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 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 ampoule 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 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 ampoule (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, with a minimum interval of 6 hours between doses. 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 a history of such hypersensitivity.

Warnings and Precautions

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

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 essential to manage them appropriately, which may include the discontinuation of the medication.

Nephrotoxicity is another potential 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 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 crucial to inform patients about the risks of embryo-fetal toxicity associated with aminoglycosides. Those who are pregnant or become pregnant while using tobramycin inhalation solution should be made aware of the potential hazards to the fetus.

While no specific laboratory tests are recommended for the safe use of tobramycin inhalation solution, healthcare providers should remain vigilant for the aforementioned adverse effects and manage them as necessary.

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 reported include increased cough, pharyngitis, increased sputum production, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion, and rash. These reactions were observed in clinical trials and may vary in frequency among patients.

Serious adverse reactions associated with tobramycin inhalation solution include bronchospasm, which can occur upon inhalation and should be treated as medically appropriate if it arises. Ototoxicity, characterized by tinnitus and hearing loss, has also been reported; management may require discontinuation of the medication if these symptoms develop. Nephrotoxicity is another serious concern linked to aminoglycosides, including tobramycin, necessitating appropriate management if renal impairment is noted. Additionally, aminoglycosides may exacerbate neuromuscular disorders, potentially leading to muscle weakness or neuromuscular blockade, which can be reversed with calcium salts, although mechanical assistance may be required in severe cases.

It is important to note that tobramycin inhalation solution is contraindicated in patients with known hypersensitivity to any aminoglycoside. Overdosage of intravenous tobramycin may result in acute toxicity, with symptoms including dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

Furthermore, aminoglycosides, including tobramycin, have been associated with embryo-fetal toxicity, indicating potential harm to the fetus. Careful consideration and management are advised in pregnant patients.

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 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 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 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 other complications.

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 evaluated 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 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 carefully consider these factors when prescribing tobramycin inhalation solution to pregnant patients.

Lactation

There are no available data on tobramycin inhalation solution use in nursing mothers to inform a drug-associated risk of major adverse effects in breastfed infants.

Systemic absorption of tobramycin following inhaled administration is expected to be minimal, which may reduce the potential for excretion in breast milk.

Caution should be exercised when administering tobramycin inhalation solution to nursing 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 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 presentation of overdosage.

Monitoring tobramycin serum concentrations can be beneficial in assessing the extent of overdosage. In cases 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 impairment.

In all instances 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 management of the overdosage.

For patients experiencing severe toxicity, hemodialysis may be a useful intervention to facilitate the removal of tobramycin from the body, thereby mitigating the effects of the overdose.

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 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 evaluation 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. Additionally, 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.

Furthermore, subcutaneous administration of tobramycin at doses of up to 100 mg/kg did not impact mating behavior or result in impairment of 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, instances of kidney damage related to the use of tobramycin inhalation solution have been noted. These events were reported voluntarily or through surveillance programs.

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 counseled to inform their physician of any history of kidney problems, 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 ampoules 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 imperative that the product is not used beyond the expiration date indicated on the ampoule when stored under refrigeration or beyond 28 days when kept at room temperature.

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

Additional Clinical Information

Aminoglycosides, including tobramycin, have the potential to cause fetal harm when administered to pregnant women, as they can cross the placenta. Notably, streptomycin has been linked to reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. While systemic absorption of tobramycin following inhaled administration is expected to be minimal, it is crucial for patients using tobramycin inhalation solution during pregnancy, or those who become pregnant while on this treatment, to be informed of the potential risks to the fetus.

FDA Insert (PDF)

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

View full prescribing information (PDF)