Tobramycin

Description

Tobramycin Inhalation Solution is a sterile, clear, colorless to pale yellow, non-pyrogenic aqueous solution with an adjusted pH and salinity. It is administered via a compressed air-driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9, with a molecular weight of 467.52. The structure of tobramycin is described as 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. Each single-use 4 mL ampule contains a 300 mg dose of tobramycin, along with sodium chloride and sulfuric acid in water for injection. Sulfuric acid and sodium hydroxide are utilized as necessary to adjust the pH to 5.0. Nitrogen is employed for sparging, filling, and pouching. The formulation is free of preservatives.

Uses and Indications

Tobramycin Inhalation Solution is indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa.

Limitations of Use: Safety and efficacy have not been established in patients under the age of six years, in patients with a forced expiratory volume in one second (FEV1) less than 40% or greater than 80% predicted, or in patients colonized with Burkholderia cepacia.

Dosage and Administration

For oral inhalation only. Healthcare professionals should administer the entire contents of one ampule twice daily by oral inhalation. This regimen should be followed in repeated cycles of 28 days on the drug, succeeded by 28 days off the drug.

Contraindications

Tobramycin Inhalation Solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Use in these patients may lead to severe allergic reactions.

Warnings and Precautions

Caution should be exercised when prescribing Tobramycin Inhalation Solution to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction. The use of aminoglycosides, including Tobramycin, may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function.

Healthcare professionals should be aware that bronchospasm can occur following the inhalation of Tobramycin Inhalation Solution. Therefore, appropriate monitoring is essential. Audiograms, serum concentration levels, and renal function should be assessed as necessary to ensure patient safety.

It is important to inform pregnant women of the potential risks associated with aminoglycoside administration, as fetal harm may occur. Women should be apprised of this hazard to the fetus prior to treatment.

For patients exhibiting any signs of auditory dysfunction or those at increased risk for such dysfunction, audiograms should be considered. The presence of tinnitus may indicate the onset of ototoxicity, and its emergence necessitates heightened caution.

In patients with renal dysfunction or those receiving concomitant parenteral tobramycin, serum concentrations of tobramycin should be monitored at the discretion of the treating physician. It is critical to note that serum concentration levels should only be obtained through venipuncture; finger prick blood sampling is not acceptable.

Additionally, laboratory tests assessing urine and renal function should be conducted as deemed appropriate by the treating physician to ensure comprehensive monitoring of the patient's condition.

Side Effects

Patients receiving Tobramycin Inhalation Solution may experience a range of adverse reactions, which can be categorized into common and serious reactions based on clinical trial data and postmarketing experiences.

Common adverse reactions reported in clinical trials include decreased forced expiratory volume, rales, increased red blood cell sedimentation rate, dysphonia, wheezing, epistaxis, pharyngolaryngeal pain, bronchitis, tonsillitis, diarrhea, eosinophilia, and increased immunoglobulins. These reactions were frequently observed among participants and should be monitored during treatment.

Postmarketing experience has identified additional adverse reactions across various systems. Ear and labyrinth disorders such as hearing loss and tinnitus have been reported. Skin and subcutaneous tissue disorders include hypersensitivity, pruritus, urticaria, and rash. Nervous system disorders may manifest as aphonia and dysgeusia. Respiratory, thoracic, and mediastinal disorders can include bronchospasm and oropharyngeal pain. Furthermore, metabolism and nutrition disorders such as decreased appetite have also been noted.

It is important to note that bronchospasm can occur with the inhalation of Tobramycin Inhalation Solution. Caution should be exercised when prescribing this medication to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction, as aminoglycosides may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function. Additionally, fetal harm may occur if aminoglycosides are administered to a pregnant woman, necessitating careful consideration of the risks and benefits in this population.

Drug Interactions

Concurrent and/or sequential use of Tobramycin Inhalation Solution with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential is contraindicated. This includes, but is not limited to, ethacrynic acid, furosemide, urea, and intravenous mannitol.

Healthcare professionals are advised to exercise caution and avoid the concomitant administration of these medications to mitigate the risk of additive toxic effects. Monitoring of renal function and auditory function may be warranted in patients receiving Tobramycin Inhalation Solution, particularly if there is a need for the use of other potentially harmful agents.

Packaging & NDC

The table below lists all NDC Code configurations of Tobramycin Inhalation, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and efficacy of Tobramycin Inhalation Solution have not been established in pediatric patients with cystic fibrosis who are under six years of age. Therefore, caution is advised when considering the use of this medication in this age group.

Geriatric Use

Clinical studies of Tobramycin Inhalation Solution did not include elderly patients aged 65 years and over. Therefore, the safety and efficacy of this medication in this age group have not been established.

