Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, slightly yellow, non-pyrogenic aqueous solution specifically formulated for administration via a compressed air-driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9, with a molecular weight of 467.52. 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 ingredients conform to USP standards, and the formulation 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.

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 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 susceptible individuals.

Warnings and Precautions

Bronchospasm may occur following the inhalation of tobramycin inhalation solution. In the event of bronchospasm, it is imperative 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 essential 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 crucial to note that aminoglycosides, including tobramycin, have the potential to cause fetal harm, indicating a risk of embryo-fetal toxicity. Therefore, appropriate counseling and precautions should be taken 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.

Most commonly reported adverse reactions 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 following inhalation and should be treated as medically appropriate. Ototoxicity, characterized by tinnitus and hearing loss, has also been reported; if these symptoms arise, management may necessitate discontinuation of the medication. Nephrotoxicity is another serious concern linked to aminoglycosides, including tobramycin. If nephrotoxicity is identified, appropriate management should be undertaken, which may involve discontinuing the inhalation solution.

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 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 not use this medication.

Signs and symptoms of acute toxicity from intravenous tobramycin overdose may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. In the event of acute toxicity, immediate withdrawal of tobramycin inhalation solution is essential, and baseline renal function tests should be conducted.

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 minimize 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 requiring such combinations.

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 for 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 specifically regarding 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. Additionally, cystic fibrosis in pregnancy poses risks to the mother, including an increased likelihood of preterm delivery. The estimated background risk of major birth defects and miscarriage for the indicated populations remains 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.

In animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, no adverse developmental outcomes were observed. However, it is important to note that ototoxicity was not evaluated in the offspring from these studies. Therefore, healthcare professionals should exercise caution and consider the potential risks when prescribing tobramycin to pregnant patients.

Lactation

There are no data on the presence of tobramycin inhalation solution in either human or animal milk, nor on the 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. The developmental and health benefits of breastfeeding should be considered alongside the mother's clinical need for tobramycin inhalation solution and any potential adverse effects on the breastfed infant from the solution or from the underlying maternal condition.

Lactating mothers are advised to monitor the breastfed infant for 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 systemic bioavailability remains low, and it is not significantly absorbed following oral administration. Therefore, 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. 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 has been associated with hearing loss. Additionally, reports of kidney damage have been noted in relation to the use of tobramycin inhalation solution. These events were reported voluntarily or identified 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 notify their physician if they experience 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 report any occurrences of ringing in the ears, dizziness, or changes in hearing, as these symptoms have been associated with hearing loss linked to the use of tobramycin inhalation solution.

It is important for patients to inform their physician if they have a history of kidney problems, 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 when 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 2° to 8°C (36° to 46°F). When removed from refrigeration or if refrigeration is not available, the solution may be stored at room temperature, not exceeding 25°C (77°F), for a maximum of 28 days.

It is essential to adhere to the expiration date indicated on the ampule when stored under refrigeration. If stored at room temperature, the solution must be used within 28 days. Care should be taken to protect the ampules 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 affect the quality of the product, provided it is 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 Akorn. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)