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 ampoule (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.

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 with use of tobramycin inhalation solution

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.

Risk of Ototoxicity Due to Mitochondrial DNA Variants

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

5.3 Nephrotoxicity

Nephrotoxicity was not seen during clinical studies with 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.

6.1 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 3 studies.

1 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 Disorders

Hearing loss: Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus. [see Warnings and Precautions (5.2)]

Skin and Subcutaneous Tissue Disorders

Hypersensitivity, pruritus, urticaria, rash

Nervous System Disorders

Aphonia, dysgeusia

Respiratory, Thoracic, and Mediastinal Disorders

Bronchospasm [see Warnings and Precautions (5.1)] oropharyngeal pain

Metabolism and Nutrition Disorders

Decreased appetite

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 [see 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 (tobramycin administered by inhalation). However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes. Doses of tobramycin ≥40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during non-clinical reproductive toxicity studies with tobramycin.

8.2 Lactation

Risk Summary

There are no data on the presence of tobramycin 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)].

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 1237 mcg/g (range 35 to 7417 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 1154 mcg/g (range 39 to 8085 mcg/g) in sputum. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation.

Distribution

Following administration of 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 Action

Tobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius.(1)It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.(3)

Tobramycin has in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. It is bactericidal in vitro at concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC).

Resistance

Treatment for 6 months with 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.

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 ampoule (300 mg tobramycin) for nebulization.

Tobramycin inhalation solution, USP 300 mg is available as follows:

5 mL single-dose ampoule (carton of 56) NDC 72603-430-56

16.2 Storage and Handling

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

Tobramycin inhalation solution ampoules should not be exposed to intense light. The solution in the ampoule is slightly yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.