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1 INDICATIONS AND USAGE Tobramycin inhalation solution 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 six years, patients with FEV 1 less than 40% or greater than 80% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ]. Tobramycin inhalation solution is an inhaled aminoglycoside antibacterial indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa. ( 1 ) Safety and efficacy have not been demonstrated in patients under the age of six years, patients with a forced expiratory volume in one second (FEV 1 ) less than 40% or greater than 80% predicted, or patients colonized with Burkholderia cepacia . ( 1 )

2 DOSAGE AND ADMINISTRATION For oral inhalation only ( 2.1 ) Administer the entire contents of one ampule twice daily by oral inhalation in repeated cycles of 28 days on drug, followed by 28 days off drug. ( 2.1 ) 2.1 Dosage Tobramycin inhalation solution is for oral inhalation only [see Dosage and Administration (2.2) ] . The recommended dosage of tobramycin inhalation solution for patients six years of age and older is to administer one single-dose ampule (300 mg/4 mL) twice daily by oral inhalation in repeated cycles of 28 days on drug, followed by 28 days off drug. The doses should be taken as close to 12 hours apart as possible and not less than 6 hours apart. The 300 mg/4 mL dose of tobramycin inhalation solution is the same for patients regardless of age or weight. Tobramycin inhalation solution has not been studied in patients less than six years old. If patients miss a dose, they should take it as soon as possible anytime up to 6 hours prior to their next scheduled dose. If less than 6 hours remain before the next dose, wait until their next scheduled dose. 2.2 Administration Instructions Tobramycin inhalation solution is administered by oral inhalation using a hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios Air compressor over an approximately 15 minute period and until sputtering from the output of the nebulizer has occurred for at least one minute. Tobramycin inhalation solution should not be diluted or mixed with dornase alfa or other medications in the nebulizer. Tobramycin inhalation solution is not for subcutaneous, intravenous, or intrathecal administration. Further patient instructions on how to administer tobramycin inhalation solution are provided in the Patient's Instructions for Use [see Patient Counseling Information (17) ]. Tobramycin inhalation solution should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days.

3 DOSAGE FORMS AND STRENGTHS Tobramycin inhalation solution, USP is supplied as a sterile, a clear, colorless or slight yellow to pale yellow color, non-pyrogenic, aqueous inhalational solution for nebulization in single-dose 4 mL ampule containing 300 mg of tobramycin, USP. Inhalation Solution: 300 mg tobramycin per 4 mL solution in a single-dose ampule. ( 16 )

4 CONTRAINDICATIONS Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. ( 4 )

5 WARNINGS AND PRECAUTIONS Caution should be exercised when prescribing tobramycin inhalation solution to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction. ( 5.1 , 5.2 , 5.3 and 5.5 ) Aminoglycoside may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. ( 5.3 ) Bronchospasm can occur with inhalation of tobramycin inhalation solution. ( 5.4 ) Audiograms, serum concentration, and renal function should be monitored as appropriate. ( 5.2 and 5.5 ) Fetal harm can occur when aminoglycosides are administered to a pregnant woman. Apprise women of the potential hazard to the fetus. ( 5.6 ) 5.1 Ototoxicity Ototoxicity with use of tobramycin inhalation solution Caution should be exercised when prescribing tobramycin inhalation solution to patients with known or suspected auditory or vestibular dysfunction. Findings related to ototoxicity as measured by audiometric evaluations and auditory adverse event reports were similar between tobramycin inhalation solution and placebo in controlled clinical trials. Hearing loss was reported in two (1.1%) tobramycin inhalation solution-treated patients and in one (0.9%) placebo-treated patient during clinical studies. Additionally, dizziness and vertigo, both of which may be manifestations of vestibular forms of ototoxicity, were observed in similar numbers of tobramycin inhalation solution- and placebo-treated patients. Dizziness occurred in two (1.1%) tobramycin inhalation solution-treated patients and one (0.9%) placebo-treated patient and vertigo occurred in two (1.1%) tobramycin inhalation solution-treated patients versus no placebo patients in clinical studies. None of the tobramycin inhalation solution patients discontinued their therapy due to hearing loss, dizziness or vertigo. Tinnitus may be a sentinel symptom of ototoxicity. No reports of tinnitus occurred in patients during clinical studies with tobramycin inhalation solution, but because it has been observed with inhaled tobramycin solutions [see Adverse Reactions (6.2) ] , onset of this symptom warrants caution. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking tobramycin inhalation solution. Monitoring may include obtaining audiometric evaluations and serum tobramycin levels. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution. 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.

toxicity 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. 5.2 Nephrotoxicity Caution should be exercised when prescribing tobramycin inhalation solution to patients with known or suspected renal dysfunction. Nephrotoxicity was not seen during tobramycin inhalation solution clinical studies but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with tobramycin inhalation solution should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician. If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution until serum concentrations fall below 2 mcg/mL. Twenty-six (14%) tobramycin inhalation solution patients and 15 (13%) placebo patients had increases in serum creatinine of at least 50% over baseline. Follow-up values were obtained for 17 of the 26 tobramycin inhalation solution patients, all of which decreased to serum creatinine values that were within normal laboratory ranges. Patients who experience an increase in serum creatinine during treatment with tobramycin inhalation solution should have their renal function closely monitored. 5.3 Neuromuscular Disorders Tobramycin inhalation solution should be used cautiously in patients with muscular disorders. Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson's disease. Prolonged respiratory paralysis may also occur in patients receiving concomitant neuromuscular blocking agents. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. 5.4 Bronchospasm Bronchospasm has been reported with inhalation of tobramycin. In clinical studies with tobramycin inhalation solution, bronchospasm was observed in one (0.5%) tobramycin inhalation solution-treated patient and in no placebo-treated patients. Wheezing occurred in ten (5%) tobramycin inhalation solution-treated patients and four (4%) placebo-treated patients. Bronchospasm and wheezing should be treated as medically appropriate. 5.5 Laboratory Tests Audiograms Clinical studies of inhaled tobramycin solutions did not identify hearing loss using audiometric tests which evaluated hearing up to 8000 Hz. Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Serum Concentrations In patients with normal renal function treated with tobramycin inhalation solution, serum tobramycin concentrations range from approximately 0.06-1.89 mcg/mL one hour after dose administration and do not require routine monitoring.

toxicity, and therefore the onset of this symptom warrants caution. Serum Concentrations In patients with normal renal function treated with tobramycin inhalation solution, serum tobramycin concentrations range from approximately 0.06-1.89 mcg/mL one hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician [see Clinical Pharmacology (12.3) ] . The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing. Renal Function The clinical studies of tobramycin inhalation solution did not reveal any imbalance in the percentage of patients who experienced at least a 50% rise in serum creatinine from baseline in either the tobramycin inhalation solution group (n=26, 14%) or the placebo group (n=15, 13%). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician. 5.6 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 tobramycin inhalation solution during pregnancy, or become pregnant while taking tobramycin inhalation solution should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ] . 5.7 Concomitant Use of Systemic Aminoglycosides Patients receiving concomitant tobramycin inhalation solution and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

6 ADVERSE REACTIONS Common adverse reactions (more than 5%) occurring more frequently in tobramycin inhalation solution patients are forced expiratory volume decreased, rales, red blood cell sedimentation rate increased, and dysphonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 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 clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to tobramycin inhalation solution in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving tobramycin inhalation solution ranged in age from 6 to 31 years. In Study 1, an eight week study, 29 patients received tobramycin inhalation solution versus 30 patients who received placebo for a total of four weeks on drug and four weeks off drug. All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. 52.5% of patients were 6 to 12 years of age while 30.5% of patients were 13-17 years old. Only 16.5% of patients were adults (> 17 years old). Eighty percent (80%) of patients were chronically colonized with Pseudomonas aeruginosa while 20.3% of patients were initially or intermittently colonized with Pseudomonas aeruginosa during the study. More patients in the placebo group discontinued/dropped out of Study 1 than in the tobramycin inhalation solution group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the tobramycin inhalation solution group discontinued/dropped out because of treatment-emergent adverse events (TEAEs) such as pulmonary exacerbations and respiratory disorders. In Study 2, a 24 week study, 161 patients received tobramycin inhalation solution versus 85 patients who received placebo in alternating four week on-off cycles for three cycles. All patients were ≤ 46 years of age (mean age 14.8 years) and 45% were females. 41% of patients were 6-12 years old while 29% of patients were 13-17 years old. Only 30% were adults (>17 years). Eighty-seven percent (87%) of patients were chronically colonized with P. aeruginosa . Only 13% were either initially or intermittently colonized with P. aeruginosa during the study. More patients in the placebo group discontinued/dropped out of Study 2 than in the tobramycin inhalation solution group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the tobramycin inhalation solution group (1.9%) compared to 2 patients in the placebo group (2.4%) withdrew due to a TEAE. The most common TEAEs causing patients to discontinue from the study drug are respiratory, thoracic, and mediastinal disorders. The most common adverse experiences reported were respiratory disorders, consistent with the underlying disease in the patient population being evaluated and these were similarly distributed between both tobramycin inhalation solution- and placebo-treated patients. The following adverse reactions were reported in at least 5% of tobramycin inhalation solution -treated patients and at rates ≥ 2% more common compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1).

cebo-treated patients. The following adverse reactions were reported in at least 5% of tobramycin inhalation solution -treated patients and at rates ≥ 2% more common compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1). Table 1: Patients with Selected Treatment-Emergent Adverse Reactions Occurring in ≥ 2% of Tobramycin Inhalation Solution Patients Adverse Reactions Tobramycin Inhalation Solution N=190 (%) Placebo N=115 (%) Forced expiratory volume decreased 59 (31%) 33 (29%) Rales 36 (19%) 18 (16%) Red blood cell sedimentation rate increased 16 (8%) 6 (5%) Dysphonia 11 (6%) 2 (2%) Wheezing 10 (5%) 4 (4%) Epistaxis 6 (3%) 0 Pharyngolaryngeal pain 5 (3%) 2 (2%) Bronchitis 5 (3%) 1 (1%) Tonsillitis 4 (2%) 0 Diarrhea 3 (2%) 1 (1%) Eosinophilia 3 (2%) 0 Immunoglobulins increased 3 (2%) 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tobramycin inhalation solution. 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. Ear and labyrinth disorders: Hearing loss, Tinnitus [see Warnings and Precautions (5.1) ] Skin and subcutaneous tissue disorders: Hypersensitivity, pruritus, urticaria, rash Nervous system disorders: Aphonia, dysgeusia Respiratory, thoracic, and mediastinal disorders: Bronchospasm [see Warnings and Precautions (5.4) ] , oropharyngeal pain Metabolism and Nutrition Disorders: Decreased appetite

<table ID="ID167" width="631" styleCode="Noautorules"><col width="225"/><col width="217"/><col width="189"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse Reactions</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Tobramycin Inhalation Solution</content><content styleCode="bold"> N=190</content> <content styleCode="bold"> (%)</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo N=115</content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Forced expiratory volume decreased </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 59 (31%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 33 (29%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Rales </td><td styleCode=" Botrule Rrule" align="center"> 36 (19%) </td><td styleCode=" Botrule Rrule" align="center"> 18 (16%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Red blood cell sedimentation rate increased </td><td styleCode=" Botrule Rrule" align="center"> 16 (8%) </td><td styleCode=" Botrule Rrule" align="center"> 6 (5%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Dysphonia </td><td styleCode=" Botrule Rrule" align="center"> 11 (6%) </td><td styleCode=" Botrule Rrule" align="center"> 2 (2%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Wheezing </td><td styleCode=" Botrule Rrule" align="center"> 10 (5%) </td><td styleCode=" Botrule Rrule" align="center"> 4 (4%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Epistaxis </td><td styleCode=" Botrule Rrule" align="center"> 6 (3%) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Pharyngolaryngeal pain </td><td styleCode=" Botrule Rrule" align="center"> 5 (3%) </td><td styleCode=" Botrule Rrule" align="center"> 2 (2%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Bronchitis </td><td styleCode=" Botrule Rrule" align="center"> 5 (3%) </td><td styleCode=" Botrule Rrule" align="center"> 1 (1%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Tonsillitis </td><td styleCode=" Botrule Rrule" align="center"> 4 (2%) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea </td><td styleCode=" Botrule Rrule" align="center"> 3 (2%) </td><td styleCode=" Botrule Rrule" align="center"> 1 (1%) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Eosinophilia </td><td styleCode=" Botrule Rrule" align="center"> 3 (2%) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"> Immunoglobulins increased </td><td styleCode=" Botrule Rrule" align="center"> 3 (2%) </td><td styleCode=" Botrule Rrule" align="center"> 0 </td></tr></tbody></table>

7 DRUG INTERACTIONS Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic or ototoxic potential should be avoided. ( 7.1 ) Tobramycin inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. ( 7.2 ) 7.1 Drugs with Neurotoxic, Nephrotoxic, or Ototoxic Potential Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. 7.2 Diuretics Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Therefore, tobramycin inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and tobramycin inhalation solution has not been evaluated.