Tobramycin is substantially excreted by the kidneys, and the risk of adverse reactions may be heightened in patients with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, it is advisable to monitor renal function closely in this population. Dose adjustments may be necessary based on renal status to mitigate the risk of potential adverse effects.

Pregnancy

Aminoglycosides, including tobramycin, have the potential to cause fetal harm. Published literature indicates that the use of streptomycin, an aminoglycoside, during pregnancy can result in total, irreversible, bilateral congenital deafness. While there are no available data on the use of Tobramycin Inhalation Solution in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, it is important to note that systemic absorption of tobramycin following inhaled administration is expected to be minimal.

Pregnant women should be advised of the potential risks to the fetus associated with the use of this medication. The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown; however, all pregnancies carry a background risk of birth defects, 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 approximately 2 to 4% and 15 to 20%, respectively.

Cystic fibrosis, a condition that may necessitate the use of tobramycin, can pose additional risks during pregnancy, including an increased likelihood of preterm delivery. Although animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis did not reveal adverse developmental outcomes, it is noteworthy that ototoxicity was not evaluated in the offspring from these studies. Furthermore, no reproduction toxicology studies have been conducted with inhaled tobramycin. In the animal studies, subcutaneous doses of tobramycin up to 100 mg/kg/day in rats and 20 mg/kg/day in rabbits were not associated with adverse developmental outcomes, although doses of 40 mg/kg/day or higher were severely maternally toxic to rabbits, preventing the evaluation of potential adverse developmental effects.

Healthcare professionals should carefully consider these factors when prescribing tobramycin to pregnant patients.

Lactation

There are no data on the presence of tobramycin in either human or animal milk, nor on the effects on the breastfed infant or milk production following oral inhalation of Tobramycin Inhalation Solution. Limited published data on other formulations of tobramycin in lactating women indicate that tobramycin is present in human milk; however, systemic absorption of tobramycin following inhaled administration is expected to be minimal.

Tobramycin may cause alterations in the intestinal flora of the breastfeeding infant. The developmental and health benefits of breastfeeding should be considered alongside the mother’s clinical need for Tobramycin Inhalation Solution and any potential adverse effects on the breastfed child from the medication or from the underlying maternal condition.

Lactating mothers are advised to monitor the breastfed infant for signs of loose or bloody stools and candidiasis (thrush, diaper rash).

Renal Impairment

Caution should be exercised when prescribing Tobramycin Inhalation Solution to patients with known or suspected renal dysfunction. It is important to monitor audiograms, serum concentration, and renal function as appropriate to ensure patient safety and therapeutic efficacy.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be considered as part of standard clinical practice.

Overdosage

In clinical trials, no overdoses have been reported with Tobramycin Inhalation Solution. However, it is important for healthcare professionals to be aware of the potential signs and symptoms associated with acute toxicity from an overdosage of intravenous tobramycin. These may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

The administration of tobramycin by inhalation results in low systemic bioavailability, and it is also noteworthy that tobramycin is not significantly absorbed following oral administration. Despite the low risk of systemic toxicity from inhalation, monitoring tobramycin serum concentrations can be beneficial in cases of suspected overdosage.

In instances of suspected overdosage, it is imperative that physicians contact the Regional Poison Control Center for guidance on effective treatment options. Additionally, healthcare professionals should consider the possibility of drug interactions that may alter drug disposition in the event of an overdosage.

Nonclinical Toxicology

A two-year inhalation toxicology study in rats was conducted to evaluate the carcinogenic potential of an inhaled solution of tobramycin. During the study, rats were exposed to tobramycin for up to 1.5 hours per day over a period of 95 weeks. Serum levels of tobramycin reached up to 35 mcg/mL, which is 35 times the average exposure levels of 1 mcg/mL observed in cystic fibrosis patients during clinical trials. The results indicated no drug-related increase in the incidence of any tumor types.

Tobramycin has also undergone a comprehensive assessment for genotoxicity through a series of in vitro and in vivo tests. The Ames bacterial reversion test, which utilized five tester strains, did not demonstrate a significant increase in revertants, both with and without metabolic activation across all strains. Furthermore, tobramycin was found to be negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and yielded negative results in the mouse micronucleus test.

In terms of reproductive toxicity, subcutaneous administration of tobramycin at doses up to 100 mg/kg did not adversely affect mating behavior or impair fertility in either male or female rats.

