Tobramycin

Description

Tobramycin Inhalation Solution, USP is a sterile solution intended for inhalation, comprising tobramycin in an aqueous medium. This clear, slightly yellow, non-pyrogenic solution is specifically formulated with adjusted pH and salinity for administration via a compressed air-driven reusable nebulizer. The chemical formula for tobramycin, USP is C18H37N5O9, with a molecular weight of 467.52 g/mol.

Each single-dose 5 mL ampule contains 300 mg of tobramycin, USP, along with 11.25 mg of sodium chloride, dissolved in sterile water for injection. The pH of the solution is adjusted to 6.0 using sulfuric acid and sodium hydroxide, while nitrogen is employed for sparging. All components of the formulation comply with USP standards, and the solution is free from preservatives.

Uses and Indications

Tobramycin inhalation solution is indicated for the management of cystic fibrosis in adults and pediatric patients aged 6 years and older who are infected with Pseudomonas aeruginosa.

Limitations of use have not been specified in the provided information. There are no teratogenic or nonteratogenic effects mentioned in the available data.

Dosage and Administration

The medication is intended for oral inhalation only. The recommended dosage for adults and pediatric patients aged 6 years and older is one single-dose ampule (300 mg) administered twice daily via oral inhalation. This regimen should be followed in alternating cycles of 28 days on the medication, followed by 28 days off.

Dosage adjustments based on body weight are not necessary. It is advised that doses be taken as close to 12 hours apart as possible; however, they should not be administered less than 6 hours apart. Each 300 mg dose should be inhaled using a hand-held PARI LC PLUS Reusable Nebulizer in conjunction with a DeVilbiss Pulmo-Aide compressor to ensure proper delivery of the medication.

Contraindications

Use of this product is contraindicated in patients with a known hypersensitivity to any aminoglycoside. This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Bronchospasm may occur following the inhalation of tobramycin inhalation solution. In the event of bronchospasm, it is essential to treat the condition as medically appropriate.

Ototoxicity is a significant concern associated with the use of tobramycin inhalation solution, with reports of tinnitus and hearing loss in patients. Should these symptoms arise, it is crucial to manage them appropriately, which may include the discontinuation of tobramycin inhalation solution.

Nephrotoxicity is another potential risk linked to aminoglycosides, including tobramycin. If signs of nephrotoxicity develop, healthcare professionals should manage the patient accordingly, which may involve discontinuing the use of tobramycin inhalation solution.

Patients with neuromuscular disorders should be monitored closely, as aminoglycosides can exacerbate muscle weakness due to a possible curare-like effect on neuromuscular function. In cases of neuromuscular blockade, administration of calcium salts may reverse the effects; however, mechanical assistance may be required.

It is important to note that aminoglycosides, including tobramycin, have the potential to cause fetal harm, indicating a risk of embryo-fetal toxicity. Therefore, careful consideration should be given when prescribing to pregnant individuals.

Side Effects

Patients receiving tobramycin inhalation solution may experience a range of adverse reactions, which can be categorized into common and serious events.

Common adverse reactions observed in clinical trials include increased cough, pharyngitis, increased sputum production, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion, and rash. These reactions were reported with varying frequencies among participants.

Serious adverse reactions associated with tobramycin inhalation solution include bronchospasm, which may occur upon inhalation. If bronchospasm occurs, it should be treated as medically appropriate. Ototoxicity, characterized by tinnitus and hearing loss, has also been reported; management may require discontinuation of the medication. Nephrotoxicity is a known risk associated with aminoglycosides, and if it develops, appropriate management, including potential discontinuation of tobramycin inhalation solution, is necessary. Additionally, aminoglycosides may exacerbate neuromuscular disorders, leading to muscle weakness due to a curare-like effect on neuromuscular function. In cases of neuromuscular blockade, administration of calcium salts may reverse the effects, although mechanical assistance may be required.

It is important to note that tobramycin inhalation solution carries a risk of embryo-fetal toxicity, which can result in fetal harm. Patients with known hypersensitivity to any aminoglycoside should avoid this treatment. Overdosage of intravenous tobramycin may lead to acute toxicity, with signs and symptoms including dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Management of overdosage should be conducted as medically appropriate.

Drug Interactions

Concurrent and/or sequential use of tobramycin inhalation solution with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential should be avoided to mitigate the risk of adverse effects.

In particular, the concomitant administration of tobramycin inhalation solution with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended. This combination may enhance the toxicity associated with aminoglycosides, necessitating careful consideration of alternative therapies or close monitoring of renal function and auditory status in patients receiving these medications together.

