These Highlights Do Not Include All The Information Needed To Use Tobramycin Inhalation Solution Pak Safely And Effectively. See Full Prescribing Information For Tobramycin Inhalation Solution Pak.

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 (5.5)]. Although there are no available data on TOBRAMYCIN INHALATION SOLUTION PAK 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.

INSTRUCTIONS FOR USE

TOBRAMYCIN INHALATION SOLUTION PAK

(tobramycin inhalation solution), for oral inhalation

Follow the instructions below for using TOBRAMYCIN INHALATION SOLUTION PAK which contains tobramycin inhalation solution and the PARI LC PLUS Reusable Nebulizer (PARI LC PLUS). If you have any questions, ask your healthcare provider or pharmacist.

Each TOBRAMYCIN INHALATION SOLUTION PAK carton (28-day supply) contains 56 tobramycin inhalation solution ampules packed in 14 foil pouches that each contain 4 single- use tobramycin inhalation solution ampules.

You will need the following supplies (See Figure A):

• 1 tobramycin inhalation solution ampule
• PARI LC PLUS Reusable Nebulizer
• DeVilbiss Pulmo-Aide (Pulmo-Aide) air compressor
• tubing to connect the nebulizer and compressor
• clean, lint-free towel
• nose clip (optional, not pictured)

Note: Read the Instructions for Use that come with your PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor for detailed instructions on how to use and care for your nebulizer and air compressor before you use it.

Do not mix the medicine in TOBRAMYCIN INHALATION SOLUTION PAK with other medicines in your nebulizer.

The medicine in TOBRAMYCIN INHALATION SOLUTION PAK (tobramycin inhalation solution) comes in a sealed foil pouch. Do not open a sealed pouch until you are ready to use a dose. After opening the pouch, unopened ampules should be returned to and stored in the pouch.

Getting ready:

• Open the PARI LC PLUS package. Place the PARI LC PLUS parts including Top and Bottom (Nebulizer Cup) Assembly, Inspiratory Valve Cap, Mouthpiece with Valve, and Tubing on a clean, dry surface or towel (See Figure B).

Preparing your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 1: Wash your hands with soap and water (See Figure C).

Step 2: Open the foil pouch (See Figure D).

Step 3: Separate 1 ampule by gently pulling apart starting at the top of the ampules and continue down to the bottom tabs (See Figure E) and use it right away.

Step 4: Hold the bottom tab on the TOBRAMYCIN INHALATION SOLUTION PAK ampule with 1 hand (See Figure F). With your other hand, hold the top of the ampule and twist off the top of the ampule (See Figure F).

• Do not squeeze the ampule until you are ready to squeeze all of the medicine into the Nebulizer Cup.

Step 5: Hold the Nebulizer Cup and twist off the Nebulizer Insert or Top in a counter-clockwise direction (See Figure G). Set the Top aside on a clean, dry, surface.

Step 6: Squeeze all the medicine from the ampule into the Nebulizer Cup (See Figure H).

Step 7: Replace the Nebulizer Insert. Line up the semi-circle on the Nebulizer Insert with the Nebulizer Outlet and twist on the Nebulizer Insert in a clockwise direction until it is tight and the alignment rings are lined up (See Figure I).

Step 8: Push the Mouthpiece straight onto the Nebulizer Cup (See Figure J).

Step 9: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Cup Top (See Figure K). The Inspiratory Valve Cap should fit tightly.

Step 10: Connect 1 end of the tubing to the compressor air outlet (See Figure L). The tubing should fit tightly.

Step 11: Plug your compressor into an electrical outlet (See Figure M).

Step 12: 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 N). Make sure to keep the Nebulizer Cup upright.

Giving your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 13: Turn on the compressor (See Figure O). You should see a steady mist coming from the Mouthpiece (See Figure P).

Step 14: Sit or stand in a comfortable, 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 only through your mouth and not through your nose.

Step 15: Keep breathing in your TOBRAMYCIN INHALATION SOLUTION PAK dose for at least 15 minutes. You will know that you have received your full dose of medicine when you hear a “sputtering noise” coming from the Mouthpiece for at least 1 minute and the Nebulizer Cup is empty.

After your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 16: Clean and disinfect your nebulizer (see manufacturer's Instructions for Use).

Care and Use of your DeVilbiss Pulmo-Aide compressor:

Follow the manufacturer's instructions for care and use of your compressor.