Postmarketing Experience

During postapproval use of tobramycin inhalation solution, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ear and Labyrinth Disorders

• Hearing loss

• Tinnitus see Warnings and Precautions (5.1)

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity

• Pruritus

• Urticaria

• Rash

Nervous System Disorders

• Aphonia

• Dysgeusia

Respiratory, Thoracic, and Mediastinal Disorders

• Bronchospasm see Warnings and Precautions (5.4)

• Oropharyngeal pain

Metabolism and Nutrition Disorders

• Decreased appetite

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use. It is important to inform patients that the long-term efficacy and safety of Tobramycin Inhalation Solution are limited, particularly in patients with severe cystic fibrosis (FEV < 40% predicted).

Patients should be instructed to complete a full 28-day course of Tobramycin Inhalation Solution, even if they begin to feel better. After this 28-day therapy, patients must discontinue the use of Tobramycin Inhalation Solution for the next 28 days, after which they can resume therapy following a 28-day on and 28-day off cycle.

For patients using multiple inhaled medications or performing chest physiotherapy, healthcare providers should clarify the order in which these therapies should be taken, recommending that Tobramycin Inhalation Solution be administered last. It is essential to use Tobramycin Inhalation Solution with the PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor, and to refer to the manufacturer’s instructions for the care and use of these devices.

Patients should be informed about the potential for ototoxicity, which may present as hearing loss or tinnitus, and that an audiogram should be considered at baseline, especially for those at increased risk of auditory dysfunction. If patients report tinnitus or hearing loss during therapy, they should be referred for audiological assessment. Additionally, patients should be made aware that vestibular toxicity may manifest as vertigo, ataxia, or dizziness.

Healthcare providers should inform patients that bronchospasm can occur with the inhalation of Tobramycin and that adverse reactions associated with aminoglycosides, such as nephrotoxicity and neuromuscular disorders, may also occur. Monitoring of hearing, serum concentrations of tobramycin, and renal function may be necessary during treatment.

It is crucial to inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman. Patients should be advised to notify their healthcare provider if they are pregnant, become pregnant, or plan to become pregnant.

In the event that a dose of Tobramycin Inhalation Solution is missed, patients should be instructed to take the missed dose as soon as possible if there are at least 6 hours until the next scheduled dose. If less than 6 hours remain, the missed dose should not be taken, and patients should resume their usual dosing schedule.

Patients should be encouraged to contact their healthcare provider with any questions. Additionally, they should be informed about the proper storage of Tobramycin Inhalation Solution ampules, which should be kept in a refrigerator (36-46 °F or 2-8 °C). If refrigeration is not available, the foil pouches (opened or unopened) may be stored at room temperature (up to 77 °F/25 °C) for up to 28 days.

It is important to remind patients that Tobramycin Inhalation Solution is light sensitive; unopened ampules should be returned to the foil pouch, and exposure to intense light should be avoided. Unrefrigerated Tobramycin Inhalation Solution, which is typically colorless to pale yellow, may darken with age, but this color change does not indicate a loss of product quality. Patients should not use Tobramycin Inhalation Solution if it appears cloudy, contains particles, or has been stored at room temperature for more than 28 days. Furthermore, it should not be used beyond the expiration date stamped on the ampule.

Storage and Handling

Tobramycin Inhalation Solution is supplied in ampules, which should be stored under refrigeration at a temperature range of 2°C to 8°C (36°F to 46°F). Upon removal from refrigeration, or if refrigeration is not available, the solution pouches, whether opened or unopened, may be stored at room temperature, not exceeding 25°C (77°F), for a maximum of 28 days.

It is essential to adhere to the expiration date indicated on the ampule when stored under refrigeration. If stored at room temperature, the solution must be used within 28 days. The ampules should be protected from intense light exposure, and unopened ampules should be returned to their original foil pouch to maintain stability.

The solution is typically colorless to pale yellow; however, it may darken with age if not stored in the recommended refrigeration conditions. This color change does not affect the quality of the product, provided it remains within the specified storage parameters.

Additional Clinical Information

Physicians should consider conducting audiograms for patients exhibiting signs of auditory dysfunction or those at increased risk, as tinnitus may indicate potential ototoxicity. In patients with normal renal function receiving Tobramycin Inhalation Solution, serum tobramycin concentrations typically range from approximately 0.06-1.89 mcg/mL one hour post-administration, and routine monitoring is not necessary. However, for patients with renal dysfunction or those receiving concomitant parenteral tobramycin, serum concentrations should be monitored at the physician's discretion, using venipuncture rather than finger prick sampling. Additionally, laboratory tests assessing urine and renal function should be performed as deemed appropriate by the treating physician.

Postmarketing experience has revealed various adverse effects, including ear and labyrinth disorders such as hearing loss and tinnitus, skin reactions like hypersensitivity and rash, nervous system issues including aphonia and dysgeusia, respiratory complications such as bronchospasm and oropharyngeal pain, and metabolic disorders like decreased appetite.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Tobramycin Inhalation as submitted by Prasco, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)