Tobramycin

Description

Tobramycin is a sterile solution for inhalation, presented as a clear, slightly yellow, non-pyrogenic aqueous solution. The pH and salinity of the formulation are specifically adjusted for administration via a compressed air-driven reusable nebulizer. The chemical formula of tobramycin is C₁₈H₃₇N₅O₉, with a molecular weight of 467.52 g/mol. The compound 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, formulated in sterile water for injection. The pH is adjusted to 6.0 using sulfuric acid and sodium hydroxide, and nitrogen is employed for sparging. All ingredients conform to USP requirements, 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.

There are no teratogenic or nonteratogenic effects associated with this drug as per the available data.

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, 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 must 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 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, careful consideration should be given when prescribing to pregnant individuals.

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 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 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 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 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.

Additionally, cystic fibrosis may pose increased risks during pregnancy, including a higher 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 demonstrate 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 effects. It is important to note that ototoxicity was not assessed in offspring during non-clinical reproductive toxicity studies involving tobramycin.

Lactation

There are no specific statements regarding nursing mothers or lactation considerations in the provided text. Therefore, the effects of this medication on lactating mothers and breastfed infants are not established. Healthcare professionals should consider the lack of data when advising lactating mothers on the use of this medication.

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

Signs and symptoms of acute toxicity resulting from an overdosage of intravenous (IV) tobramycin may manifest as dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. These symptoms necessitate prompt recognition and management to mitigate potential complications.

In cases where tobramycin is administered via inhalation, it is important to note that this route results in low systemic bioavailability. Additionally, tobramycin is not significantly absorbed when taken orally. Monitoring tobramycin serum concentrations can be beneficial in assessing the extent of overdosage.

Immediate action is required upon suspicion of acute toxicity. The first step is the withdrawal of the tobramycin inhalation solution. Following this, baseline tests of renal function should be conducted to evaluate any potential impairment.

Healthcare professionals are advised to contact the Regional Poison Control Center for guidance on effective treatment strategies in all instances of suspected overdosage. It is also crucial to consider the possibility of drug interactions that may alter drug disposition during the management of overdosage.

In certain cases, hemodialysis may be employed as a method to facilitate the removal of tobramycin from the body, thereby aiding in the management 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 with tobramycin inhalation solution includes reports of hearing loss associated with its use. Additionally, cases of airway narrowing have been documented. It is important to note that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage. Furthermore, there are reports indicating that aminoglycosides, the class to which tobramycin belongs, may lead to irreversible congenital deafness when administered to pregnant women.

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, as this medication can lead to airway narrowing. Additionally, patients must be encouraged to notify their physician if they experience ringing in the ears, dizziness, or any changes in hearing, given that tobramycin inhalation solution has been linked to hearing loss.

It is also 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, healthcare providers should counsel pregnant women that aminoglycosides, including tobramycin, can result in irreversible congenital deafness if administered during pregnancy.

Storage and Handling

Tobramycin inhalation solution is supplied in ampoules that should be stored under refrigeration at a temperature range of 2ºC to 8ºC (36ºF to 46ºF). If refrigeration is unavailable, the solution pouches, whether opened or unopened, may be stored at room temperature (up to 25ºC or 77ºF) for a maximum of 28 days. It is imperative that the solution 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 typically slightly yellow; 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

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)