8 USE IN SPECIFIC POPULATIONS Aminoglycosides can cause fetal harm when administered to a pregnant woman. ( 8.1 ) Nursing mothers: discontinue drug or nursing, taking into consideration the importance of the drug to a mother. ( 8.2 ) 8.1 Pregnancy Risk Summary 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 (5.6) ]. Although there are no available data on use of tobramycin inhalation solution in pregnant women to be able to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations) . In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data) . Advise pregnant 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 inhaled tobramycin. 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. Subcutaneous doses of tobramycin ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin. 8.2 Lactation Risk Summary There are no data on the presence of tobramycin in either human or animal milk, the effects on the breastfed infant, or the effects on milk production following oral inhalation of tobramycin inhalation solution. 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 tobramycin inhalation solution and any potential adverse effects on the breastfed child from tobramycin inhalation solution 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).

d any potential adverse effects on the breastfed child from tobramycin inhalation solution 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 The safety and efficacy of tobramycin inhalation solution have not been studied in pediatric cystic fibrosis patients under six years of age. 8.5 Geriatric Use Clinical studies of tobramycin inhalation solution did not include patients aged 65 years and over. 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 of 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 for or against dose adjustment [see Warnings and Precautions (5.2 , 5.5 )] . Serum concentrations of tobramycin in patients with renal dysfunction, or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.

8.1 Pregnancy Risk Summary 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 (5.6) ]. Although there are no available data on use of tobramycin inhalation solution in pregnant women to be able to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations) . In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data) . Advise pregnant 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 inhaled tobramycin. 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. Subcutaneous doses of tobramycin ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin.

8.5 Geriatric Use Clinical studies of tobramycin inhalation solution did not include patients aged 65 years and over. 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 )].

10 OVERDOSAGE No overdoses have been reported with tobramycin inhalation solution in clinical trials. Signs and symptoms of acute toxicity from overdosage of intravenous tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Administration by inhalation results in low systemic bioavailability of tobramycin. Tobramycin is not significantly absorbed following oral administration. Tobramycin serum concentrations may be helpful in monitoring overdosage. 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.

11 DESCRIPTION Tobramycin inhalation solution, USP is a sterile, a clear, colorless or slight yellow to pale yellow color, non-pyrogenic, aqueous solution with pH and salinity adjusted. Tobramycin inhalation solution, USP is administered by a compressed air driven reusable nebulizer. The chemical formula for tobramycin, USP is C 18 H 37 N 5 O 9 and the molecular weight is 467.52. Tobramycin, USP 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. The structural formula for tobramycin, USP is: Each single-dose 4 mL ampule of tobramycin inhalation solution, USP contains one 300 mg dose of tobramycin, with sodium chloride and sulfuric acid in water for injection. Sulfuric acid and sodium hydroxide are used, as needed, to adjust the pH to 5.0. Nitrogen is used for sparging, filling and pouching. The formulation contains no preservatives. Tobramycin structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tobramycin inhalation solution is an aminoglycoside antibacterial [see Clinical Pharmacology (12.4) ]. 12.3 Pharmacokinetics Tobramycin inhalation solution contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. 1 The bioavailability of tobramycin inhalation solution may vary because of individual differences in nebulizer performance and airway pathology. 2 Sputum Concentrations Thirty minutes after inhalation of the first 300 mg dose of tobramycin inhalation solution, the maximum geometric mean concentration of tobramycin was 814 mcg/g (ranging from 23 to 2843 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Three hours after inhalation started, sputum tobramycin concentrations declined to approximately 15% of those observed at 30 minutes. After four weeks of therapy with tobramycin inhalation solution average mean sputum tobramycin concentrations obtained 10 minutes following administration were 717 mcg/g. Distribution Following administration of tobramycin inhalation solution, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible. Elimination Tobramycin is not metabolized. The elimination half-life of tobramycin from serum is approximately two hours after intravenous (IV) administration. The elimination half-life following the inhalation of tobramycin inhalation solution is approximately 4.4 hours. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin following inhalation is likely eliminated in expectorated sputum. 12.4 Microbiology Mechanism of Action Tobramycin, an aminoglycoside antibacterial, acts primarily by disrupting protein synthesis in the bacterial cell which eventually leads to death of the cell. Tobramycin has activity against a wide range of gram-negative bacteria including P. aeruginosa . It is bactericidal at or above the minimal inhibitory concentration (MIC) needed to inhibit growth of bacteria. Mechanism of Resistance The predominant mechanism of resistance to tobramycin in P. aeruginosa isolated from CF patients is impermeability and to a lesser extent enzymatic modification and other mechanisms which cumulatively lead to decreased susceptibility of P. aeruginosa to tobramycin. Cross Resistance Cross resistance between aminoglycosides exists but the cross resistance is variable. Development of Resistance Treatment for six months with tobramycin inhalation solution in one clinical trial did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increases in minimal inhibitory concentrations (MIC) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of cystic fibrosis patients. Susceptibility Testing The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physicians as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physicians as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Susceptibility Testing Techniques Dilution Techniques Quantitative methods can be used to determine the minimum inhibitory concentration (MIC) of tobramycin that will inhibit the growth of the bacteria being tested. The MIC provides an estimate of the susceptibility of bacteria to tobramycin. The MIC should be determined using a standardized procedure. 3, 5 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tobramycin powder. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. 4, 5 This procedure uses paper disks impregnated with 10 mcg of tobramycin to test the susceptibility of bacteria to tobramycin. Susceptibility Test Interpretive Criteria In vitro susceptibility test interpretive criteria for inhaled tobramycin have not been determined. The relation of the in vitro MIC and/or disk diffusion susceptibility test results to clinical efficacy of inhaled tobramycin against the bacteria tested should be monitored. Quality Control Parameters for Susceptibility Testing In vitro susceptibility test quality control parameters exist for tobramycin so that laboratories that test the susceptibility of bacterial isolates to tobramycin can determine if the susceptibility test is performing correctly. Standardized dilution techniques and diffusion methods require the use of laboratory control bacteria to monitor the technical aspects of the laboratory procedures. Standard tobramycin powder should provide the following MIC and a 10 mcg tobramycin disk should produce the following zone diameters with the indicated quality control strains (Table 2). Table 2: Acceptable Quality Control Ranges for Tobramycin Bacteria MIC Range (mcg/mL) Disk Diffusion Zone Diameter (mm) Pseudomonas æruginosa ATCC 27853 0.25-1 19-25 Other No trends in the treatment-emergent isolation of other bacterial respiratory pathogens such as Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, or Staphylococcus aureus were observed in clinical trials of tobramycin inhalation solution relative to placebo. There was a slight increase in isolation of Candida spp in sputum at the end of the tobramycin inhalation solution treatment cycle in clinical trials.

12.3 Pharmacokinetics Tobramycin inhalation solution contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. 1 The bioavailability of tobramycin inhalation solution may vary because of individual differences in nebulizer performance and airway pathology. 2 Sputum Concentrations Thirty minutes after inhalation of the first 300 mg dose of tobramycin inhalation solution, the maximum geometric mean concentration of tobramycin was 814 mcg/g (ranging from 23 to 2843 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Three hours after inhalation started, sputum tobramycin concentrations declined to approximately 15% of those observed at 30 minutes. After four weeks of therapy with tobramycin inhalation solution average mean sputum tobramycin concentrations obtained 10 minutes following administration were 717 mcg/g. Distribution Following administration of tobramycin inhalation solution, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible. Elimination Tobramycin is not metabolized. The elimination half-life of tobramycin from serum is approximately two hours after intravenous (IV) administration. The elimination half-life following the inhalation of tobramycin inhalation solution is approximately 4.4 hours. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin following inhalation is likely eliminated in expectorated sputum.

12.4 Microbiology Mechanism of Action Tobramycin, an aminoglycoside antibacterial, acts primarily by disrupting protein synthesis in the bacterial cell which eventually leads to death of the cell. Tobramycin has activity against a wide range of gram-negative bacteria including P. aeruginosa . It is bactericidal at or above the minimal inhibitory concentration (MIC) needed to inhibit growth of bacteria. Mechanism of Resistance The predominant mechanism of resistance to tobramycin in P. aeruginosa isolated from CF patients is impermeability and to a lesser extent enzymatic modification and other mechanisms which cumulatively lead to decreased susceptibility of P. aeruginosa to tobramycin. Cross Resistance Cross resistance between aminoglycosides exists but the cross resistance is variable. Development of Resistance Treatment for six months with tobramycin inhalation solution in one clinical trial did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increases in minimal inhibitory concentrations (MIC) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of cystic fibrosis patients. Susceptibility Testing The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physicians as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial. Susceptibility Testing Techniques Dilution Techniques Quantitative methods can be used to determine the minimum inhibitory concentration (MIC) of tobramycin that will inhibit the growth of the bacteria being tested. The MIC provides an estimate of the susceptibility of bacteria to tobramycin. The MIC should be determined using a standardized procedure. 3, 5 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tobramycin powder. Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations. 4, 5 This procedure uses paper disks impregnated with 10 mcg of tobramycin to test the susceptibility of bacteria to tobramycin. Susceptibility Test Interpretive Criteria In vitro susceptibility test interpretive criteria for inhaled tobramycin have not been determined. The relation of the in vitro MIC and/or disk diffusion susceptibility test results to clinical efficacy of inhaled tobramycin against the bacteria tested should be monitored. Quality Control Parameters for Susceptibility Testing In vitro susceptibility test quality control parameters exist for tobramycin so that laboratories that test the susceptibility of bacterial isolates to tobramycin can determine if the susceptibility test is performing correctly. Standardized dilution techniques and diffusion methods require the use of laboratory control bacteria to monitor the technical aspects of the laboratory procedures.

cin so that laboratories that test the susceptibility of bacterial isolates to tobramycin can determine if the susceptibility test is performing correctly. Standardized dilution techniques and diffusion methods require the use of laboratory control bacteria to monitor the technical aspects of the laboratory procedures. Standard tobramycin powder should provide the following MIC and a 10 mcg tobramycin disk should produce the following zone diameters with the indicated quality control strains (Table 2). Table 2: Acceptable Quality Control Ranges for Tobramycin Bacteria MIC Range (mcg/mL) Disk Diffusion Zone Diameter (mm) Pseudomonas æruginosa ATCC 27853 0.25-1 19-25 Other No trends in the treatment-emergent isolation of other bacterial respiratory pathogens such as Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, or Staphylococcus aureus were observed in clinical trials of tobramycin inhalation solution relative to placebo. There was a slight increase in isolation of Candida spp in sputum at the end of the tobramycin inhalation solution treatment cycle in clinical trials.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year rat inhalation toxicology study to assess carcinogenic potential of an inhaled solution of tobramycin has been completed. Rats were exposed to tobramycin for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin up to 35 mcg/mL were measured in rats, 35x the average 1 mcg/mL exposure levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumors. Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with five 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year rat inhalation toxicology study to assess carcinogenic potential of an inhaled solution of tobramycin has been completed. Rats were exposed to tobramycin for up to 1.5 hours per day for 95 weeks. Serum levels of tobramycin up to 35 mcg/mL were measured in rats, 35x the average 1 mcg/mL exposure levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumors. Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with five 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.

