tell your healthcare provider as soon as possible if you think you or your child has not received the full TOBI Podhaler dose. Your healthcare provider should show you how to use TOBI Podhaler the right way. Each TOBI Podhaler package contains o 4 weekly packs (28-day supply), each containing ▪ ▪ ▪ Or: o 7-day pack (7-day supply) containing: ▪ ▪ Or: o 1-day pack (1-day supply) containing: ▪ ▪ Note: Do not Do not do not Each Podhaler device is only used for 1 week (7 days). o o o Getting ready: Wash and dry your hands Preparing your TOBI Podhaler dose Your Podhaler device comes in a storage case with a lid. The device has a removable mouthpiece, capsule chamber and a button at its base (See Figure C). Step 1: Step 2: Step 3: Note: Each blister card contains 8 TOBI Podhaler capsules: 4 capsules for inhalation in the morning and 4 capsules for inhalation in the evening. Step 4 Step 5: Step 6: Note: Step 7: Do not Step 8: Do not Step 9 Do not Taking your TOBI Podhaler dose Note: You will need to repeat Step 10 to Step 14 for each capsule so you inhale each capsule 2 times to empty the capsule. Step 10: Do not Step 11: Step 12 Step 13: Remove hold your breath Step 14: Do not Step 15 using the same capsule inhale 2 times from each capsule Step 16: Step 17 is “What to do with a capsule that has not been emptied” What to do with a capsule that has not been emptied: (See Figure T) o o o (See Figure U) o o o Note: o o using the same capsule Step 18: After your TOBI Podhaler dose: Step 19: Do not Step 20: Do not Step 21 dry cloth Do not Step 22: Step 23: How should I store TOBI Podhaler? Keep the TOBI Podhaler capsules and Podhaler device in a dry place. This Patient Information and Instructions for Use have been approved by the U. Food and Drug Administration. copyright 2020 Mylan Inc. Tobi registered registered Manufactured for: Mylan Specialty L. Manufactured by: Mylan Pharmaceuticals Inc. Revised: 7/2020 Instructions for Use Figure A Instructions for Use Figure B Instructions for Use Figure C Instructions for Use Figure D Instructions for Use Figure E Instructions for Use Figure F Instructions for Use Figures G and H Instructions for Use Figure I Instructions for Use Figure J Instructions for Use Figure K Instructions for Use Figure L Instructions for Use Figure M Instructions for Use Figure N Instructions for Use Figure O Instructions for Use Figure P Instructions for Use Figures Q and R Instructions for Use Figure S Instructions for Use Figure T Instructions for Use Figure U Instructions for Use Figure V Instructions for Use Figure W Instructions for Use Figure X.
Label
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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. , 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 1 1 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 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 TOBI Podhaler TOBI Respiratory, thoracic, and mediastinal disorders Cough 48. 1 Lung disorder This includes adverse events of pulmonary or cystic fibrosis exacerbations 33. 1 Productive cough 18. 6 Dyspnea 15. 4 Oropharyngeal pain 14. 5 Dysphonia 13. 8 Hemoptysis 13. 4 Nasal congestion 8. 2 Wheezing 6. 2 Chest discomfort 6. 9 Throat irritation 4. 9 Gastrointestinal disorders Nausea 7. 6 Vomiting 6. 7 Diarrhea 4. 9 Dysgeusia 3. 5 Infections and infestations Upper respiratory tract infection 6. 6 Investigations Pulmonary function test decreased 6. 1 Forced expiratory volume decreased 3. 0 Blood glucose increased 2. 5 Vascular disorders Epistaxis 2. 9 Nervous system disorders Headache 11. 0 General disorders and administration site conditions Pyrexia 15. 4 Musculoskeletal and connective tissue disorders Musculoskeletal chest pain 4. 8 Skin and subcutaneous tissue disorders Rash 2. 4 Adverse drug reactions that occurred in <2% of patients treated with TOBI Podhaler in Study 1 were: bronchospasm (TOBI Podhaler 1. 5%); deafness including deafness unilateral (reported as mild to moderate hearing loss or increased hearing loss) (TOBI Podhaler 1. 5%); and tinnitus (TOBI Podhaler 1. 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 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%) 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 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. , 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 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%). 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.
