NDC 43598-605 Tobramycin Inhalation Solution

Tobramycin Inhalation Solution

NDC Product Code 43598-605

NDC Code: 43598-605

Proprietary Name: Tobramycin Inhalation Solution What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Tobramycin Inhalation Solution What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

  • 43598 - Dr. Reddy�s Laboratories Inc.
    • 43598-605 - Tobramycin Inhalation Solution

NDC 43598-605-56

Package Description: 14 POUCH in 1 CARTON > 4 AMPULE in 1 POUCH (43598-605-04) > 5 mL in 1 AMPULE

NDC Product Information

Tobramycin Inhalation Solution with NDC 43598-605 is a a human prescription drug product labeled by Dr. Reddy�s Laboratories Inc.. The generic name of Tobramycin Inhalation Solution is tobramycin inhalation solution. The product's dosage form is inhalant and is administered via respiratory (inhalation) form.

Labeler Name: Dr. Reddy�s Laboratories Inc.

Dosage Form: Inhalant - A special class of inhalations consisting of a drug or combination of drugs, that by virtue of their high vapor pressure can be carried by an air current into the nasal passage where they exert their effect; the container from which the inhalant generally is administered is known as an inhaler.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Tobramycin Inhalation Solution Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TOBRAMYCIN 300 mg/5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • SULFURIC ACID (UNII: O40UQP6WCF)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • NITROGEN (UNII: N762921K75)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Respiratory (inhalation) - Administration within the respiratory tract by inhaling orally or nasally for local or systemic effect.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Aminoglycoside Antibacterial - [EPC] (Established Pharmacologic Class)
  • Aminoglycosides - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Dr. Reddy�s Laboratories Inc.
Labeler Code: 43598
FDA Application Number: ANDA207080 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-14-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Tobramycin Inhalation Solution Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

Tobramycin inhalation solution 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 (FEV1) <25% or >75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)].

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 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 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 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. 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.   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 Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor. Tobramycin inhalation solution 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 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 inhalational solution for nebulization in single-dose 5 mL ampules. Each 5 mL ampule contains 300 mg of tobramycin.

4 Contraindications

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

5.1 Bronchospasm

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.

5.2 Ototoxicity

Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides.   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. Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with tobramycin inhalation solution therapy during clinical studies, however in postmarketing experience, patients receiving tobramycin inhalation solution 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 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.

5.3 Nephrotoxicity

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.

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 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)].

5.6 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

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)]

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.  Tobramycin inhalation solution was studied in two phase 3 clinical studies involving 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.   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.  Table 1: Percent of Patients With Selected Adverse Reactions Occurring in >5% of Tobramycin Inhalation Solution PatientsAdverse ReactionTobramycin Inhalation Solution (n=258)%Placebo (n=262)%Cough Increased46.147.3Pharyngitis38.039.3Sputum Increased37.639.7Dyspnea33.738.5Hemoptysis19.423.7Lung Function Decreased116.315.3Voice Alteration12.86.5Taste Perversion6.66.9Rash5.46.11 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration.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 Voice Alteration and Tinnitus Voice alteration and tinnitus were the only adverse reactions reported by significantly more tobramycin inhalation solution-treated patients. 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. 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 tobramycin inhalation solution and placebo groups.   Changes in Serum Creatinine Nine (3%) patients in the tobramycin inhalation solution 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 tobramycin inhalation solution group, creatinine decreased at the next visit.

6.2 Postmarketing Experience

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 disordersHearing 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

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.

8.1 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 (5.5)]. Although there are no available data on tobramycin inhalation solution 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 tobramycin inhalation solution is 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 tobramycin inhalation solution 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 tobramycin inhalation solution and any potential adverse effects on the breastfed infant 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 in pediatric patients under 6 years of age has not been established. The use of tobramycin inhalation solution 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 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)].

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.

11 Description

Tobramycin inhalation solution, USP is a tobramycin solution for inhalation. It is a sterile, to clear, colorless to 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 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-α-D-ribo hexopyranosyl-(1→6)]-2-deoxy-L-streptamine. The structural formula for tobramycin is:Each single-dose 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. All ingredients meet USP requirements. The formulation contains no preservatives.

12.1 Mechanism Of Action

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

12.3 Pharmacokinetics

Absorption 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) Following administration of tobramycin inhalation solution, 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 tobramycin inhalation solution by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the tobramycin inhalation solution 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 tobramycin inhalation solution by cystic fibrosis patients, the average concentration of tobramycin was 1,237 mcg/g (range 35 to 7,417 mcg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin inhalation solution regimen, the average concentration of tobramycin at ten minutes after inhalation was 1,154 mcg/g (range 39 to 8,085 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 tobramycin inhalation solution, 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 tobramycin inhalation solution administration, is probably eliminated primarily in expectorated sputum.

12.4 Microbiology

Mechanism of ActionTobramycin 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 tobramycin inhalation solution 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 tobramycin inhalation solution. The relationship between in vitro susceptibility test results and clinical outcome with tobramycin inhalation solution 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.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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.