14 CLINICAL STUDIES Two, double-blind, randomized, placebo-controlled, parallel group clinical studies (Study 1 and Study 2), which randomized and dosed 306 patients, were conducted in cystic fibrosis patients with P. aeruginosa . The osmolality of the drug formulation used in these studies differed from the to-be-marketed product. To rely upon the efficacy and safety established in the placebo-controlled studies, an additional study was conducted as a bridge to the to-be-marketed drug. The bridging study assessed the efficacy and tolerability of aerosolized Tobramycin Inhalation Solution with osmolality similar to tobramycin inhalation solution over a 4-week treatment in 324 patients with cystic fibrosis. Results of this study showed that the Tobramycin Inhalation Solution in this study had similar efficacy as that seen in the placebo-controlled studies. The compressors in the placebo-controlled studies and the bridging study differed from the PARI VIOS compressor to be used with tobramycin inhalation solution. In vitro cascade impaction studies demonstrated that the various compressors used in the clinical trials delivered equivalent doses and respirable fractions of the to-be-marketed tobramycin inhalation solution and TOBI with the marketed compressor (PARI VIOS) when used with the same nebulizer (PARI LC Plus Reusable nebulizer). All subjects enrolled in both efficacy studies had baseline FEV 1 % predicted ≥ 40% and ≤80% (mean baseline FEV 1 of 60% of predicted normal) and infected with P. aeruginosa . Subjects who were less than 6 years of age, or who had a baseline creatinine of ≥ 1.5 mg/dL, or who had Burkholderia cepacia isolated from sputum were excluded. A total of 190 patients, 29 in Study 1 and 161 in Study 2, received tobramycin inhalation solution therapy on an outpatient basis. Of these, 55% were males and 45% were females. Eighty-two (43.2%) patients were between 6 and 12 years of age, 54 (28.4%) patients were between 13 and 17 years of age, and the remaining 54 (28.4%) patients were greater than 17 years of age. Of the patients who received tobramycin inhalation solution, only 89.7% of patients in Study 1 had at least one concomitant medication, while all patients in Study 2 also received at least one concomitant medication. These concomitant medications include mucolytics, steroidal and nonsteroidal anti-inflammatory drugs, bronchodilators, rehabilitative physiotherapies and if necessary, antibiotics for bacterial infections other than P. aeruginosa . Study 1 Study 1 was a double-blind, single cycle study that randomized 59 patients to receive tobramycin inhalation solution (n=29) or placebo (n=30) for one cycle of treatment (28 days on treatment followed by 28 days off treatment). All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. All randomized patients were included in the primary analysis except for one patient who had missing baseline information. Tobramycin inhalation solution significantly improved lung function compared with placebo as measured by the absolute change in FEV 1 % predicted from baseline to the end of Cycle 1 dosing in the primary analysis population. Treatment with tobramycin inhalation solution and placebo resulted in absolute increases in FEV 1 % predicted of 16% and 5%, respectively (LS mean difference = 11%; 95% CI: 3, 19; p=0.003). This analysis is adjusted for the covariate of baseline FEV 1 % predicted, using multiple imputation for missing data.

population. Treatment with tobramycin inhalation solution and placebo resulted in absolute increases in FEV 1 % predicted of 16% and 5%, respectively (LS mean difference = 11%; 95% CI: 3, 19; p=0.003). This analysis is adjusted for the covariate of baseline FEV 1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV 1 % predicted over eight weeks. Study 2 Study 2 was a randomized, double-blind, 3-cycle, placebo-controlled trial. A total of 247 eligible patients were randomized 2:1 to receive three cycles of tobramycin inhalation solution (n=161) or placebo (n=86). As in Study 1, each cycle comprised 28 days on treatment followed by 28 days off treatment. All patients were ≤46 years of age (mean age 14.8 years) and 44.9% were females. In this study, two randomized patients in the placebo group were not included in the primary efficacy analysis; one withdrew consent without taking any trial medication and the other withdrew due to an adverse drug reaction. Tobramycin inhalation solution significantly improved lung function compared with placebo as measured by the absolute change in FEV 1 % predicted from baseline to the end of Cycle 3 "ON" period. Treatment with tobramycin inhalation solution and placebo resulted in absolute increases in FEV 1 % predicted of 7% and 1%, respectively (LS mean difference = 6%; 95% CI: 3, 10; p<0.001). This analysis is adjusted for the covariate of baseline FEV 1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV 1 % predicted over 24 weeks from Study 2. Figure 1: FEV 1 % of Predicted Normal–Absolute Change from Baseline (Adjusted mean)–ITT Population In Study 2, 9.9% of patients treated with tobramycin inhalation solution and 24.7% of patients who received placebo had unplanned hospitalizations due to the disease. Also in Study 2, 6.2% of patients treated with tobramycin inhalation solution and 16.5% of placebo patients received parenteral tobramycin. Figure 1

15 REFERENCES Neu HC. Tobramycin: an overview. [Review]. J Infect Dis. 1976; Suppl 134:S3-19. Weber A, Smith A, Williams-Warren J, et al. Nebulizer delivery of tobramycin to the lower respiratory tract. Pediatr Pulmonol. 1994; 17(5):331-9. Clinical and laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard -9 th edition. CLSI document M07-A9. CLSI 940 West Valley Rd. Suite 1400, Wayne PA 19087-1898. 2012 CLSI Performance Standards for Antimicrobial Susceptibility Testing: 22 nd Informational supplement CLSI document M100-S22. CLSI 2012. CLSI Performance standards for Antimicrobial Disk Susceptibility Tests: Approved standard -11 th ed. CLSI document M02-A11. CLSI 2012. PARI Vios Aerosol Delivery System with LC Plus Nebulizer: Instructions for Use. PARI Respiratory Equipment, Inc. 2010; 310D0028 Rev A 6-10.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tobramycin inhalation solution, USP 300 mg/4 mL is supplied as a sterile, a clear, colorless or slight yellow to pale yellow color, non-pyrogenic, aqueous solution and is available as follows: NDC 72603-630-56: 4 mL single-dose ampule (carton of 14 foil pouches each containing four ampules) 16.2 Storage and Handling Tobramycin inhalation solution, USP should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution, USP pouches (opened or unopened) may be stored at room temperature [up to 25°C (77°F)] for up to 28 days. Tobramycin inhalation solution, USP should not be used beyond the expiration date stamped on the ampule when stored under refrigeration 2°C to 8°C (36°F to 46°F) or beyond 28 days when stored at room temperature [up to 25°C (77°F)]. Tobramycin inhalation solution, USP ampules should not be exposed to intense light. Tobramycin inhalation solution, USP is light sensitive; unopened ampules should be returned to the foil pouch. The solution in the ampule is colorless to pale yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.

16.2 Storage and Handling Tobramycin inhalation solution, USP should be stored under refrigeration at 2°C to 8°C (36°F to 46°F). Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution, USP pouches (opened or unopened) may be stored at room temperature [up to 25°C (77°F)] for up to 28 days. Tobramycin inhalation solution, USP should not be used beyond the expiration date stamped on the ampule when stored under refrigeration 2°C to 8°C (36°F to 46°F) or beyond 28 days when stored at room temperature [up to 25°C (77°F)]. Tobramycin inhalation solution, USP ampules should not be exposed to intense light. Tobramycin inhalation solution, USP is light sensitive; unopened ampules should be returned to the foil pouch. The solution in the ampule is colorless to pale yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Information for Patients Information on the long term efficacy and safety of tobramycin inhalation solution is limited. There is no information in patients with severe cystic fibrosis (FEV 1 < 40% predicted). Patients should be advised to complete a full 28-day course of tobramycin inhalation solution, even if they are feeling better. After 28 days of therapy, patients should stop tobramycin inhalation solution therapy for the next 28 days, and then resume therapy for the next 28 day on and 28 day off cycle. For patients taking several different inhaled medications and/or performing chest physiotherapy, advise the patient regarding the order they should take the therapies. It is recommended that tobramycin inhalation solution be taken last. Tobramycin inhalation solution is to be used with the PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor. Refer to the manufacturer's instructions for care and use of the nebulizer and compressor. 17.1 Ototoxicity Inform patients that ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients treated with tobramycin. Physicians should consider an audiogram at baseline, particularly for patients at increased risk of auditory dysfunction. If a patient reports tinnitus or hearing loss during tobramycin inhalation solution therapy, the physician should refer that patient for audiological assessment. Patients should be reminded that vestibular toxicity may manifest as vertigo, ataxia, or dizziness. 17.2 Bronchospasm Inform patients that bronchospasm can occur with inhalation of tobramycin. 17.3 Risks Associated with Aminoglycosides Inform patients of adverse reactions associated with aminoglycosides such as nephrotoxicity and neuromuscular disorders. 17.4 Laboratory Tests Inform patients of the need to monitor hearing, serum concentrations of tobramycin, or renal function as necessary during treatment with tobramycin inhalation solution. 17.5 Embryo-Fetal Toxicity Inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman. Advise them to inform their doctor if they are pregnant, become pregnant, or plan to become pregnant. 17.6 Administration Patients should be informed about what to do in the event they miss a dose of tobramycin inhalation solution: In case a dose of tobramycin inhalation solution is missed and there are at least 6 hours until the next dose, patients should be instructed to take the prescribed dose of tobramycin inhalation solution as soon as possible. Otherwise, the missed dose should not be taken and the patient should resume the usual dosing schedule. Patients should be advised to contact their healthcare provider if they have questions. 17.7 Storage Instructions You should store tobramycin inhalation solution ampules in a refrigerator (36°F to 46°F or 2°C to 8°C). However, when you don't have a refrigerator available (e.g., transporting your tobramycin inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 77°F/25°C) for up to 28 days. Tobramycin inhalation solution is light sensitive; unopened ampules should be returned to the foil pouch. Avoid exposing tobramycin inhalation solution ampules to intense light.

tobramycin inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 77°F/25°C) for up to 28 days. Tobramycin inhalation solution is light sensitive; unopened ampules should be returned to the foil pouch. Avoid exposing tobramycin inhalation solution ampules to intense light. Unrefrigerated tobramycin inhalation solution, which is normally colorless to pale yellow, may darken with age; however, the color change does not indicate any change in the quality of the product. You should not use tobramycin inhalation solution if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days. You should not use tobramycin inhalation solution beyond the expiration date stamped on the ampule. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Mankind Pharma Limited Paonta Sahib, Sirmaur Himachal Pradesh 173025, India. Issued: April 2024, V-01 All trademarks referenced herein are the property of their prospective owners