Packaging & NDC

The table below lists all NDC Code configurations of Tobramycin, 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 under 6 years of age. Consequently, the use of tobramycin inhalation solution is not indicated in children younger than 6 years.

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 geriatric patients are more likely to experience decreased renal function, it is advisable to monitor renal function closely in this population. This monitoring may help mitigate potential risks associated with the use of tobramycin in elderly patients.

Pregnancy

Aminoglycosides, including tobramycin, have the potential to cause fetal harm. Published literature indicates that the use of streptomycin, an aminoglycoside, during pregnancy can lead to total, irreversible, bilateral congenital deafness. While there are no available data on the use of tobramycin inhalation solution in pregnant women to assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, it is anticipated that systemic absorption of tobramycin following inhaled administration is minimal.

Pregnant women should be informed of the potential risks to the fetus associated with the use of tobramycin. The estimated background risk of major birth defects and miscarriage in the general population is unknown; however, it is recognized that 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 in pregnant patients may pose additional risks, 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 important to note that ototoxicity was not evaluated in the offspring from these studies. Furthermore, no reproductive toxicity studies have been conducted with tobramycin inhalation solution. In the animal studies, 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 exercise caution and consider the potential risks when prescribing tobramycin inhalation solution to pregnant women.

Lactation

There are no specific statements or information regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on lactating mothers and breastfed infants are not established. Healthcare professionals should consider the absence of data when advising lactating mothers on the use of this medication.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with aminoglycosides, including tobramycin inhalation solution. In cases where nephrotoxicity develops, it is essential to manage the patient appropriately, which may include the discontinuation of the medication. Monitoring of renal function is recommended to ensure patient safety and to guide any necessary adjustments in therapy.

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 outlined 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 prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Acute toxicity resulting from an overdosage of intravenous (IV) tobramycin can manifest through a variety of signs and symptoms. Healthcare professionals should be vigilant for indications such as dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

When tobramycin is administered via inhalation, it is important to note that it exhibits low systemic bioavailability, and it is not significantly absorbed when taken orally. Therefore, monitoring tobramycin serum concentrations can be a useful tool in assessing potential overdosage.

In the event of suspected overdosage, immediate action is required. The first step is to withdraw the tobramycin inhalation solution. Following this, baseline tests of renal function should be conducted to evaluate any potential impairment. It is also crucial for physicians to contact the Regional Poison Control Center for guidance on effective treatment strategies in all cases of suspected overdosage.

Additionally, healthcare professionals should consider the possibility of drug interactions that may alter drug disposition, which could complicate the management of overdosage. In certain cases, hemodialysis may be beneficial in facilitating the removal of tobramycin from the body, thereby mitigating the effects of toxicity.

Nonclinical Toxicology

A two-year inhalation toxicology study in rats was conducted to evaluate the carcinogenic potential of tobramycin inhalation solution. In this study, rats were exposed to the clinical formulation of 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 in the rats, which is significantly higher than the average serum 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 type of tumor.

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 of up to 100 mg/kg did not adversely affect mating behavior or result in impairment of fertility in either male or female rats.

Postmarketing Experience

Postmarketing experience has revealed that tobramycin inhalation solution can cause narrowing of the airway. Additionally, it has been associated with hearing loss. The data indicate that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage. Furthermore, it has been noted that aminoglycosides, including tobramycin, may lead to irreversible congenital deafness when administered to pregnant women.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use, to ensure they understand the proper use and potential risks associated with tobramycin inhalation solution.

Patients must be informed to report any instances of shortness of breath or wheezing following the administration of tobramycin inhalation solution, as this medication can lead to airway narrowing.

It is important for patients to notify their physician if they experience ringing in the ears, dizziness, or any changes in hearing, as tobramycin inhalation solution has been linked to hearing loss.

Patients should also be encouraged to disclose any history of kidney problems to their physician, given that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage.

Pregnant women should be specifically advised that aminoglycosides, including tobramycin, can result in irreversible congenital deafness if administered during pregnancy.

Storage and Handling

Tobramycin Inhalation Solution, USP is supplied in ampules and should be stored under refrigeration at a temperature range of 2º to 8ºC (36º to 46ºF). If refrigeration is unavailable, the solution may be stored at room temperature, not exceeding 25ºC (77ºF), for a maximum of 28 days. It is essential to adhere to the expiration date indicated on the ampule when stored under refrigeration. Similarly, the solution should not be used beyond 28 days if stored at room temperature.

Care should be taken to protect the ampules from intense light exposure. The solution may appear slightly yellow, and while it may darken with age if not refrigerated, this color change does not affect the product's quality as long as it is stored according to the recommended conditions.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)