Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, slightly yellow, non-pyrogenic aqueous solution specifically formulated for inhalation. It is designed for administration via a compressed air-driven reusable nebulizer, with pH and salinity adjusted accordingly. The chemical formula for tobramycin is C₁₈H₃₇N₅O₉, and it has a molecular weight of 467.51 g/mol. 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-dose 5 mL ampule contains 300 mg of tobramycin 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 inhalation solution, USP 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: The safety and efficacy of tobramycin inhalation solution have not been established in patients younger than 6 years of age.

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, succeeded by 28 days off the medication.

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 delivered using a hand-held PARI LC PLUS Reusable Nebulizer in conjunction with a DeVilbiss Pulmo-Aide compressor to ensure proper administration.

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 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. Therefore, caution is advised when prescribing to pregnant individuals.

In summary, healthcare professionals should remain vigilant for signs of bronchospasm, ototoxicity, nephrotoxicity, and neuromuscular effects in patients receiving tobramycin inhalation solution, and manage these conditions as medically appropriate.

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 receiving this treatment; management may require discontinuation of the medication. Nephrotoxicity, a known risk associated with aminoglycosides, necessitates appropriate management if it develops, which may include discontinuation of tobramycin inhalation solution. Additionally, patients with neuromuscular disorders may experience exacerbated 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, although mechanical assistance may be required.

It is important to note that aminoglycosides, including tobramycin, can cause embryo-fetal toxicity, posing a risk of fetal harm. Hypersensitivity reactions may occur in patients with known sensitivities to any aminoglycoside. Furthermore, overdosage of intravenous tobramycin can lead to acute toxicity, with symptoms including dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

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 primarily 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 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 aminoglycoside use. The estimated background risk of major birth defects and miscarriage in the general U.S. population is 2% to 4% and 15% to 20%, respectively. However, the specific background risk for the indicated populations remains unknown. Additionally, cystic fibrosis in pregnant women may increase the risk of preterm delivery and presents further risks to maternal health.

Animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis did not reveal adverse developmental outcomes. However, ototoxicity was not assessed in the offspring from these studies. It is important to note that no reproductive toxicity studies have been conducted with tobramycin inhalation solution. In the aforementioned 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 weigh the potential benefits against the risks when considering the use of tobramycin inhalation solution in pregnant patients.

Lactation

There are no specific statements or considerations regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on breastfed infants or its excretion in breast milk remain undetermined. Healthcare professionals should exercise caution and consider the potential risks and benefits when prescribing this medication to lactating mothers.

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 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 the systemic bioavailability is low, and it is not significantly absorbed when taken orally. 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 to withdraw the tobramycin inhalation solution. Subsequently, baseline tests of renal function should be conducted to evaluate any potential impact on the kidneys.

It is imperative for physicians to contact the Regional Poison Control Center for guidance on effective treatment strategies in all cases of suspected overdosage. Additionally, the potential for drug interactions that may alter drug disposition should be taken into account.

For cases of severe overdosage, hemodialysis may be considered as a method 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 impair fertility in either male or female rats.

Postmarketing Experience

Postmarketing experience has identified reports of hearing loss associated with the use of tobramycin inhalation solution. Additionally, there have been reports of kidney damage linked to the use of this medication in the postmarketing setting. These events were reported voluntarily or through surveillance programs.

Patient Counseling

Healthcare providers should advise patients 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 should be informed to report any instances of shortness of breath or wheezing following the administration of tobramycin inhalation solution to their physician, as these symptoms may indicate an adverse reaction.

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 associated with hearing loss.

Patients with a history of kidney problems should be advised to inform their physician, given that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage.

Pregnant women should be counseled that aminoglycosides, including tobramycin, can lead to irreversible congenital deafness if administered during pregnancy, and they should discuss any concerns with their healthcare provider.

Storage and Handling

Tobramycin inhalation solution, USP is supplied in ampules and should be stored under refrigeration at a temperature range of 2 to 8ºC (36 to 46ºF). If refrigeration is unavailable, the solution may be stored at room temperature, not exceeding 25ºC (77ºF), for a maximum of 28 days after removal from the refrigerator. 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.

Care should be taken to protect the ampules from intense light exposure. The solution is typically slightly yellow; however, it may darken over time if not stored in the recommended refrigeration conditions. This color change does not signify a decline in product quality, provided the storage guidelines are followed.

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 Lupin Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)