SPL PATIENT PACKAGE INSERT Patient Information Tobramycin Inhalation Solution ( toh-bruh- mahy -sin ) for oral inhalation use What is tobramycin inhalation solution? Tobramycin inhalation solution is a prescription medicine that is used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa . Tobramycin inhalation solution contains an antibacterial medicine called tobramycin (an aminoglycoside). It is not known if tobramycin inhalation solution is safe and effective: in children under 6 years of age in people who have decreased lung volume or a forced expiratory volume in one second (FEV 1 ) less than 40% or greater than 80% predicted in people who are colonized with a bacterium called Burkholderia cepacia Do not take tobramycin inhalation solution if you are allergic to tobramycin, any of the ingredients in tobramycin inhalation solution, or to any other aminoglycoside antibacterial. See the end of this Patient Information for a complete list of ingredients in tobramycin inhalation solution. Before you take tobramycin inhalation solution, 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 are pregnant or plan to become pregnant. Tobramycin inhalation solution is in a class of medicines that can harm your unborn baby and may be connected with complete deafness in babies at birth. The deafness affects both ears and cannot be changed. are breastfeeding or plan to breastfeed. It is not known if tobramycin passes into your breast milk. Tobramycin, the medicine in tobramycin inhalation solution may cause the following symptoms in your breastfed baby: loose or bloody stools yeast infection in the mouth or throat (thrush) diaper rash Call your baby's healthcare provider if your breastfed baby has any of these problems. Talk to your healthcare provider about the best way to feed your baby during treatment with tobramycin inhalation solution. are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking tobramycin inhalation solution. Your blood levels of tobramycin will be checked. Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. How should I take Tobramycin Inhalation Solution? See the step-by-step Instructions for Use at the end of this Patient Information leaflet about the right way to take your tobramycin inhalation solution. Take tobramycin inhalation solution exactly as your healthcare provider tells you to. Do not change your dose or stop taking tobramycin inhalation solution unless your healthcare provider tells you to. The usual dose of tobramycin inhalation solution for adults and children over 6 years of age is: 1 single-dose ampule of tobramycin inhalation solution inhaled 2 times each day using your hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios air compressor.

on solution unless your healthcare provider tells you to. The usual dose of tobramycin inhalation solution for adults and children over 6 years of age is: 1 single-dose ampule of tobramycin inhalation solution inhaled 2 times each day using your hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios air compressor. Each dose of tobramycin inhalation solution should be taken as close to 12 hours apart as possible. You should not take your dose of tobramycin inhalation solution less than 6 hours apart. Tobramycin inhalation solution is taken as a breathing treatment (inhalation) with a hand-held PARI LC Reusable Nebulizer with a PARI Vios air compressor. Do not use any other nebulizer for your tobramycin inhalation solution treatment. Do not mix or dilute tobramycin inhalation solution with dornase alfa or other medicines in your nebulizer system. Each treatment of tobramycin inhalation solution should take about 15 minutes. Tobramycin inhalation solution should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth. If you forget to take tobramycin inhalation solution and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. After taking tobramycin inhalation solution for 28 days, you should stop taking it and wait 28 days. After you have stopped taking tobramycin inhalation solution for 28 days, you should start taking tobramycin inhalation solution 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. If you are taking several other medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling tobramycin inhalation solution or as directed by your healthcare provider. Taking tobramycin inhalation solution with certain other medicines can cause serious side effects. If you are taking tobramycin inhalation solution, 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 ethacrynic acid, furosemide, or intravenous mannitol Urea 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 take too much tobramycin inhalation solution, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of Tobramycin inhalation solution? Tobramycin inhalation solution can cause serious side effects, including: hearing loss or ringing in the ears (ototoxicity). Some people who were treated with tobramycin, the medicine in tobramycin inhalation solution had hearing loss or ringing in the ears. 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, dizziness, or difficulty with balance. worsening kidney problems (nephrotoxicity). Your healthcare provider may do a blood test and urine test to check how your kidneys are working while you are taking tobramycin inhalation solution. worsening muscle weakness (neuromuscular disorder). Tobramycin inhalation solution can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson's disease). severe breathing problems (bronchospasm).

ng while you are taking tobramycin inhalation solution. worsening muscle weakness (neuromuscular disorder). Tobramycin inhalation solution can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson's disease). severe breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm while taking tobramycin inhalation solution: o shortness of breath with wheezing o coughing and chest tightness The most common side effects of tobramycin inhalation solution include: worsening of lung problems or cystic fibrosis noisy breathing (rales) abnormal red blood cell activity changes in your voice (hoarseness) These are not all of the possible side effects of tobramycin inhalation solution. 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 tobramycin inhalation solution. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tobramycin inhalation solution for a condition for which it was not prescribed. Do not give tobramycin inhalation solution to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about tobramycin inhalation solution that is written for health professionals. What are the ingredients in tobramycin inhalation solution? Active ingredient: tobramycin Inactive ingredients: sodium chloride, sulfuric acid in water for injection, and sodium hydroxide (for pH adjustment) What is Psuedomonas aeriguinosa? It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the infection is not properly managed, it will continue to damage your lungs causing further problems to your breathing. For more information, call 1-800-206-7821. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 04/2024, V-01 Instructions for Use Tobramycin inhalation solution ( toh-bruh- mahy -sin ) Follow the instructions below for taking tobramycin inhalation solution. If you have any questions, ask your healthcare provider or pharmacist. Tobramycin inhalation solution is available as a 28-day supply containing 56 ampules including 14 foil pouches. Each foil pouch contains 4 tobramycin inhalation solution ampules. Supplies you will need to take tobramycin inhalation solution (See Figure A): 1 ampule of tobramycin inhalation solution PARI LC PLUS reusable nebulizer PARI Vios compressor tubing to connect the nebulizer and compressor clean paper or cloth towels nose clips (optional) (Figure A) Tobramycin inhalation solution is used only in a PARI LC PLUS re-usable Nebulizer connected to a PARI LC PLUS Vios air compressor. Make sure you know how to use your nebulizer machine before you use it to breathe in tobramycin inhalation solution . Do not mix tobramycin inhalation solution with other medicines in your nebulizer. Tobramycin inhalation solution comes in a sealed foil pouch. Do not open a sealed pouch until you are ready to use a dose of tobramycin inhalation solution. After opening the pouch, unused ready-to-use ampules should be returned to, and stored in, the pouch. Getting ready: Put your PARI LC PLUS Reusable Nebulizer Top and Bottom (Nebulizer Cup) Assembly, Inspiratory Valve Cap, Mouthpiece with Valve, and Tubing on a clean and dry surface. Wash your hands with soap and water.

After opening the pouch, unused ready-to-use ampules should be returned to, and stored in, the pouch. Getting ready: Put your PARI LC PLUS Reusable Nebulizer Top and Bottom (Nebulizer Cup) Assembly, Inspiratory Valve Cap, Mouthpiece with Valve, and Tubing on a clean and dry surface. Wash your hands with soap and water. Preparing your tobramycin inhalation solution dose: Step 1: Open foil pouch. (See Figure B) (Figure B) Step 2: Separate 1 ampule by gently pulling apart at the bottom tabs (See Figure C) and use it right away. (Figure C) Step 3: Hold the bottom tab on the tobramycin inhalation solution ampule with 1 hand (See Figure D). With your other hand, hold the top of the ampule and twist off the top of the ampule (See Figure D). Do not squeeze the ampule until you are ready to squeeze all the medicine into the Nebulizer Cup. (Figure D) Step 4: Hold the Nebulizer Cup and twist off the Nebulizer Cup Top in a counter-clockwise direction (See Figure E). Set the Top aside on a clean, dry surface. (Figure E) Step 5: Squeeze all of the medicine from the ampule into the Nebulizer Cup (See Figure F). (Figure F) Step 6: Line up the semi-circle on the Nebulizer Cup Top with the Nebulizer Cup Outlet and twist on the Nebulizer Cup Top in a clock-wise direction until it is tight. (See Figure G). (Figure G) Step 7: Push the mouthpiece straight onto the Nebulizer Cup Outlet (See Figure H). (Figure H) Step 8: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Cup Top (See Figure I). The Inspiratory Valve Cap should fit tightly. (Figure I) Step 9: Connect 1 end of the tubing to the compressor air outlet. The tubing should fit tightly (See Figure J). (Figure J) Step 10: Plug your compressor plug into an electrical outlet (See Figure K). (Figure K) Step 11: Hold the Nebulizer Cup upright and firmly push the free end of the tubing straight up onto the Air Intake on the bottom of the Nebulizer Cup (See Figure L). Make sure to keep the Nebulizer Cup upright. (Figure L) Giving your Tobramycin inhalation solution dose: Step 12: Turn on the compressor (Figure M) and check the Mouthpiece. You should see a steady mist coming from the Mouthpiece (Figure N). If you do not see a steady mist coming from the mouthpiece, check all tubing connections and make sure that the compressor is working the right way. (Figure M) (Figure N) Step 13: Sit or stand in a comfortable, upright position that will let you breathe normally. Place the Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth (See Figure O). Nose clips may help you breathe only through your mouth and not through your nose. (Figure O) Step 14: Keep breathing in your tobramycin inhalation solution dose for at least 15 minutes. You will know that you have received your full dose of medicine when you hear a "spitting noise" coming from the Mouthpiece for at least 1 minute and the Nebulizer Cup is empty. After your Tobramycin Inhalation Solution Dose: Step 15: Clean and disinfect your nebulizer (see manufacturer's instructions). Care and Use of Your PARI Vios ® Compressor Follow the manufacturer's instructions for care and use of your compressor. How should I store Tobramycin inhalation solution ? Store tobramycin inhalation solution in the refrigerator at 36°F to 46°F (2°C to 8°C) until needed. After removing from the refrigerator, or if refrigeration is not available, tobramycin inhalation solution foil pouches (opened or unopened) may be stored at room temperature up to 77°F (25°C) for up to 28 days. If tobramycin inhalation solution is not stored in the refrigerator but at room temperature up to 77°F (25°C) it may turn dark. If tobramycin inhalation solution turns dark, it does not change how well tobramycin inhalation solution works.

unopened) may be stored at room temperature up to 77°F (25°C) for up to 28 days. If tobramycin inhalation solution is not stored in the refrigerator but at room temperature up to 77°F (25°C) it may turn dark. If tobramycin inhalation solution turns dark, it does not change how well tobramycin inhalation solution works. Tobramycin inhalation solution can still be used as long as it is stored at room temperature up to 77°F (25°C). Do not use tobramycin inhalation solution after the expiration date printed on the ampule. Keep tobramycin inhalation solution ampules in the foil pouch and away from light. Return unopened ampules to the foil pouch Keep tobramycin inhalation solution and all medicines out of the reach of children. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Mankind Pharma Limited Paonta Sahib, Sirmaur Himachal Pradesh 173025, India. All trademarks referenced herein are the property of their prospective owners Issued: April 2024, V-01 1 .. . . . . . . .. . . . ... .... ......

