Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, colorless to 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, USP is C18H37N5O9, and it has a molecular weight of 467.52 g/mol. The structural designation of tobramycin, USP is 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, along with 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 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, but not less than 6 hours apart. 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 is contraindicated in patients with a known hypersensitivity to any aminoglycoside due to the risk of severe allergic reactions.

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, indicating a risk of embryo-fetal toxicity. Healthcare providers should exercise caution 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 is a known risk associated with aminoglycosides, and if it develops, appropriate management, including potential discontinuation of tobramycin inhalation solution, is necessary. Additionally, aminoglycosides may exacerbate neuromuscular disorders, 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 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 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 Inhalation Solution, 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 in pediatric patients under 6 years of age have not been established. 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 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.

Healthcare professionals should advise pregnant women of the potential risks to the fetus associated with aminoglycoside use. The estimated background risk of major birth defects and miscarriage in the general population is not well defined for the indicated populations; 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, it is important to note that cystic fibrosis may increase the risk of preterm delivery. Although no reproductive toxicity studies have been conducted with tobramycin inhalation solution administered via inhalation, 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. Ototoxicity was not assessed in offspring during non-clinical reproductive toxicity studies involving tobramycin.

Lactation

There are no specific statements or information regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on lactating mothers and breastfed infants are not established. Healthcare professionals should consider the absence 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 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.

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 may provide valuable information in assessing the extent of overdosage.

Upon suspicion of acute toxicity, 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.

In all instances of suspected overdosage, it is imperative for healthcare providers to contact the Regional Poison Control Center. This resource can offer guidance on effective treatment options. Furthermore, clinicians should remain aware of the potential for drug interactions that may alter drug disposition in cases of overdosage.

For patients experiencing significant toxicity, hemodialysis may be a beneficial 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 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 tumor type.

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 has revealed several adverse events reported voluntarily or through surveillance programs. Notably, there have been associations with hearing loss (ototoxicity), prompting patients to inform their healthcare providers if they experience any changes in hearing or ringing in the ears.

Additionally, tobramycin inhalation solution is recognized for its potential to worsen kidney function (nephrotoxicity), particularly in individuals with pre-existing or suspected renal impairment. Monitoring of kidney function through blood tests may be warranted during treatment.

Exacerbation of muscle weakness has been observed in patients with pre-existing neuromuscular disorders, including myasthenia gravis and Parkinson’s disease.

Commonly reported side effects include increased cough, sore throat, increased sputum production, hemoptysis, decreased lung function, difficulty breathing, voice changes, alterations in taste, and rash.

Patients are advised to promptly report any severe respiratory issues, such as bronchospasm characterized by shortness of breath, wheezing, coughing, and chest tightness, to their healthcare provider.

For further reporting of side effects, patients may contact the FDA at 1-800-FDA-1088.

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.

Additionally, breastfeeding women should be advised to monitor their infants for any signs of diarrhea and/or bloody stools, as these may be indicative of adverse effects related to the medication.

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 refrigeration is unavailable, opened or unopened pouches of tobramycin inhalation solution may be stored at room temperature, not exceeding 25ºC (77ºF), for a maximum of 28 days.

It is imperative that tobramycin inhalation solution is not used beyond the expiration date indicated on the ampule when stored under refrigeration, or beyond 28 days when kept at room temperature. Additionally, the ampules should be protected from intense light exposure.

The solution within the ampule is typically slightly yellow; however, it may darken over time if not stored in the refrigerator. This color change does not signify a decline in product quality, provided that the solution has been stored according to the recommended conditions.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

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

View full prescribing information (PDF)