How should I store TOBRAMYCIN INHALATION SOLUTION PAK?

• Store tobramycin inhalation solution in the refrigerator between 36°F to 46°F (2°C to 8°C) until needed.
• You may store the tobramycin inhalation solution in the foil pouches (opened or unopened) at room temperature between 68°F to 77°F (20°C to 25°C) for up to 28 days.
• Do not use tobramycin inhalation solution after the expiration date stamped on the ampule.
• Keep tobramycin inhalation solution in the foil pouch and out of the light.
• Tobramycin inhalation solution is normally slightly yellow, but may get darker with age if unrefrigerated. The color change does not change how the medicine works.
• Do not use tobramycin inhalation solution if it is cloudy, has particles in the solution, or if it has been stored at room temperature for more than 28 days. Throw the applicable ampule(s) away in your household trash and get a new ampule.

Keep TOBRAMYCIN INHALATION SOLUTION PAK 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.

Revised: 08/2023

Additional Information

PARI LC PLUS^® Reusable Nebulizer: 1-800-327-8632

DeVilbiss^® Pulmo-Aide^® Air Compressor: 1-800-338-1988

TOBRAMYCIN INHALATION SOLUTION PAK: 1-877-236-7239

Manufactured by:

Woodstock Sterile Solutions, Inc.

Woodstock, IL 60098

Distributed by:

Genericus, Inc.,

Glen Allen, 23060 VA

899D9999 Rev. F 08/2023

© 2023 PulmoFlow, Inc. All rights reserved.

• Tobramycin inhalation solution should be stored under refrigeration at 2-8°C/36-46°F. Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution pouches (opened or unopened) may be stored at room temperature (up to 25°C/77°F) for up to 28 days. Tobramycin inhalation solution should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2-8°C/36-46°F) or beyond 28 days when stored at room temperature (25°C/77°F).
• Tobramycin inhalation solution 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.

Signs and symptoms of acute toxicity from overdosage of IV tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. 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.

• 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.
• Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.

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.

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 C₁₈H₃₇N₅O₉ 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.

Ototoxicity with use of Tobramycin Inhalation Solution

Transient tinnitus occurred in eight tobramycin inhalation solution 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. In postmarketing experience, patients receiving tobramycin inhalation solution have reported hearing loss. 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 might 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 [see Adverse Reactions (6.2)].

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.

Bronchospasm can occur with inhalation of tobramycin inhalation solution. In clinical studies with tobramycin inhalation solution, changes in FEV1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of tobramycin inhalation solution should be treated as medically appropriate.

TOBRAMYCIN INHALATION SOLUTION PAK co-packaged kit (NDC 70644-899-99) is available in cartons containing one reusable PARI LC PLUS nebulizer (Model No.: 022B81-T) and 14 tobramycin inhalation solution pouches. Each pouch contains four 300 mg/5 ml ampules of tobramycin inhalation solution for a total of 56 ampules in each carton. Each carton constitutes a 28 day supply.

The safety and efficacy of tobramycin inhalation solution have not been studied in pediatric patients under 6 years of age.

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 (5.3)].

Nephrotoxicity was not seen during clinical studies with tobramycin inhalation solution 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.

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 with tobramycin inhalation solution. Subjects who were less than 6 years of age, had a baseline creatinine of > 2 mg/dL, or had B. cepacia isolated from sputum were excluded. All subjects had baseline FEV₁% predicted between 25% and 75%. In these clinical studies, 258 patients received tobramycin inhalation solution therapy on an outpatient basis (see Table 2) using a PARI LC PLUS nebulizer along with a DeVilbiss Pulmo-Aide compressor.

All patients received either tobramycin inhalation solution 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 anti-pseudomonal therapy, Beta 2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa.

In each study, tobramycin inhalation solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the tobramycin inhalation solution group in Study 1 by an average increase in FEV₁% predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, tobramycin inhalation solution-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 FEV₁% predicted over 24 weeks for both studies.

Figure 1: Relative Change From Baseline in FEV ₁ % Predicted

In each study, tobramycin inhalation solution 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 tobramycin inhalation solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with tobramycin inhalation solution required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of tobramycin inhalation solution patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics.

The relationship between in vitro susceptibility test results and clinical outcome with tobramycin inhalation solution therapy is not clear. However, 4 tobramycin inhalation solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 μg/mL did not experience an improvement in FEV₁ or a decrease in sputum bacterial density.

Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

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)]

• Concurrent and/or sequential use 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).

• TOBRAMYCIN INHALATION SOLUTION PAK is a co-packaging of tobramycin inhalation solution ampules with a PARI LC PLUS Reusable Nebulizer. Administer as follows: One single-use ampule (300 mg/5 mL) of tobramycin inhalation solution twice a day by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug.
• The 300 mg/5 mL dose of tobramycin inhalation solution is the same for all patients regardless of age or weight.
• The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

TOBRAMYCIN INHALATION SOLUTION PAK (co-packaging of tobramycin inhalation solution and PARI LC PLUS Reusable Nebulizer) is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with P. aeruginosa. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV₁ < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)].

Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4)].

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 PAK 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)].

• Bronchospasm: Can occur with inhalation of tobramycin inhalation solution. Treat as medically appropriate, if it occurs (5.1).
• Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin inhalation solution. If noted, manage as medically appropriate, including potentially discontinuing tobramycin inhalation solution (5.2).
• Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin inhalation solution (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)

• TOBRAMYCIN INHALATION SOLUTION PAK is a co-packaging of tobramycin inhalation solution with a PARI LC PLUS^® Reusable Nebulizer (2.1).
• Administer tobramycin inhalation solution as one single–use ampule (300 mg/5 mL) twice a day 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 using the PARI LC PLUS Reusable Nebulizer and DeVilbiss^® Pulmo-Aide^® compressor (2.2).

Inhalation solution: 300 mg/5 mL in a single-use ampule.

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 neuromuscular blocking agents. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.

The following adverse reactions have been identified during post approval 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: 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

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.

Tobramycin inhalation solution was studied in two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin inhalation solution 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. Adverse reactions reported in these studies are described below:

• The most frequent adverse reactions in the tobramycin inhalation arm were cough, pharyngitis, and increased sputum (see Table 1).
• Thirty-three patients (13%) treated with tobramycin inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.
• Eight patients from the tobramycin inhalation solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms.

Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin inhalation solution patients during the two Phase III studies.

Selected adverse reactions that occurred in less than or equal to 5% of patients treated with tobramycin inhalation solution:

Ear and labyrinth disorders

Tinnitus

Musculoskeletal and connective tissue disorders

Myalgia

Infections and infestations

Laryngitis

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instructions for Administration

Instruct patients to read the Instructions for Use before starting TOBRAMYCIN INHALATION SOLUTION PAK. Instruct patients to use the tobramycin inhalation solution in TOBRAMYCIN INHALATION SOLUTION PAK only with the PARI LC PLUS Reusable Nebulizer included in the TOBRAMYCIN INHALATION SOLUTION PAK.

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.

Each dose of tobramycin inhalation solution is administered by oral inhalation using only the co-packaged PARI LC PLUS Reusable Nebulizer (Model No. 022B81-TA) included in the TOBRAMYCIN INHALATION SOLUTION PAK, along with a DeVilbiss Pulmo-Aide air compressor (Model No. 5650D).

Tobramycin inhalation solution is not for subcutaneous, intravenous or intrathecal administration.

Prior to administration, read the Patient Information/Instructions for Use for TOBRAMYCIN INHALATION SOLUTION PAK for detailed information on how to use TOBRAMYCIN INHALATION SOLUTION PAK and follow the manufacturer's instructions for use and care of the DeVilbiss Pulmo-Aide air compressor.

The entire tobramycin inhalation solution treatment should take approximately 15 minutes to complete. Continue treatment until all the tobramycin inhalation solution has been delivered, and there is no longer any mist being produced.

Tobramycin inhalation solution should not be diluted or mixed with other drugs including dornase alfa in the nebulizer. Instruct patients on multiple therapies to take their medications prior to inhaling the tobramycin inhalation solution, or as directed by their physician. 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.

A two-year rat inhalation toxicology study to assess carcinogenic potential of tobramycin inhalation solution has been completed. Rats were exposed to tobramycin inhalation solution 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.

Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided if possible.

NDC 70644-899-99

Genericus

Tobramycin Inhalation Solution Pak

300 mg/5 mL Ampules

56 Single-Use Ampules of Tobramycin Inhalation Solution, USP

co-packaged with 1 PARI LC PLUS® Reusable Nebulizer Set

For more information, call 1-877-236-7239

Store in Refrigerator

Includes One PARI LC PLUS Nebulizer Set

Rx only

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 (5.5)]. Although there are no available data on TOBRAMYCIN INHALATION SOLUTION PAK 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.