<table ID="ID190" width="590" styleCode="Noautorules"><col width="590"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Patient Information</content> <content styleCode="bold"> Tobramycin Inhalation Solution</content> <content styleCode="bold"> (</content> toh-bruh-<content styleCode="bold"> mahy</content> -sin<content styleCode="bold"> )</content> <content styleCode="bold"> for oral inhalation use</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What is </content><content styleCode="bold"> tobramycin inhalation solution? </content> Tobramycin inhalation solution is a prescription medicine that is used to treat people with cystic fibrosis who have a bacterial infection called <content styleCode="italics">Pseudomonas aeruginosa</content> . Tobramycin inhalation solution contains an antibacterial medicine called tobramycin (an aminoglycoside). It is not known if tobramycin inhalation solution is safe and effective: <list listType="unordered" styleCode="disc"><item>in children under 6 years of age </item><item>in people who have decreased lung volume or a forced expiratory volume in one second (FEV₁) less than 40% or greater than 80% predicted </item><item>in people who are colonized with a bacterium called <content styleCode="italics">Burkholderia cepacia</content></item></list> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Do not take </content><content styleCode="bold"> tobramycin inhalation solution</content> if you are allergic to tobramycin, any of the ingredients in tobramycin inhalation solution, or to any other aminoglycoside antibacterial. <content styleCode="bold"> See the end of this Patient Information for a complete list of ingredients in </content><content styleCode="bold"> tobramycin inhalation solution.</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Before you take </content><content styleCode="bold"> tobramycin inhalation solution, tell your healthcare provider about all of your medical conditions, including if you: </content> <list listType="unordered" styleCode="disc"><item>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.</item><item>have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from your mother.</item><item>have dizziness </item><item>have or have had kidney problems </item><item>have or have had problems with muscle weakness such as myasthenia gravis or Parkinson&apos;s disease </item><item>have or have had breathing problems such as wheezing, coughing, or chest tightness </item><item>are pregnant or plan to become pregnant. Tobramycin inhalation solution is in a class of medicines that can harm your unborn baby and may be connected with complete deafness in babies at birth. The deafness affects both ears and cannot be changed. </item><item>are breastfeeding or plan to breastfeed. It is not known if tobramycin passes into your breast milk.

Tobramycin inhalation solution is in a class of medicines that can harm your unborn baby and may be connected with complete deafness in babies at birth. The deafness affects both ears and cannot be changed. </item><item>are breastfeeding or plan to breastfeed. It is not known if tobramycin passes into your breast milk. Tobramycin, the medicine in tobramycin inhalation solution may cause the following symptoms in your breastfed baby: </item></list><list listType="unordered" styleCode="circle"><item>loose or bloody stools </item><item>yeast infection in the mouth or throat (thrush) </item><item>diaper rash </item></list><content styleCode="bold"> Call your baby&apos;s healthcare provider if your breastfed baby has any of these problems. </content> Talk to your healthcare provider about the best way to feed your baby during treatment with tobramycin inhalation solution. <list listType="unordered" styleCode="disc"><item>are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking tobramycin inhalation solution. Your blood levels of tobramycin will be checked. </item></list><content styleCode="bold"> Tell your healthcare provider about all the medicines you take, </content> including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> How should I take </content><content styleCode="bold"> Tobramycin Inhalation Solution? </content> <list listType="unordered" styleCode="disc"><item><content styleCode="bold"> See the step-by-step Instructions for Use </content> at the end of this Patient Information leaflet about the right way to take your tobramycin inhalation solution. </item><item>Take tobramycin inhalation solution exactly as your healthcare provider tells you to. <content styleCode="bold"> Do not </content> change your dose or stop taking tobramycin inhalation solution unless your healthcare provider tells you to. </item><item>The usual dose of tobramycin inhalation solution for adults and children over 6 years of age is: </item></list><list listType="unordered" styleCode="circle"><item>1 single-dose ampule of tobramycin inhalation solution inhaled 2 times each day using your hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios air compressor. </item></list><list listType="unordered" styleCode="disc"><item>Each dose of tobramycin inhalation solution should be taken as close to 12 hours apart as possible. </item><item>You should not take your dose of tobramycin inhalation solution less than 6 hours apart. </item><item>Tobramycin inhalation solution is taken as a breathing treatment (inhalation) with a hand-held PARI LC Reusable Nebulizer with a PARI Vios air compressor. <content styleCode="bold"> Do not </content> use any other nebulizer for your tobramycin inhalation solution treatment. </item><item>Do not mix or dilute tobramycin inhalation solution with dornase alfa or other medicines in your nebulizer system. </item><item>Each treatment of tobramycin inhalation solution should take about 15 minutes. </item><item>Tobramycin inhalation solution should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth. </item><item>If you forget to take tobramycin inhalation solution and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. </item><item>After taking tobramycin inhalation solution for 28 days, you should stop taking it and wait 28 days.

tobramycin inhalation solution and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. </item><item>After taking tobramycin inhalation solution for 28 days, you should stop taking it and wait 28 days. After you have stopped taking tobramycin inhalation solution for 28 days, you should start taking tobramycin inhalation solution 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. </item></list> If you are taking several other medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling tobramycin inhalation solution or as directed by your healthcare provider. Taking tobramycin inhalation solution with certain other medicines can cause serious side effects. If you are taking tobramycin inhalation solution, you should discuss with your healthcare provider if you should take: <list listType="unordered" styleCode="disc"><item>other medicines that may harm your nervous system, kidneys, or hearing </item><item>&quot;water pills&quot; (diuretics) such as ethacrynic acid, furosemide, or intravenous mannitol </item><item>Urea </item></list> 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. <list listType="unordered" styleCode="disc"><item>If you take too much tobramycin inhalation solution, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What are the possible side effects of </content><content styleCode="bold"> Tobramycin inhalation solution? </content> <content styleCode="bold"> Tobramycin inhalation solution</content><content styleCode="bold"> can cause serious side effects, including: </content> <list listType="unordered" styleCode="disc"><item><content styleCode="bold"> hearing loss or ringing in the ears (ototoxicity). </content> Some people who were treated with tobramycin, the medicine in tobramycin inhalation solution had hearing loss or ringing in the ears. 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, dizziness, or difficulty with balance. </item><item><content styleCode="bold"> worsening kidney problems (nephrotoxicity). </content> Your healthcare provider may do a blood test and urine test to check how your kidneys are working while you are taking tobramycin inhalation solution. </item><item><content styleCode="bold"> worsening muscle weakness (neuromuscular disorder). </content> Tobramycin inhalation solution can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson&apos;s disease).</item><item><content styleCode="bold"> severe breathing problems (bronchospasm).

worsening muscle weakness (neuromuscular disorder). </content> Tobramycin inhalation solution can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson&apos;s disease).</item><item><content styleCode="bold"> severe breathing problems (bronchospasm). </content> Tell your healthcare provider right away if you get any of these symptoms of bronchospasm while taking tobramycin inhalation solution: </item></list> o shortness of breath with wheezing o coughing and chest tightness <content styleCode="bold"> The most common side effects of </content><content styleCode="bold"> tobramycin inhalation solution include: </content> <list listType="unordered" styleCode="disc"><item>worsening of lung problems or cystic fibrosis </item><item>noisy breathing (rales) </item><item>abnormal red blood cell activity </item><item>changes in your voice (hoarseness) </item></list> These are not all of the possible side effects of tobramycin inhalation solution. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> General information about the safe and effective use of </content><content styleCode="bold"> tobramycin inhalation solution. </content> Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use tobramycin inhalation solution for a condition for which it was not prescribed. Do not give tobramycin inhalation solution to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about tobramycin inhalation solution that is written for health professionals. </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What are the ingredients in </content><content styleCode="bold"> tobramycin inhalation solution? </content> <content styleCode="bold"> Active ingredient: </content> tobramycin <content styleCode="bold"> Inactive ingredients: </content> sodium chloride, sulfuric acid in water for injection, and sodium hydroxide (for pH adjustment) </td></tr><tr><td valign="bottom" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> What is Psuedomonas aeriguinosa? </content> It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the infection is not properly managed, it will continue to damage your lungs causing further problems to your breathing. For more information, call 1-800-206-7821. </td></tr></tbody></table>

DESCRIPTION TOBREX ® (tobramycin ophthalmic ointment) 0.3% is a sterile topical ophthalmic antibiotic formulation prepared specifically for topical therapy of external ophthalmic infections. Each gram of TOBREX (tobramycin ophthalmic ointment) 0.3% contains: Active: tobramycin 0.3% (3 mg). Preservative: chlorobutanol 0.5%. Inactives: mineral oil, white petrolatum. Tobramycin is a water-soluble aminoglycoside antibiotic active against a wide variety of gram-negative and gram-positive ophthalmic pathogens. The chemical structure of tobramycin is: Molecular Formula: C 18 H 37 N 5 O 9 Molecular Weight: 467.52 g/mol Chemical Name: 0-{3-amino-3-deoxy-α-D-gluco-pyranosyl-(1→4) }-0-{2,6-diamino-2,3,6-trideoxy-α-D-ribohexo-pyranosyl-(1→6) }-2-deoxystreptamine. chemical structure of tobramycin

CLINICAL PHARMACOLOGY In Vitro Data: In vitro studies have demonstrated tobramycin is active against susceptible strains of the following microorganisms: Staphylococci , including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci , including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae . Pseudomonas aeruginosa , Escherichia coli, Klebsiella pneumoniae , Enterobacter aerogenes , Proteus mirabilis , Morganella morganii , most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius , Moraxella lacunata , Acinetobacter calcoaceticus and some Neisseria species . Bacterial susceptibility studies demonstrate that in some cases, microorganisms resistant to gentamicin retain susceptibility to tobramycin.

INDICATIONS AND USAGE TOBREX ® (tobramycin ophthalmic ointment) 0.3 % is a topical antibiotic indicated in the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany the use of TOBREX (tobramycin ophthalmic ointment) 0.3%. Clinical studies have shown tobramycin to be safe and effective for use in children.

WARNINGS NOT FOR INJECTION INTO THE EYE. Sensitivity to topically applied aminoglycosides may occur in some patients. Severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, itching, urticaria, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a sensitivity reaction to TOBREX (tobramycin ophthalmic ointment) 0.3% occurs, discontinue use.

PRECAUTIONS General: As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Ophthalmic ointments may retard corneal wound healing. Cross-sensitivity to other aminoglycoside antibiotics may occur; if hypersensitivity develops with this product, discontinue use and institute appropriate therapy. Patients should be advised not to wear contact lenses if they have signs and symptoms of ocular infections. Information for Patients: Do not touch tube tip to any surface, as this may contaminate the ointment. Do not use the product if the imprinted carton seals have been damaged, or removed. Pregnancy: Reproduction studies in three types of animals at doses up to thirty-three times the normal human systemic dose have revealed no evidence of impaired fertility or harm to the fetus due to tobramycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Because of the potential for adverse reactions in nursing infants from TOBREX ® (tobramycin ophthalmic ointment) 0.3%, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 2 months has not been established. Geriatric Use: No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients.

Pregnancy: Reproduction studies in three types of animals at doses up to thirty-three times the normal human systemic dose have revealed no evidence of impaired fertility or harm to the fetus due to tobramycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Because of the potential for adverse reactions in nursing infants from TOBREX ® (tobramycin ophthalmic ointment) 0.3%, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS: The most frequent adverse reactions to TOBREX (tobramycin ophthalmic ointment) 0.3% are hypersensitivity and localized ocular toxicity, including lid itching and swelling, and conjunctival erythema. These reactions occur in less than three of 100 patients treated with TOBREX ® (tobramycin ophthalmic ointment) 0.3%. Postmarketing Experience: Additional adverse reactions identified from postmarketing use include anaphylactic reaction, Stevens-Johnson syndrome, and erythema multiforme. The following additional adverse reactions have been reported with systemic aminoglycosides: Neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy. Aminoglycosides may aggravate muscle weakness in patients with known or suspected neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, because of their potential effect on neuromuscular function.

DOSAGE AND ADMINISTRATION In mild to moderate disease, apply a half-inch ribbon into the affected eye(s) 2 or 3 times per day. In severe infections, instill a half-inch ribbon into the affected eye(s) every 3 to 4 hours until improvement, following which treatment should be reduced prior to discontinuation. How to Apply TOBREX (tobramycin ophthalmic ointment) 0.3%: 1. Tilt your head back. 2. Place a finger on your cheek just under your eye and gently pull down until a ''V'' pocket is formed between your eyeball and your lower lid. 3. Place a small amount (about ½ inch) of TOBREX ® (tobramycin ophthalmic ointment) 0.3% in the ''V'' pocket. Do not let the tip of the tube touch your eye. 4. Look downward before closing your eye.