Precautions
TOBI Podhaler is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside ( 4.
Special Population Medication
USE IN SPECIFIC POPULATIONS
Aminoglycosides can cause fetal harm. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [ Warnings and Precautions (5. 5) [see Clinical Pharmacology (12. 3) (see Clinical Considerations (see Data 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. 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. Cystic fibrosis may increase the risk for preterm delivery. 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. 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) (see 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). 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. 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. 5) 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. 5) 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. Adequate data do not exist for the use of TOBI Podhaler in patients after organ transplantation.
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).
Drug Interactions
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.
Other Information
OVERDOSAGE
The maximum tolerated daily dose of TOBI Podhaler has not been established. In the event of accidental oral ingestion of TOBI Podhaler capsules, systemic toxicity is unlikely as tobramycin is poorly absorbed. Tobramycin serum concentrations may be helpful in monitoring overdosage. Acute toxicity should be treated with immediate withdrawal of TOBI Podhaler, and baseline tests of renal function should be undertaken. Hemodialysis may be helpful in removing tobramycin from the body. In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.
NONCLINICAL TOXICOLOGY
Carcinogenicity studies were not conducted with TOBI Podhaler. A 2-year rat inhalation toxicology study to assess carcinogenic potential of TOBI (tobramycin inhalation solution, USP) has been completed. Rats were exposed to TOBI for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin of up to 35 mcg/mL were measured in rats, in contrast to the maximum 1.99 +/- 0.59 mcg/mL level observed in cystic fibrosis patients in TOBI Podhaler clinical trials. There was no drug-related increase in the incidence of any variety of tumor. Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal 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.
CLINICAL STUDIES
The Phase 3 clinical development program included two placebo-controlled studies (Studies 2 and 3) and one open-label study (Study 1), which randomized and dosed 157 and 517 patients, respectively, with a clinical diagnosis of cystic fibrosis, confirmed by quantitative pilocarpine iontophoresis sweat chloride test, well-characterized disease causing mutations in each CFTR gene, or abnormal nasal transepithelial potential difference characteristic of cystic fibrosis. In the placebo-controlled studies, all patients were aged between 6 and 21 years old and had an FEV 1 P. aeruginosa 1 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 beta 2 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 1 1 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. 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 en dash Study 2: Mean Relative Change in FEV 1 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 1 1 1 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 time to administer a dose of TOBI Podhaler (10 th th 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 1 1 Figure 1 en dash Study 2: Mean Relative Change in FEV1 % Predicted from Baseline in Cycles 1 to 3 by Treatment Group.
REFERENCES
1. 2. 3.
Patient Information
TOBI (TOH-bee) Podhaler (POD-hay-ler) (tobramycin inhalation powder) for oral inhalation use Important information: Do not swallow TOBI Podhaler capsules. TOBI Podhaler capsules are used only with the Podhaler device and inhaled through your mouth (oral inhalation). Never place a capsule in the mouthpiece of the Podhaler device. Read this Patient Information leaflet before you start using TOBI Podhaler and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. What is TOBI Podhaler? TOBI Podhaler is a prescription medicine used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa It is not known if TOBI Podhaler is safe and effective: 1 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: What are the possible side effects of TOBI Podhaler? Tell your healthcare provider about all the medicines you take 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: How should I use TOBI Podhaler? o o What are the possible side effects of TOBI Podhaler? TOBI Podhaler can cause serious side effects, including: severe breathing problems (bronchospasm) o o hearing loss or ringing in the ears (ototoxicity) worsening kidney problems (nephrotoxicity) worsening muscle weakness 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: 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 Inactive ingredients Patient Information Figure A.