INSTRUCTIONS FOR USE

TOBRAMYCIN INHALATION SOLUTION PAK

(tobramycin inhalation solution), for oral inhalation

Follow the instructions below for using TOBRAMYCIN INHALATION SOLUTION PAK which contains tobramycin inhalation solution and the PARI LC PLUS Reusable Nebulizer (PARI LC PLUS). If you have any questions, ask your healthcare provider or pharmacist.

Each TOBRAMYCIN INHALATION SOLUTION PAK carton (28-day supply) contains 56 tobramycin inhalation solution ampules packed in 14 foil pouches that each contain 4 single- use tobramycin inhalation solution ampules.

You will need the following supplies (See Figure A):

• 1 tobramycin inhalation solution ampule
• PARI LC PLUS Reusable Nebulizer
• DeVilbiss Pulmo-Aide (Pulmo-Aide) air compressor
• tubing to connect the nebulizer and compressor
• clean, lint-free towel
• nose clip (optional, not pictured)

Note: Read the Instructions for Use that come with your PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor for detailed instructions on how to use and care for your nebulizer and air compressor before you use it.

Do not mix the medicine in TOBRAMYCIN INHALATION SOLUTION PAK with other medicines in your nebulizer.

The medicine in TOBRAMYCIN INHALATION SOLUTION PAK (tobramycin inhalation solution) comes in a sealed foil pouch. Do not open a sealed pouch until you are ready to use a dose. After opening the pouch, unopened ampules should be returned to and stored in the pouch.

Getting ready:

• Open the PARI LC PLUS package. Place the PARI LC PLUS parts including Top and Bottom (Nebulizer Cup) Assembly, Inspiratory Valve Cap, Mouthpiece with Valve, and Tubing on a clean, dry surface or towel (See Figure B).

Preparing your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 1: Wash your hands with soap and water (See Figure C).

Step 2: Open the foil pouch (See Figure D).

Step 3: Separate 1 ampule by gently pulling apart starting at the top of the ampules and continue down to the bottom tabs (See Figure E) and use it right away.

Step 4: Hold the bottom tab on the TOBRAMYCIN INHALATION SOLUTION PAK ampule with 1 hand (See Figure F). With your other hand, hold the top of the ampule and twist off the top of the ampule (See Figure F).

• Do not squeeze the ampule until you are ready to squeeze all of the medicine into the Nebulizer Cup.

Step 5: Hold the Nebulizer Cup and twist off the Nebulizer Insert or Top in a counter-clockwise direction (See Figure G). Set the Top aside on a clean, dry, surface.

Step 6: Squeeze all the medicine from the ampule into the Nebulizer Cup (See Figure H).

Step 7: Replace the Nebulizer Insert. Line up the semi-circle on the Nebulizer Insert with the Nebulizer Outlet and twist on the Nebulizer Insert in a clockwise direction until it is tight and the alignment rings are lined up (See Figure I).

Step 8: Push the Mouthpiece straight onto the Nebulizer Cup (See Figure J).

Step 9: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Cup Top (See Figure K). The Inspiratory Valve Cap should fit tightly.

Step 10: Connect 1 end of the tubing to the compressor air outlet (See Figure L). The tubing should fit tightly.

Step 11: Plug your compressor into an electrical outlet (See Figure M).

Step 12: 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 N). Make sure to keep the Nebulizer Cup upright.

Giving your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 13: Turn on the compressor (See Figure O). You should see a steady mist coming from the Mouthpiece (See Figure P).

Step 14: Sit or stand in a comfortable, 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 only through your mouth and not through your nose.

Step 15: Keep breathing in your TOBRAMYCIN INHALATION SOLUTION PAK dose for at least 15 minutes. You will know that you have received your full dose of medicine when you hear a “sputtering noise” coming from the Mouthpiece for at least 1 minute and the Nebulizer Cup is empty.

After your TOBRAMYCIN INHALATION SOLUTION PAK dose:

Step 16: Clean and disinfect your nebulizer (see manufacturer's Instructions for Use).

Care and Use of your DeVilbiss Pulmo-Aide compressor:

Follow the manufacturer's instructions for care and use of your compressor.

How should I store TOBRAMYCIN INHALATION SOLUTION PAK?