HOW SUPPLIED TOBREX (tobramycin ophthalmic ointment) 0.3% is supplied as a 3.5 g sterile ointment in an aluminum tube with a white polyethylene tip and white polyethylene cap as follows: 3.5 g containing tobramycin 0.3% (3 mg/g).................................................. NDC 0078-0813-01 Storage: Store at 2°C to 25°C (36°F to 77°F). After opening, TOBREX (tobramycin ophthalmic ointment) 0.3% can be used until the expiration date on the tube. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis Revised: June 2021 T2021-76

1 INDICATIONS AND USAGE TOBI is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older 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 >75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ]. TOBI is an aminoglycoside antibacterial indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa . ( 1 ) 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 >75% predicted, or patients colonized with Burkholderia cepacia. ( 1 )

2 DOSAGE AND ADMINISTRATION • For oral inhalation only. ( 2.1 ) • The recommended dosage for adults and pediatric patients 6 years of age and older is one single-dose ampoule (300 mg) twice daily by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. ( 2.1 ) • Dosage is not adjusted by weight. ( 2.1 ) • Take doses as close to 12 hours apart as possible; but not less than 6 hours apart. ( 2.1 ) • Administer each 300 mg dose by inhalation using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. ( 2.2 ) 2.1 Dosage TOBI is for oral inhalation only [see Dosage and Administration (2.2) ] . The recommended dosage of TOBI for both adults and pediatric patients 6 years of age and older is one single-dose ampoule (300 mg) administered twice daily for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg twice daily. TOBI is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop TOBI therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart. If patients miss a dose, they should take it as soon as possible anytime up to 6 hours prior to their next scheduled dose. If less than 6 hours remain before the next dose, wait until their next scheduled dose. 2.2 Administration Instructions TOBI is administered by oral inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. TOBI should not be diluted or mixed with dornase alfa or other medications in the nebulizer. TOBI is not for subcutaneous, intravenous or intrathecal administration. Prior to administration of TOBI, read the Patient Information/Instructions for Use for TOBI for detailed information on how to use TOBI, and follow the manufacturer’s instructions for use and care of the PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor. TOBI is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breathe through the mouth. Instruct patients on multiple therapies to take their medications, prior to inhaling TOBI or as directed by their physician. TOBI should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days.

3 DOSAGE FORMS AND STRENGTHS TOBI is supplied as a sterile inhalational solution for nebulization in single-dose 5 mL ampoules. Each 5 mL ampoule contains 300 mg of tobramycin. Inhalation Solution: 300 mg per 5 mL solution in a single-dose ampoule ( 3 )

5 WARNINGS AND PRECAUTIONS • Bronchospasm: Can occur with inhalation of TOBI. Treat as medically appropriate, if it occurs. ( 5.1 ) • Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving TOBI. If noted, manage as medically appropriate, including potentially discontinuing TOBI. ( 5.2 ) • Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing TOBI. ( 5.3 ) • Neuromuscular Disorders: Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. ( 5.4 ) • Embryo-fetal Toxicity: Aminoglycosides can cause fetal harm ( 5.5 , 8.1 ) 5.1 Bronchospasm Bronchospasm can occur with inhalation of TOBI. In clinical studies with TOBI, changes in FEV 1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of TOBI should be treated as medically appropriate. 5.2 Ototoxicity Ototoxicity with use of TOBI Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Transient tinnitus occurred in eight TOBI treated patients versus no placebo patients in the clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants further clinical investigation. Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with TOBI therapy during clinical studies, however in postmarketing experience, patients receiving TOBI have reported hearing loss. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking TOBI. Monitoring might include obtaining audiometric evaluations and serum tobramycin levels. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing TOBI. 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 Nephrotoxicity was not seen during clinical studies with TOBI but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with TOBI should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician.

with TOBI but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with TOBI should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician. If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing TOBI. 5.4 Neuromuscular Disorders Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease. Prolonged respiratory paralysis may also occur in patients receiving concomitant neuromuscular blocking agents. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. 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 during pregnancy, or become pregnant while taking TOBI 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Bronchospasm [see Warnings and Precautions (5.1) ] • Ototoxicity [see Warnings and Precautions (5.2) ] • Nephrotoxicity [see Warnings and Precautions (5.3) ] • Neuromuscular Disorders [see Warnings and Precautions (5.4) ] • Embryo-fetal Toxicity [see Warnings and Precautions (5.5) ] • Concomitant Use of Systemic Aminoglycosides [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence >5%) are increased cough, pharyngitis, increased sputum, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion and rash. ( 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 was studied in two Phase 3 clinical studies involving 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received TOBI in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks. Table 1 lists the percent of patients with selected adverse reactions that occurred in >5% of TOBI patients during the two Phase 3 studies. Table 1: Percent of Patients With Selected Adverse Reactions Occurring in >5% of TOBI Patients Adverse Reaction Tobramycin Inhalation Solution (n = 258) % Placebo (n = 262) % Cough Increased 46.1 47.3 Pharyngitis 38.0 39.3 Sputum Increased 37.6 39.7 Dyspnea 33.7 38.5 Hemoptysis 19.4 23.7 Lung Function Decreased Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. 16.3 15.3 Voice Alteration 12.8 6.5 Taste Perversion 6.6 6.9 Rash 5.4 6.1 Selected adverse reactions that occurred in less than or equal to 5% of patients treated with TOBI: Ear and Labyrinth Disorders: Tinnitus Musculoskeletal and Connective Tissue Disorders: Myalgia Infections and Infestations: Laryngitis Voice Alteration and Tinnitus Voice alteration and tinnitus were the only adverse reactions reported by significantly more TOBI-treated patients. Thirty-three patients (13%) treated with TOBI complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods. Eight patients from the TOBI group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the TOBI treatment regimen, and were not associated with loss of hearing in audiograms. Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the TOBI and placebo groups. Changes in Serum Creatinine Nine (3%) patients in the TOBI group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the TOBI group, creatinine decreased at the next visit.

ces such as dizziness were similar in the TOBI and placebo groups. Changes in Serum Creatinine Nine (3%) patients in the TOBI group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the TOBI group, creatinine decreased at the next visit. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TOBI. 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. Ear and Labyrinth Disorders Hearing loss: Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus [see Warnings and Precautions (5.2) ] . Skin and Subcutaneous Tissue Disorders Hypersensitivity, pruritus, urticaria, rash Nervous System Disorders Aphonia, dysgeusia Respiratory, Thoracic, and Mediastinal Disorders Bronchospasm [see Warnings and Precautions (5.1) ] oropharyngeal pain Metabolism and Nutrition Disorders Decreased appetite

<table styleCode="Noautorules" width="100%"><caption>Table 1: Percent of Patients With Selected Adverse Reactions Occurring in &gt;5% of TOBI Patients</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Tobramycin Inhalation Solution</content></paragraph><paragraph><content styleCode="bold">(n = 258)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 262)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cough Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>46.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>47.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pharyngitis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sputum Increased</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>37.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>38.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hemoptysis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Lung Function Decreased<footnote ID="_Ref41991609">Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Voice Alteration</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Taste Perversion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6

agraph>12.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Taste Perversion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6 .6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.9</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5.4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6.1</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Concurrent and/or sequential use of TOBI with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. ( 7.1 ) • Concomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended due to possible enhancement of aminoglycoside toxicity. ( 7.2 ) 7.1 Drugs with Neurotoxic, Nephrotoxic or Ototoxic Potential Concurrent and/or sequential use of TOBI with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. 7.2 Diuretics Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and TOBI has not been evaluated.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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 [see Warnings and Precautions (5.5) ]. Although there are no available data on TOBI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ] . There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ) . Advise pregnant 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 reproductive toxicity studies have been conducted with TOBI (tobramycin administered by inhalation). 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 TOBI 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 and any potential adverse effects on the breastfed infant from TOBI 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 The safety and efficacy of TOBI in pediatric patients under 6 years of age has not been established. The use of TOBI is not indicated in children <6 years of age [see Indications and Usage (1) and Dosage and Administration (2) ]. 8.5 Geriatric Use Clinical studies of TOBI did not include patients aged 65 years and over.

he safety and efficacy of TOBI in pediatric patients under 6 years of age has not been established. The use of TOBI is not indicated in children <6 years of age [see Indications and Usage (1) and Dosage and Administration (2) ]. 8.5 Geriatric Use Clinical studies of TOBI did not include patients aged 65 years and over. 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 (5.3) ].

8.1 Pregnancy Risk Summary 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 [see Warnings and Precautions (5.5) ]. Although there are no available data on TOBI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ] . There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ) . Advise pregnant 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 reproductive toxicity studies have been conducted with TOBI (tobramycin administered by inhalation). 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.

Risk Summary 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 [see Warnings and Precautions (5.5) ]. Although there are no available data on TOBI use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ] . There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ) . Advise pregnant 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. Risk Summary There are no data on the presence of TOBI 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 and any potential adverse effects on the breastfed infant from TOBI or from the underlying maternal condition.

8.4 Pediatric Use The safety and efficacy of TOBI in pediatric patients under 6 years of age has not been established. The use of TOBI is not indicated in children <6 years of age [see Indications and Usage (1) and Dosage and Administration (2) ].

8.5 Geriatric Use Clinical studies of TOBI did not include patients aged 65 years and over. 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 (5.3) ].

10 OVERDOSAGE Signs and symptoms of acute toxicity from overdosage of intravenous (IV) tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Administration by inhalation results in low systemic bioavailability of tobramycin. Tobramycin is not significantly absorbed following oral administration. Tobramycin serum concentrations may be helpful in monitoring overdosage. Acute toxicity should be treated with immediate withdrawal of TOBI, and baseline tests of renal function should be undertaken. 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. Hemodialysis may be helpful in removing tobramycin from the body.

11 DESCRIPTION TOBI ® is a tobramycin solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for tobramycin is C 18 H 37 N 5 O 9 and the molecular weight is 467.52 g/mol. Tobramycin 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. The structural formula for tobramycin is: Each single-dose 5 mL ampoule contains 300 mg tobramycin and 11.25 mg sodium chloride in sterile water for injection. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet USP requirements. The formulation contains no preservatives. Tobramycin Structural Formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4) ] . 12.3 Pharmacokinetics Absorption TOBI contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. (1) The bioavailability of TOBI may vary because of individual differences in nebulizer performance and airway pathology. (2) Following administration of TOBI, tobramycin remains concentrated primarily in the airways. Serum Concentrations The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of TOBI by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the TOBI regimen, the average serum tobramycin concentration one hour after dosing was 1.05 mcg/mL. Sputum Concentrations Ten minutes after inhalation of the first 300-mg dose of TOBI by cystic fibrosis patients, the average concentration of tobramycin was 1237 mcg/g (range 35 to 7417 mcg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the TOBI regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 mcg/g (range 39 to 8085 mcg/g) in sputum. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation. Distribution Following administration of TOBI, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible. Elimination Metabolism Tobramycin is not metabolized. Excretion The elimination half-life of tobramycin from serum is approximately 2 and 3 hours after intravenous (IV) administration and inhalation, respectively. Systemically absorbed tobramycin is primarily excreted unchanged in the urine principally by glomerular filtration. Unabsorbed tobramycin, following TOBI administration, is probably eliminated primarily in expectorated sputum. 12.4 Microbiology Mechanism of Action Tobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius .( 1 ) It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.( 3 ) Tobramycin has in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa . It is bactericidal in vitro at concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC). Resistance Treatment for 6 months with TOBI in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients [see Clinical Studies (14) ] . Susceptibility Test Methods Interpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician. Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear.

ceptibility is noted, the results should be reported to the clinician. Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear. A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have a different level of in vitro susceptibility to tobramycin.

