Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, colorless to light 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 g/mol. 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 in water for injection. The pH of the solution is adjusted to 6.0 using sulfuric acid and sodium hydroxide, and nitrogen is utilized 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: Safety and efficacy 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 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 individuals with a history of such hypersensitivity.

Warnings and Precautions

Bronchospasm may occur following the inhalation of tobramycin inhalation solution. In the event of bronchospasm, it is essential to treat the patient using appropriate medical interventions.

Ototoxicity is a significant concern, as tinnitus and hearing loss have been reported in patients receiving tobramycin inhalation solution. Should these symptoms arise, it is crucial to manage them appropriately, which may include the discontinuation of tobramycin inhalation solution.

Nephrotoxicity is a known risk associated with 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 may experience exacerbated muscle weakness due to the potential curare-like effects of aminoglycosides 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, have been associated with embryo-fetal toxicity, which can result in fetal harm. It is imperative to consider this risk when prescribing tobramycin inhalation solution to pregnant patients.

Side Effects

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

Serious adverse reactions have also been reported. Bronchospasm may occur with the inhalation of tobramycin inhalation solution and should be treated as medically appropriate if it arises. Ototoxicity, characterized by tinnitus and hearing loss, has been noted in patients; 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 advised. Additionally, aminoglycosides may exacerbate neuromuscular disorders due to a potential 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 aminoglycosides, including tobramycin, can cause embryo-fetal toxicity, posing a risk of fetal harm. Signs and symptoms of acute toxicity from intravenous tobramycin overdosage may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Patients with known hypersensitivity to any aminoglycoside should not receive tobramycin inhalation solution.

Drug Interactions

Concurrent and/or sequential use of tobramycin inhalation solution with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential is contraindicated. This precaution is essential to mitigate the risk of compounded toxic effects.

In particular, the concomitant administration of tobramycin inhalation solution with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended. The combination of these medications may enhance the toxicity associated with aminoglycosides, necessitating careful consideration of alternative therapeutic options. Monitoring for signs of toxicity is advised if such combinations are deemed necessary.

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 primarily 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 can 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 aminoglycosides. 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 pregnancy may pose additional risks, including an increased likelihood of preterm delivery. Although no reproductive toxicity studies have been conducted specifically with tobramycin inhalation solution, subcutaneous administration of tobramycin at doses of up to 100 mg/kg/day in rats and 20 mg/kg/day in rabbits during organogenesis did not result in adverse developmental outcomes. However, doses of tobramycin at or above 40 mg/kg/day were associated with severe maternal toxicity in rabbits, which limited the evaluation of potential adverse developmental outcomes. It is important to note that ototoxicity was not assessed in offspring during non-clinical reproductive toxicity studies involving tobramycin.

Lactation

There are no data on the presence of tobramycin inhalation solution in either human or animal milk, nor on its effects on the breastfed infant or 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.

Tobramycin may cause alterations in the intestinal flora of the breastfeeding infant. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for tobramycin inhalation solution and any potential adverse effects on the breastfed infant from the medication or from the underlying maternal condition.

Healthcare professionals should advise lactating mothers to monitor breastfed infants for signs of loose or bloody stools and candidiasis (thrush, diaper rash).

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 renal function is recommended to ensure patient safety and to make necessary dosing adjustments based on the patient's renal status.

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. Additionally, tobramycin is not significantly absorbed when taken orally, which may influence the clinical management of overdosage cases.

Monitoring tobramycin serum concentrations can be beneficial in assessing the extent of overdosage. In instances of suspected acute toxicity, immediate withdrawal of the tobramycin inhalation solution is essential. Furthermore, baseline tests of renal function should be conducted to evaluate any potential renal impairment.

In all cases of suspected overdosage, it is imperative for physicians to contact the Regional Poison Control Center for guidance on effective treatment strategies. It is also crucial to consider the possibility of drug interactions that may alter drug disposition, which could complicate the clinical scenario.

For patients experiencing severe overdosage, hemodialysis may be a useful intervention to facilitate 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, regardless of metabolic activation. 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 with tobramycin inhalation solution includes reports of hearing loss associated with its use. Additionally, there have been observations of airway narrowing in patients receiving this treatment. It is important to note that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage. Furthermore, the use of aminoglycosides during pregnancy has been linked to the risk of irreversible congenital deafness in the offspring.

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. Additionally, patients should be encouraged 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.

It is important for patients to 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. Furthermore, pregnant women should be counseled 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 2ºC to 8ºC (36ºF to 46ºF). If removed from refrigeration or 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 or to the 28-day limit when stored at room temperature. The ampules should be protected from intense light to maintain product integrity.

The solution is typically colorless to light 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 has been stored according to the specified guidelines.

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 Sun Pharmaceutical Industries, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)