• Store tobramycin inhalation solution in the refrigerator between 36°F to 46°F (2°C to 8°C) until needed.
• You may store the tobramycin inhalation solution in the foil pouches (opened or unopened) at room temperature between 68°F to 77°F (20°C to 25°C) for up to 28 days.
• Do not use tobramycin inhalation solution after the expiration date stamped on the ampule.
• Keep tobramycin inhalation solution in the foil pouch and out of the light.
• Tobramycin inhalation solution is normally slightly yellow, but may get darker with age if unrefrigerated. The color change does not change how the medicine works.
• Do not use tobramycin inhalation solution if it is cloudy, has particles in the solution, or if it has been stored at room temperature for more than 28 days. Throw the applicable ampule(s) away in your household trash and get a new ampule.

Keep TOBRAMYCIN INHALATION SOLUTION PAK 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.

Revised: 08/2023

Additional Information

PARI LC PLUS^® Reusable Nebulizer: 1-800-327-8632

DeVilbiss^® Pulmo-Aide^® Air Compressor: 1-800-338-1988

TOBRAMYCIN INHALATION SOLUTION PAK: 1-877-236-7239

Manufactured by:

Woodstock Sterile Solutions, Inc.

Woodstock, IL 60098

Distributed by:

Genericus, Inc.,

Glen Allen, 23060 VA

899D9999 Rev. F 08/2023

© 2023 PulmoFlow, Inc. All rights reserved.

• Tobramycin inhalation solution should be stored under refrigeration at 2-8°C/36-46°F. Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution pouches (opened or unopened) may be stored at room temperature (up to 25°C/77°F) for up to 28 days. Tobramycin inhalation solution should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2-8°C/36-46°F) or beyond 28 days when stored at room temperature (25°C/77°F).
• Tobramycin inhalation solution 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.

Signs and symptoms of acute toxicity from overdosage of IV tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. 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.

• 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.
• Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.
• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.

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.

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 C₁₈H₃₇N₅O₉ 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.

Ototoxicity with use of Tobramycin Inhalation Solution

Transient tinnitus occurred in eight tobramycin inhalation solution 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. In postmarketing experience, patients receiving tobramycin inhalation solution have reported hearing loss. 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 might 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 [see Adverse Reactions (6.2)].

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.

Bronchospasm can occur with inhalation of tobramycin inhalation solution. In clinical studies with tobramycin inhalation solution, changes in FEV1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of tobramycin inhalation solution should be treated as medically appropriate.

TOBRAMYCIN INHALATION SOLUTION PAK co-packaged kit (NDC 70644-899-99) is available in cartons containing one reusable PARI LC PLUS nebulizer (Model No.: 022B81-T) and 14 tobramycin inhalation solution pouches. Each pouch contains four 300 mg/5 ml ampules of tobramycin inhalation solution for a total of 56 ampules in each carton. Each carton constitutes a 28 day supply.

The safety and efficacy of tobramycin inhalation solution have not been studied in pediatric patients under 6 years of age.

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 (5.3)].

Nephrotoxicity was not seen during clinical studies with tobramycin inhalation solution 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.

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 with tobramycin inhalation solution. Subjects who were less than 6 years of age, had a baseline creatinine of > 2 mg/dL, or had B. cepacia isolated from sputum were excluded. All subjects had baseline FEV₁% predicted between 25% and 75%. In these clinical studies, 258 patients received tobramycin inhalation solution therapy on an outpatient basis (see Table 2) using a PARI LC PLUS nebulizer along with a DeVilbiss Pulmo-Aide compressor.

All patients received either tobramycin inhalation solution 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 anti-pseudomonal therapy, Beta 2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa.

In each study, tobramycin inhalation solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the tobramycin inhalation solution group in Study 1 by an average increase in FEV₁% predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, tobramycin inhalation solution-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 FEV₁% predicted over 24 weeks for both studies.

Figure 1: Relative Change From Baseline in FEV ₁ % Predicted

In each study, tobramycin inhalation solution 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 tobramycin inhalation solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with tobramycin inhalation solution required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of tobramycin inhalation solution patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics.

The relationship between in vitro susceptibility test results and clinical outcome with tobramycin inhalation solution therapy is not clear. However, 4 tobramycin inhalation solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 μg/mL did not experience an improvement in FEV₁ or a decrease in sputum bacterial density.

Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

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)]

• Concurrent and/or sequential use 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).

• TOBRAMYCIN INHALATION SOLUTION PAK is a co-packaging of tobramycin inhalation solution ampules with a PARI LC PLUS Reusable Nebulizer. Administer as follows: One single-use ampule (300 mg/5 mL) of tobramycin inhalation solution twice a day by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug.
• The 300 mg/5 mL dose of tobramycin inhalation solution is the same for all patients regardless of age or weight.
• The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

TOBRAMYCIN INHALATION SOLUTION PAK (co-packaging of tobramycin inhalation solution and PARI LC PLUS Reusable Nebulizer) is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with P. aeruginosa. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV₁ < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)].

Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4)].

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 PAK 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)].

• Bronchospasm: Can occur with inhalation of tobramycin inhalation solution. Treat as medically appropriate, if it occurs (5.1).
• Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin inhalation solution. If noted, manage as medically appropriate, including potentially discontinuing tobramycin inhalation solution (5.2).
• Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin inhalation solution (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)

• TOBRAMYCIN INHALATION SOLUTION PAK is a co-packaging of tobramycin inhalation solution with a PARI LC PLUS^® Reusable Nebulizer (2.1).
• Administer tobramycin inhalation solution as one single–use ampule (300 mg/5 mL) twice a day 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 using the PARI LC PLUS Reusable Nebulizer and DeVilbiss^® Pulmo-Aide^® compressor (2.2).

Inhalation solution: 300 mg/5 mL in a single-use ampule.

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 neuromuscular blocking agents. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.

The following adverse reactions have been identified during post approval 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: 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

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.

Tobramycin inhalation solution was studied in two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin inhalation solution 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. Adverse reactions reported in these studies are described below:

• The most frequent adverse reactions in the tobramycin inhalation arm were cough, pharyngitis, and increased sputum (see Table 1).
• Thirty-three patients (13%) treated with tobramycin inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.
• Eight patients from the tobramycin inhalation solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms.

Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin inhalation solution patients during the two Phase III studies.

Selected adverse reactions that occurred in less than or equal to 5% of patients treated with tobramycin inhalation solution:

Ear and labyrinth disorders

Tinnitus

Musculoskeletal and connective tissue disorders

Myalgia

Infections and infestations

Laryngitis

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Instructions for Administration

Instruct patients to read the Instructions for Use before starting TOBRAMYCIN INHALATION SOLUTION PAK. Instruct patients to use the tobramycin inhalation solution in TOBRAMYCIN INHALATION SOLUTION PAK only with the PARI LC PLUS Reusable Nebulizer included in the TOBRAMYCIN INHALATION SOLUTION PAK.

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.

Each dose of tobramycin inhalation solution is administered by oral inhalation using only the co-packaged PARI LC PLUS Reusable Nebulizer (Model No. 022B81-TA) included in the TOBRAMYCIN INHALATION SOLUTION PAK, along with a DeVilbiss Pulmo-Aide air compressor (Model No. 5650D).

Tobramycin inhalation solution is not for subcutaneous, intravenous or intrathecal administration.

Prior to administration, read the Patient Information/Instructions for Use for TOBRAMYCIN INHALATION SOLUTION PAK for detailed information on how to use TOBRAMYCIN INHALATION SOLUTION PAK and follow the manufacturer's instructions for use and care of the DeVilbiss Pulmo-Aide air compressor.

The entire tobramycin inhalation solution treatment should take approximately 15 minutes to complete. Continue treatment until all the tobramycin inhalation solution has been delivered, and there is no longer any mist being produced.

Tobramycin inhalation solution should not be diluted or mixed with other drugs including dornase alfa in the nebulizer. Instruct patients on multiple therapies to take their medications prior to inhaling the tobramycin inhalation solution, or as directed by their physician. 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.

A two-year rat inhalation toxicology study to assess carcinogenic potential of tobramycin inhalation solution has been completed. Rats were exposed to tobramycin inhalation solution 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.

Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided if possible.

NDC 70644-899-99

Genericus

Tobramycin Inhalation Solution Pak

300 mg/5 mL Ampules

56 Single-Use Ampules of Tobramycin Inhalation Solution, USP

co-packaged with 1 PARI LC PLUS® Reusable Nebulizer Set

For more information, call 1-877-236-7239

Store in Refrigerator

Includes One PARI LC PLUS Nebulizer Set

Rx only