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 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 hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.Table 2: Dosing Regimens in Clinical Studies Cycle 1Cycle 2Cycle 3 28 days28 days28 days28 days28 days28 daysTobramycin Inhalation Solution Tobramycin Inhalation Solution No drug Tobramycin Inhalation Solution No drug Tobramycin Inhalation Solution 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 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 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, 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 FEV1% PredictedIn 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 Log10 CFUsPatients 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 antipseudomonal antibacterial 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 antipseudomonal antibacterials.   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 mcg/mL did not experience an improvement in FEV1 or a decrease in sputum bacterial density. Treatment with tobramycin inhalation solution 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 tobramycin inhalation solution regimen.

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.

16.1 How Supplied

Tobramycin inhalation solution, USP 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 43598-605-56 5 mL single-dose ampule (carton of 56)

16.2 Storage And Handling

Tobramycin inhalation solution, USP should be stored under refrigeration at 2ºC to 8ºC or 36ºF 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 (2ºC to 8ºC or 36ºF to 46ºF) or beyond 28 days when stored at room temperature (25ºC or 77ºF).   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.

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)].   Embryofetal 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)]. Rx Only Manufactured by:Holopack Verpackungstechnik GmbH Bahnhofstrasse 20 73453 Abtsgmünd-Untergröningen Germany   Distributed by: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 US   Issued: February 2019

Instructions For Use Section

INSTRUCTIONS FOR USETobramycin Inhalation Solution (toe-brah-MYE-sin)for oral inhalation useRead this Instructions for Use before you start using tobramycin inhalation solution inhalationsolution and each time you get a refill. There may be new information. This leaflet does not takethe place of talking to your healthcare provider about your medical condition or treatment.Tobramycin inhalation solution is made for inhalation using a PARI LC PLUS™ ReusableNebulizer and a DeVilbiss® Pulmo-Aide® air compressor. Tobramycin inhalation solution can betaken at home, school, or at work. The following instructions tell you how to use the DeVilbissPulmo-Aide air compressor and PARI LC PLUS Reusable Nebulizer to administer tobramycininhalation solution.You will need the following supplies (See Figure A): 1 tobramycin inhalation solution plastic ampule (tobramycin inhalation solution ispackaged 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 yourtobramycin inhalation solution therapy.Note: Read the manufacturer care and use instructions for important information.Prepare Your Tobramycin Inhalation Solution for Inhalation TherapyStep 1: Wash your hands thoroughly with soap and water.Step 2: Open the foil pouch.Step 3: Separate 1 tobramycin inhalation solution ampule by gently pulling apart at the bottomtabs (See Figure B). Place the remaining tobramycin inhalation solution ampules in therefrigerator.(Figure B)Step 4: Check the expiration date stamped on the tobramycin inhalation solution ampule (See FigureC). Do not use the tobramycin inhalation solution ampule if the expiration date has passed.(Figure C)Step 5: Check that the tobramycin inhalation solution ampule medicine is clear and does nothave particles. Unrefrigerated tobramycin inhalation solution, which is normally slightly yellow, maydarken with age. This color change does not mean there is any change in the quality ofthe medicine. Do not use the tobramycin inhalation solution ampule if the medicine is cloudy or hasparticles. 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 paperor 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 Topcounter-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 Cupupright 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 tubingshould fit tightly.(Figure G)Step 10: Plug in your compressor to an electrical outlet (See Figure H).(See Figure H).Step 11. Open the tobramycin inhalation solution ampule by holding the bottom with one handand twisting off the top of the ampule with the other hand as indicated by the arrow (See FigureI). Be careful not to squeeze the ampule until you are ready to empty its contents into theNebulizer Cup.(Figure I)Step 12: Squeeze all the medicine of the tobramycin inhalation solution 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).(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 thecompressor to the Air Intake on the bottom of the Nebulizer Cup (See Figure N).Make sure tokeep the Nebulizer Cup upright. (Figure N)Giving your Tobramycin Inhalation Solution Inhalation TherapyStep 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, checkall 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 onlythrough your mouth (See Figure Q). Nose clips may help you breathe through your mouth andnot through your nose. Do not block the airflow with your tongue.(Figure Q)Step 20: Keep breathing in your tobramycin inhalation solution medicine for at least 15 minutes to get your full dose. Continue therapy until all your tobramycin inhalation solution 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 tobramycin inhalation solution therapy should take about 15 minutes to complete.  If you are interrupted, need to cough or rest during your tobramycin inhalation solution 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 Tobramycin Inhalation Solution Inhalation TherapyCleaning Your NebulizerTo 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 manufacturers instructions for care and use of your compressor.   Filter Change: 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 tobramycin inhalation solution? · Store tobramycin inhalation solution ampules in a refrigerator between 36°F to 46°F (2°C to 8°C) until needed.· You may store the tobramycin inhalation solution ampules in the foil pouches (opened or unopened) at room temperature 77°F (25°C) for up to 28 days. Do not use tobramycin inhalation solution ampules if they have been stored at room temperature for more than 28 days. · Protect tobramycin inhalation solution ampules from light.  Keep tobramycin inhalation solution 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 Tobramycin Inhalation Solution: 1-888-375-3784   Brands listed are trademarks of their respective owners.   Rx Only Manufactured by: Holopack Verpackungstechnik GmbH Bahnhofstrasse 20 73453 Abtsgmünd-Untergröningen Germany   Distributed by: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 US Issued: February 2019

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