Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, slightly yellow, non-pyrogenic aqueous solution specifically formulated for inhalation via a compressed air-driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9, with a molecular weight of 467.52. The active ingredient, tobramycin, is characterized 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-dose 5 mL ampule contains 300 mg of tobramycin, USP, and 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, and 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 is an aminoglycoside antibacterial 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: The safety and efficacy of tobramycin have not been established in patients under the age of 6 years, in patients with forced expiratory volume in 1 second (FEV1) less than 25% or greater than 75% of predicted values, or in patients colonized with Burkholderia cepacia.

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, but not less than 6 hours apart to ensure optimal therapeutic effect.

Each 300 mg dose should be administered 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 individuals with such sensitivities.

Warnings and Precautions

Bronchospasm may occur following the inhalation of tobramycin. In such instances, it is imperative to treat the bronchospasm as medically appropriate.

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

Nephrotoxicity is a known risk with aminoglycosides, including tobramycin. If signs of nephrotoxicity develop, healthcare professionals should manage the patient accordingly, which may involve discontinuing the medication.

Patients with neuromuscular disorders should be monitored closely, as aminoglycosides can exacerbate muscle weakness due to a potential 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.

Aminoglycosides, including tobramycin, are associated with embryo-fetal toxicity and can cause fetal harm. It is crucial for healthcare providers to counsel patients regarding the risks during pregnancy.

Side Effects

Patients receiving tobramycin may experience a range of adverse reactions. The most common adverse reactions reported include increased cough, pharyngitis, increased sputum production, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion, and rash.

Serious adverse reactions associated with tobramycin include bronchospasm, which can occur with inhalation of the medication and should be treated as medically appropriate. Ototoxicity, characterized by tinnitus and hearing loss, has also been reported; if these symptoms arise, management may require discontinuation of tobramycin. Nephrotoxicity is another serious concern linked to aminoglycosides, including tobramycin. If nephrotoxicity develops, appropriate management should be initiated, which may include discontinuation of the drug. Additionally, aminoglycosides may exacerbate neuromuscular disorders, potentially 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 necessary.

It is important to note that tobramycin can cause embryo-fetal toxicity, posing a risk of fetal harm.

Patients may also exhibit signs and symptoms of acute toxicity from intravenous tobramycin overdosage, which can include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. In instances of suspected overdosage, immediate withdrawal of tobramycin is recommended, along with baseline tests of renal function. Physicians should contact the Regional Poison Control Center for guidance on effective treatment, and hemodialysis may be beneficial in removing tobramycin from the body.

Drug Interactions

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

In particular, the concomitant administration of tobramycin 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 therapeutic options.

Monitoring for signs of toxicity is advised when tobramycin is used in conjunction with these agents, and dosage adjustments may be required based on clinical judgment and patient response.

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 in pediatric patients under 6 years of age have not been established. Consequently, the use of tobramycin is not indicated in children younger than 6 years.

Geriatric Use

Clinical studies of tobramycin did not include elderly patients aged 65 years and over. Therefore, the safety and efficacy of tobramycin in this population 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 demographic. 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 in pregnant women to assess the 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 informed of the potential risks to the fetus associated with the use of tobramycin. The estimated background risk of major birth defects and miscarriage for the general population is unknown; however, it is acknowledged 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 administered by inhalation. 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 when prescribing tobramycin to pregnant women and consider the potential risks to both the mother and the fetus.

Lactation

There are no specific statements regarding nursing mothers or lactation considerations in the provided text. Therefore, the effects of the medication on breastfed infants and the excretion of the drug in human milk remain undetermined. Healthcare professionals should exercise caution when prescribing this medication to lactating mothers, considering the absence of data on its safety and efficacy during breastfeeding.

Renal Impairment

Patients with renal impairment may experience nephrotoxicity associated with aminoglycosides, including tobramycin. In cases where nephrotoxicity develops, it is essential to manage the patient appropriately, which may include the discontinuation of tobramycin. Monitoring renal function is crucial in this population to ensure safe and effective use of the medication.

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 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.

Given that tobramycin is administered via inhalation with low systemic bioavailability and is not significantly absorbed when taken orally, the risk of systemic toxicity is primarily associated with IV administration. Monitoring tobramycin serum concentrations may provide valuable information in assessing the extent of overdosage.

In the event of suspected overdosage, immediate action is required. The first step is the withdrawal of tobramycin therapy. It is also essential to conduct baseline tests of renal function to evaluate any potential impairment. Healthcare providers are advised to contact the Regional Poison Control Center for guidance on effective treatment strategies in all cases of suspected overdosage.

Additionally, it is important to consider the potential for drug interactions that may alter drug disposition, which could exacerbate the effects of an overdose. 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. In this study, rats were exposed to tobramycin for up to 1.5 hours per day over a period of 95 weeks, utilizing the clinical formulation of the drug. 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 tumor type.

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 involved five tester strains, did not demonstrate a significant increase in revertants, both with and without metabolic activation across all strains tested. 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, there is evidence suggesting 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 it may lead to airway narrowing. It is crucial for patients to communicate any experiences of ringing in the ears, dizziness, or changes in hearing, as these symptoms have been associated with hearing loss linked to the use of this medication.

Additionally, patients should disclose any history of kidney problems to their physician, as tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage. Pregnant women should be specifically cautioned that aminoglycosides, including tobramycin, can result in irreversible congenital deafness if administered during pregnancy.

Storage and Handling

Tobramycin inhalation solution is supplied in ampules and should be stored under refrigeration at a temperature range of 2º to 8ºC (36º to 46ºF). When removed from refrigeration or if refrigeration is not available, the solution pouches, whether opened or unopened, may be stored at room temperature (up to 25ºC/77ºF) for a maximum of 28 days.

It is essential to adhere to the expiration date stamped on the ampule when stored under refrigeration. If the solution is stored at room temperature, it should not be used beyond 28 days. Care should be taken to protect the ampules from intense light exposure.

The solution in the ampule may appear slightly yellow, and while it may darken with age if not stored in the recommended refrigeration conditions, this color change does not indicate a decline in product quality, provided it remains within the specified storage parameters.

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 Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)