12.1 Mechanism of Action Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4) ] . Mechanism of Action Tobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius .( 1 ) It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.( 3 ) Tobramycin has in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa . It is bactericidal in vitro at concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC).

12.3 Pharmacokinetics Absorption TOBI contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. (1) The bioavailability of TOBI may vary because of individual differences in nebulizer performance and airway pathology. (2) Following administration of TOBI, tobramycin remains concentrated primarily in the airways. Serum Concentrations The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of TOBI by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the TOBI regimen, the average serum tobramycin concentration one hour after dosing was 1.05 mcg/mL. Sputum Concentrations Ten minutes after inhalation of the first 300-mg dose of TOBI by cystic fibrosis patients, the average concentration of tobramycin was 1237 mcg/g (range 35 to 7417 mcg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the TOBI regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 mcg/g (range 39 to 8085 mcg/g) in sputum. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation. Distribution Following administration of TOBI, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible. Elimination Metabolism Tobramycin is not metabolized. Excretion The elimination half-life of tobramycin from serum is approximately 2 and 3 hours after intravenous (IV) administration and inhalation, respectively. Systemically absorbed tobramycin is primarily excreted unchanged in the urine principally by glomerular filtration. Unabsorbed tobramycin, following TOBI administration, is probably eliminated primarily in expectorated sputum.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI has been completed. Rats were exposed to TOBI for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of tobramycin of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI has been completed. Rats were exposed to TOBI for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of tobramycin of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in 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.

14 CLINICAL STUDIES Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa . Subjects who were less than 6 years of age, had a baseline creatinine of >2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV 1 % predicted between 25% and 75%. In these clinical studies, 258 patients received TOBI therapy on an outpatient basis (see Table 2) using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Table 2: Dosing Regimens in Clinical Studies Cycle 1 Cycle 2 Cycle 3 28 days 28 days 28 days 28 days 28 days 28 days TOBI TOBI No drug TOBI No drug TOBI No drug regimen 300 mg 300 mg 300 mg n = 258 twice daily twice daily twice daily Placebo placebo No drug placebo No drug placebo No drug regimen twice daily twice daily twice daily n = 262 All patients received either TOBI or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral antipseudomonal therapy, β2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME, Genentech). In each study, TOBI-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the TOBI group in Study 1 by an average increase in FEV 1 % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, TOBI-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV 1 % predicted over 24 weeks for both studies. Figure 1: Relative Change From Baseline in FEV 1 % Predicted In each study, TOBI therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle (see Figure 2). Figure 2: Absolute Change From Baseline in Log 10 CFUs Patients treated with TOBI were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with TOBI required an average of 9.6 days of parenteral antipseudomonal, antibacterial treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of TOBI patients and 53% of placebo patients were treated with parenteral antipseudomonal antibacterials. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear. However, four TOBI patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥128 mcg/mL did not experience an improvement in FEV 1 or a decrease in sputum bacterial density. Treatment with TOBI did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P.

did not experience an improvement in FEV 1 or a decrease in sputum bacterial density. Treatment with TOBI did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ≥16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the TOBI regimen. Figure 1: Relative Change From Baseline in FEV1% Predicted Figure 2: Absolute Change From Baseline in Log10 CFUs

<table width="100%"><caption>Table 2: Dosing Regimens in Clinical Studies</caption><col width="19%"/><col width="13%"/><col width="14%"/><col width="13%"/><col width="13%"/><col width="14%"/><col width="12%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cycle 1</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cycle 2</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cycle 3</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">28 days</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TOBI</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TOBI</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TOBI</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TOBI</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>regimen</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>300 mg</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>300 mg</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>300 mg</paragraph></td><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>n = 258</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="t

valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="t op"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Placebo</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>placebo</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>placebo</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>placebo</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>No drug</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>regimen</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>twice daily</paragraph></td><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>n = 262</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>

15 REFERENCES 1. Neu HC. Tobramycin: an overview. [Review]. J Infect Dis 1976; Suppl 134:S3-19. 2. Weber A, Smith A, Williams-Warren J et al. Nebulizer delivery of tobramycin to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9. 3. Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TOBI is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 5 mL single-dose ampoule (300 mg tobramycin) for nebulization. TOBI 300 mg is available as follows: 5 mL single-dose ampoule (carton of 56) NDC 49502-345-73 16.2 Storage and Handling TOBI should be stored under refrigeration at 2ºC–8ºC/36ºF–46ºF. Upon removal from the refrigerator, or if refrigeration is unavailable, TOBI pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. TOBI should not be used beyond the expiration date stamped on the ampoule when stored under refrigeration (2ºC–8ºC/36ºF–46ºF) or beyond 28 days when stored at room temperature (25ºC/77ºF). TOBI ampoules should not be exposed to intense light. The solution in the ampoule is slightly yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Difficulty Breathing: Advise patients to inform their physicians if they experience shortness of breath or wheezing after administration of tobramycin inhalation solution. Tobramycin inhalation solution 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 tobramycin inhalation solution 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 tobramycin inhalation solution 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) ] . Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Manufactured by: Woodstock Sterile Solutions, Inc. Woodstock, IL 60098 U.S.A. © 2023 Viatris Inc. TOBI is a registered trademark of BGP Products Operations GmbH, a Viatris Company. The brands listed are trademarks of their respective owners. WS:TOBRIS:R2

PATIENT INFORMATION TOBI (TOH-bee) (tobramycin inhalation solution) for oral inhalation use What is TOBI? TOBI is a prescription medicine that is used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa . TOBI contains an antibacterial medicine called tobramycin (an aminoglycoside). It is not known if TOBI is safe and effective: • in children under 6 years of age • in people who have an FEV 1 less than 25% or greater than 75% predicted • in people who are colonized with a bacterium called Burkholderia cepacia Do not take TOBI if you are allergic to tobramycin, any of the ingredients in TOBI, or to any other aminoglycoside antibacterial. See the end of this Patient Information for a complete list of ingredients in TOBI. Before you take TOBI, 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 • are pregnant or plan to become pregnant. TOBI is in a class of drugs that can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if TOBI passes into your breast milk. • are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking TOBI. Your blood levels of tobramycin will be checked. Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. How should I take TOBI? • See the step-by-step Instructions for Use about the right way to take your TOBI. • Take TOBI exactly as your healthcare provider tells you. Do not change your dose or stop taking TOBI unless your healthcare provider tells you to. • The usual dose for adults and children over 6 years of age is: o 1 single-use ampule of TOBI inhaled 2 times each day using a hand-held PARI LC PLUS ™ Reusable Nebulizer and a DeVilbiss ® Pulmo-Aide ® air compressor. • Each dose of TOBI should be taken as close to 12 hours apart as possible. • You should not take your dose less than 6 hours apart. • TOBI is taken as a breathing treatment (inhalation) with a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Do not use any other nebulizer for your TOBI treatment. • Do not mix or dilute TOBI with dornase alfa or other medicines in your nebulizer system. • Each treatment should take about 15 minutes. • TOBI should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth. • If you forget to take TOBI and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. • After using TOBI for 28 days, you should stop using it and wait 28 days. After you have stopped using TOBI for 28 days, you should start using TOBI again for 28 days.

hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. • After using TOBI for 28 days, you should stop using it and wait 28 days. After you have stopped using TOBI for 28 days, you should start using TOBI 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. If you are taking several medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling TOBI or as directed by your healthcare provider. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter prescription medicines, vitamins, and herbal supplements. Using TOBI with certain other medicines can cause serious side effects. If you are using TOBI, 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 ethacrynic acid, furosemide, or intravenous mannitol • urea 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. What are the possible side effects of TOBI? TOBI may cause serious side effects, including: • severe breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm with using TOBI: o shortness of breath with wheezing o coughing and chest tightness • hearing loss or ringing in the ears (ototoxicity). Tell your healthcare provider right away if you have hearing loss or you hear noises in your ears such as ringing or hissing. Tell your healthcare provider if you develop vertigo, difficulty with balance or dizziness. • worsening kidney problems (nephrotoxicity). TOBI is in a class of drugs 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. • worsening muscle weakness (neuromuscular disorder). TOBI is in a class of drugs which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson’s disease). The most common side effects of TOBI include: o increased cough o coughing up blood o voice changes o sore throat o decreased lung function o loss or change in taste o increased sputum o trouble breathing o rash These are not all of the possible side effects of TOBI. 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 Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TOBI for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about TOBI that is written for health professionals. What are the ingredients in TOBI? Active ingredient: tobramycin Inactive ingredients: sodium chloride in sterile water for injection, sulfuric acid, sodium hydroxide, and nitrogen What is Pseudomonas aeruginosa? It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis.

Pseudomonas aeruginosa? It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the infection is not properly managed, it will continue to damage your lungs causing further problems to your breathing. Manufactured for: Mylan Specialty L.P., Morgantown, WV 26505 U.S.A. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 2/2023 © 2023 Viatris Inc. TOBI is a registered trademark of BGP Products Operations GmbH, a Viatris Company. The brands listed are trademarks of their respective owners. WS:PIL:TOBRIS:R2

<table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">TOBI (TOH-bee) </content></paragraph><paragraph><content styleCode="bold">(tobramycin inhalation solution) </content></paragraph><paragraph><content styleCode="bold">for oral inhalation use</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">What is TOBI? </content></paragraph><paragraph>TOBI is a prescription medicine that is used to treat people with cystic fibrosis who have a bacterial infection called <content styleCode="italics">Pseudomonas aeruginosa</content>. TOBI contains an antibacterial medicine called tobramycin (an aminoglycoside).</paragraph><paragraph>It is not known if TOBI is safe and effective:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>in children under 6 years of age</item><item><caption>&#x2022;</caption>in people who have an FEV₁ less than 25% or greater than 75% predicted</item><item><caption>&#x2022;</caption>in people who are colonized with a bacterium called <content styleCode="italics">Burkholderia cepacia</content></item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take TOBI</content> if you are allergic to tobramycin, any of the ingredients in TOBI, or to any other aminoglycoside antibacterial.</paragraph><paragraph><content styleCode="bold">See the end of this Patient Information for a complete list of ingredients in TOBI.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Before you take TOBI, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>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.</item><item><caption>&#x2022;</caption>have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from your mother.</item><item><caption>&#x2022;</caption>have dizziness</item><item><caption>&#x2022;</caption>have or have had kidney problems</item><item><caption>&#x2022;</caption>have or have had problems with muscle weakness such as myasthenia gravis or Parkinson&#x2019;s disease</item><item><caption>&#x2022;</caption>have or have had breathing problems such as wheezing, coughing, or chest tightness</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. TOBI is in a class of drugs that can harm your unborn baby.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. It is not known if TOBI passes into your breast milk. </item><item><caption>&#x2022;</caption>are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking TOBI.

