Tobramycin

Warnings and Precautions, Ototoxicity ( 5.2 ) 2/2023 Warnings and Precautions, Ototoxicity ( 5.2 ) 2/2023

1 INDICATIONS AND USAGE Tobramycin inhalation solution, USP 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 ) 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies ( 14 )]. Tobramycin inhalation solution, USP 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 ) 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 ampule (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 TM Reusable Nebulizer with a DeVilbiss ® Pulmo-Aide ® compressor. ( 2.2) 2.1 Dosage Tobramycin inhalation solution, USP is for oral inhalation only [see Dosage and Administration ( 2.2 )] . The recommended dosage of tobramycin inhalation solution for both adults and pediatric patients 6 years of age and older is one single-dose ampule (300 mg) administered twice daily for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg twice daily. Tobramycin inhalation solution, USP is administered twice daily in alternating periods of 28 days. 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/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 Tobramycin inhalation solution, USP is administered by oral inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS TM Reusable Nebulizer with a DeVilbiss ® Pulmo-Aide ® compressor. Tobramycin inhalation solution should not be diluted or mixed with dornase alfa or other medications in the nebulizer. Tobramycin inhalation solution, USP is not for subcutaneous, intravenous or intrathecal administration. Prior to administration of tobramycin inhalation solution, read the Patient Information/Instructions for Use for tobramycin inhalation solution for detailed information on how to use tobramycin inhalation solution and follow the manufacturer's instructions for use and care of the PARI LC PLUS TM Reusable Nebulizer and DeVilbiss ® Pulmo-Aide ® air compressor. Tobramycin inhalation solution, USP 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 tobramycin inhalation solution or as directed by their physician. Tobramycin inhalation solution, USP 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 )

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 Lifestar Pharma LLC at 1-888-995-4337 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). 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 I …

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) Concomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended due to possible enhancement of aminoglycoside toxicity. (7.2) See 17 for PATIENT COUNSELING INFORMATION and FDA- approved patient labeling. Revised: February, 2023 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 aminoglycoside concentrations in serum and tissue. 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). 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 …

12.1 Mechanism of Action Tobramycin inhalation solution is an aminoglycoside antibacterial [see Clinical Pharmacology (12.4) ].

11 DESCRIPTION TOBRAMYCIN INHALATION SOLUTION PAK contains tobramycin inhalation solution, USP and the PARI LC PLUS Reusable Nebulizer (PARI LC PLUS). Tobramycin inhalation solution is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven PARI LC PLUS Reusable Nebulizer. The chemical formula for tobramycin is C 18 H 37 N 5 O 9 and the molecular weight is 467.52. Tobramycin is O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-a-D- ribo - hexopyranosyl-(1→6)]-2-deoxy-L-streptamine. The structural formula for tobramycin is: Each single-use 5 mL ampule 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. The formulation contains no preservatives. The inhalation solution has an osmolality in the range 135 to 200 mOsmol/kg. The PARI LC PLUS Reusable Nebulizer has the following performance characteristics with tobramycin inhalation solution [measured using Next Generation Impactor (NGI) at 15 L/min continuous flow, standard conditions (50%RH, 23°C)]: (1) Delivered Dose: 174 mg; (2) Fine Particle Dose (< 5μm): 97 mg; (3) Nebulization Time: 13 min.; (4) Mass Median Aerodynamic Diameter: 4.3 μm; (5) Geometric Standard Deviation (GSD): 2.2 μm. Structural Formula for Tobramycin

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 tobramycin inhalation solution, 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tobramycin inhalation solution, USP, 300 mg is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 5 mL single-dose ampule (300 mg tobramycin) for nebulization. Tobramycin inhalation solution, USP 300 mg is available as follows: NDC 68180-962-56 5 mL single-dose ampule packed in carton of 56 ampules (14 pouches, each containing 4 ampules). 16.2 STORAGE AND HANDLING Tobramycin inhalation solution, USP should be stored under refrigeration at 2 to 8oC/36 to 46oF. 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 25oC/77oF) 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 to 8oC/36 to 46oF) or beyond 28 days when stored at room temperature (25oC/77oF). Tobramycin inhalation solution, USP ampules should not be exposed to intense light. The solution in the ampule 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.

16.1 How Supplied Tobramycin inhalation solution, USP, 300 mg is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 5 mL single-dose ampule (300 mg tobramycin) for nebulization. Tobramycin inhalation solution, USP 300 mg is available as follows: NDC 68180-962-56 5 mL single-dose ampule packed in carton of 56 ampules (14 pouches, each containing 4 ampules).