lass of drugs that can harm your unborn baby.</item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. It is not known if TOBI passes into your breast milk. </item><item><caption>&#x2022;</caption>are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking TOBI. Your blood levels of tobramycin will be checked.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content> including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take TOBI?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">See the step-by-step Instructions for Use </content>about the right way to take your TOBI.</item><item><caption>&#x2022;</caption>Take TOBI exactly as your healthcare provider tells you. <content styleCode="bold">Do not</content> change your dose or stop taking TOBI unless your healthcare provider tells you to. </item><item><caption>&#x2022;</caption>The usual dose for adults and children over 6 years of age is:<list listType="unordered"><item><caption>o</caption>1 single-use ampule of TOBI inhaled 2 times each day using a hand-held PARI LC PLUS^&#x2122;Reusable Nebulizer and a DeVilbiss^&#xAE;Pulmo-Aide^&#xAE;air compressor.</item></list></item><item><caption>&#x2022;</caption>Each dose of TOBI should be taken as close to 12 hours apart as possible.</item><item><caption>&#x2022;</caption>You should not take your dose less than 6 hours apart.</item><item><caption>&#x2022;</caption>TOBI is taken as a breathing treatment (inhalation) with a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. <content styleCode="bold">Do not</content> use any other nebulizer for your TOBI treatment.</item><item><caption>&#x2022;</caption>Do not mix or dilute TOBI with dornase alfa or other medicines in your nebulizer system.</item><item><caption>&#x2022;</caption>Each treatment should take about 15 minutes.</item><item><caption>&#x2022;</caption>TOBI should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth.</item><item><caption>&#x2022;</caption>If you forget to take TOBI and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. </item><item><caption>&#x2022;</caption>After using TOBI for 28 days, you should stop using it and wait 28 days. After you have stopped using TOBI for 28 days, you should start using TOBI 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. </item></list><paragraph>If you are taking several medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling TOBI or as directed by your healthcare provider.

even if you are feeling better. It is important that you keep to the 28-day on, 28-day off cycle. </item></list><paragraph>If you are taking several medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling TOBI or as directed by your healthcare provider. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter prescription medicines, vitamins, and herbal supplements.</paragraph><paragraph>Using TOBI with certain other medicines can cause serious side effects.</paragraph><paragraph>If you are using TOBI, you should discuss with your healthcare provider if you should take:</paragraph><list listType="unordered"><item><caption>&#x2022;</caption>other medicines that may harm your nervous system, kidneys, or hearing</item><item><caption>&#x2022;</caption>&#x201C;water pills&#x201D; (diuretics) such as ethacrynic acid, furosemide, or intravenous mannitol</item><item><caption>&#x2022;</caption>urea</item></list><paragraph>Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.</paragraph><paragraph>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.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of TOBI? </content></paragraph><paragraph><content styleCode="bold">TOBI may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>severe breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm with using TOBI:<list listType="unordered"><item><caption>o</caption>shortness of breath with wheezing</item><item><caption>o</caption>coughing and chest tightness</item></list></item><item><caption>&#x2022;</caption>hearing loss or ringing in the ears (ototoxicity). Tell your healthcare provider right away if you have hearing loss or you hear noises in your ears such as ringing or hissing. Tell your healthcare provider if you develop vertigo, difficulty with balance or dizziness.</item><item><caption>&#x2022;</caption>worsening kidney problems (nephrotoxicity). TOBI is in a class of drugs 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.</item><item><caption>&#x2022;</caption>worsening muscle weakness (neuromuscular disorder). TOBI is in a class of drugs which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson&#x2019;s disease).</item></list><paragraph>The most common side effects of TOBI include:</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><list listType="unordered"><item><caption>o</caption>increased cough</item><item><caption>o</caption>coughing up blood</item><item><caption>o</caption>voice changes</item></list></td><td valign="top"><list listType="unordered"><item><caption>o</caption>sore throat</item><item><caption>o</caption>decreased lung function </item><item><caption>o</caption>loss or change in taste</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item><caption>o</caption>increased sputum</item><item><caption>o</caption>trouble breathing </item><item><caption>o</caption>rash</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>These are not all of the possible side effects of TOBI. </paragraph><paragraph>Call your doctor for medical advice about side effects.

tem><item><caption>o</caption>trouble breathing </item><item><caption>o</caption>rash</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>These are not all of the possible side effects of TOBI. </paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of TOBI</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TOBI for a condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about TOBI that is written for health professionals.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in TOBI? </content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> tobramycin</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> sodium chloride in sterile water for injection, sulfuric acid, sodium hydroxide, and nitrogen </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What is Pseudomonas aeruginosa?</content></paragraph><paragraph>It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the infection is not properly managed, it will continue to damage your lungs causing further problems to your breathing.</paragraph><paragraph>Manufactured for: Mylan Specialty L.P., Morgantown, WV 26505 U.S.A.</paragraph><paragraph>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).</paragraph></td></tr></tbody></table>

Instructions for Use TOBI (TOH-bee) (tobramycin inhalation solution) for oral inhalation use Read this Instructions for Use before you start using TOBI inhalation solution and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. TOBI is made for inhalation using a PARI LC PLUS™ Reusable Nebulizer and a DeVilbiss® Pulmo-Aide® air compressor. TOBI can be taken at home, school, or at work. The following instructions tell you how to use the DeVilbiss Pulmo-Aide air compressor and PARI LC PLUS Reusable Nebulizer to administer TOBI. You will need the following supplies (See Figure A) : • 1 TOBI plastic ampule (TOBI is packaged with 4 ampules in each foil pouch) • DeVilbiss Pulmo-Aide air compressor • PARI LC PLUS Reusable Nebulizer • Tubing to connect the nebulizer and compressor • Clean paper or cloth towels • Nose clips (optional) (Figure A) It is important that your nebulizer and compressor function properly before starting your TOBI therapy. Note: Read the manufacturer care and use instructions for important information. Prepare Your TOBI for Inhalation Therapy Step 1: Wash your hands thoroughly with soap and water. Step 2: Open the foil pouch. Step 3: Separate 1 TOBI ampule by gently pulling apart at the bottom tabs (See Figure B) . Place the remaining TOBI ampules in the refrigerator. (Figure B) Step 4: Check the expiration date stamped on the TOBI ampule (See Figure C) . Do not use the TOBI ampule if the expiration date has passed. (Figure C) Step 5: Check that the TOBI ampule medicine is clear and does not have particles. • Unrefrigerated TOBI, which is normally slightly yellow, may darken with age. This color change does not mean there is any change in the quality of the medicine. • Do not use the TOBI ampule if the medicine is cloudy or has particles. • Throw it away and get a new one. Step 6: Lay out the parts of a PARI LC PLUS Reusable Nebulizer package on a clean, dry paper or cloth towel. You should have the following parts (See Figure D) : • Nebulizer Top and Bottom (Nebulizer Cup) Assembly • Inspiratory Valve Cap • Mouthpiece with Valve • Tubing (Figure D) Step 7: Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting off (See Figure E). (Figure E) Step 8: Place the Nebulizer Top on the clean paper or cloth towel by standing the Nebulizer Cup upright on the towel (See Figure F). (Figure F) Step 9: Connect one end of the tubing to the compressor air outlet (See Figure G). The tubing should fit tightly. (Figure G) Step 10: Plug in your compressor to an electrical outlet (See Figure H) . (Figure H) Step 11: Open the TOBI ampule by holding the bottom tab with 1 hand and twisting off the top of the TOBI ampule with the other hand (See Figure I). Be careful not to squeeze the TOBI ampule until you are ready to empty all the medicine into the Nebulizer Cup. (Figure I) Step 12 : Squeeze all the medicine of the TOBI ampule into the Nebulizer Cup (See Figure J) . (Figure J) Step 13: Replace the Nebulizer Top. To replace the Nebulizer Top insert the Nebulizer Top into the Nebulizer Cup with the semi-circle halfway down the stem of the Nebulizer Top facing the Nebulizer Outlet. Turn the Nebulizer Top clockwise until securely fastened to the nebulizer Cup. (See Figure K).

ure J) . (Figure J) Step 13: Replace the Nebulizer Top. To replace the Nebulizer Top insert the Nebulizer Top into the Nebulizer Cup with the semi-circle halfway down the stem of the Nebulizer Top facing the Nebulizer Outlet. Turn the Nebulizer Top clockwise until securely fastened to the nebulizer Cup. (See Figure K). (Figure K) Step 14: Push the Mouthpiece straight onto the Nebulizer Outlet (See Figure L) . (Figure L) Step 15: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Top (See Figure M). The Inspiratory Valve Cap will fit tightly. (Figure M) Step 16: Hold the Nebulizer Cup upright and firmly push the free end of the tubing from the compressor to the Air Intake on the bottom of the Nebulizer Cup (See Figure N). Make sure to keep the Nebulizer Cup upright. (Figure N) Giving your TOBI Inhalation Therapy Step 17: Turn on the compressor (See Figure O) . (Figure O) Step 18: Check for a steady mist from the Mouthpiece (See Figure P). If there is no mist, check all tubing connections and make sure that the compressor is working properly. (Figure P) Step 19: Sit or stand in an upright position that will allow you to breathe normally. Place the Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth (See Figure Q). Nose clips may help you breathe through your mouth and not through your nose. Do not block the airflow with your tongue. (Figure Q) Step 20 : Keep breathing in your TOBI medicine for at least 15 minutes to get your full dose. Continue therapy until all your TOBI medicine is gone, and there is no longer any mist being made. You may hear a sputtering sound coming from the Mouthpiece when the Nebulizer Cup is empty. The entire TOBI therapy should take about 15 minutes to complete. If you are interrupted, need to cough or rest during your TOBI treatment, turn off the compressor to save your medicine. Turn the compressor back on when you are ready to restart your treatment. Follow the nebulizer cleaning and disinfecting instructions after completing your therapy. After your TOBI Inhalation Therapy Cleaning Your Nebulizer To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is made, and your therapy will not be as effective. Replace the nebulizer if clogging occurs. 1) Remove tubing from nebulizer and disassemble nebulizer parts. 2) Wash all parts (except tubing) with warm water and liquid dish soap. 3) Rinse thoroughly with warm water and shake out water. 4) Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store. You can also wash all parts of the nebulizer in a dishwasher (except tubing). 1) Place the nebulizer parts in a dishwasher basket. 2) Place the dishwasher basket on the top rack of the dishwasher. 3) Remove and dry the parts when the cycle is complete. Disinfecting Your Nebulizer Your nebulizer is for your use only. Do not share your nebulizer with other people. You must disinfect the nebulizer every other treatment day. Failure to disinfect the nebulizer every other treatment day could lead to serious or fatal illness. Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth. Care and Use of Your Pulmo-Aide Compressor Follow the manufacturer instructions for care and use of your compressor. Filter Change: • DeVilbiss Compressor filters should be changed every 6 months or sooner if the filter turns completely gray in color.

water for a full 10 minutes. Dry parts on a clean, lint-free cloth. Care and Use of Your Pulmo-Aide Compressor Follow the manufacturer instructions for care and use of your compressor. Filter Change: • DeVilbiss Compressor filters should be changed every 6 months or sooner if the filter turns completely gray in color. Compressor Cleaning: • With power switch in the “Off” position, unplug power cord from wall outlet. • Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free. Caution: Do not submerge in water because this will damage the compressor. How should I store TOBI? • Store TOBI ampules in a refrigerator between 36°F to 46°F (2°C to 8°C) until needed. • You may store the TOBI ampules in the foil pouches (opened or unopened) at room temperature 77°F (25°C) for up to 28 days. • Do not use TOBI ampules if they have been stored at room temperature for more than 28 days. • Protect TOBI ampules from light. Keep TOBI and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Additional Information Nebulizer: 1-800-327-8632 Compressor: 1-800-338-1988 TOBI: Call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Manufactured by: Woodstock Sterile Solutions, Inc. Woodstock, IL 60098 U.S.A. © 2023 Viatris Inc. TOBI is a registered trademark of BGP Products Operations GmbH, a Viatris Company. The brands listed are trademarks of their respective owners. WS:IFU:TOBRIS:R2 Revised: 2/2023 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 Figure G Instructions for Use Figure 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 Figure Q