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. The structural designation of tobramycin 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, and 11.25 mg of sodium chloride, dissolved in sterile water for injection. The pH is adjusted to 6.0 using sulfuric acid and sodium hydroxide, and nitrogen is utilized 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.

Safety and efficacy have not been established in patients under the age of 6 years, those 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 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 due to the potential for severe allergic reactions, which may pose significant health risks.

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 tobramycin inhalation solution to pregnant patients.

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. Ototoxicity, characterized by tinnitus and hearing loss, has been noted in patients; if these symptoms arise, management may include discontinuation of the medication. Nephrotoxicity, a known risk associated with aminoglycosides, may develop, necessitating appropriate management, which could involve discontinuing tobramycin 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 avoid this treatment.

In cases of overdosage, symptoms of acute toxicity from intravenous tobramycin may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Management of these symptoms should be conducted as medically appropriate.

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 (tobramycin 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 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 geriatric patients are more likely to experience decreased renal function, it is advisable to monitor renal function closely in this population. This monitoring may help mitigate potential risks associated with the use of tobramycin in elderly patients.

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 other complications.

In animal reproduction studies, subcutaneous administration of tobramycin during organogenesis in pregnant rats and rabbits did not demonstrate 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 administered by inhalation. In the studies performed, doses of tobramycin up to 100 mg/kg/day in rats and 20 mg/kg/day in rabbits did not result in adverse developmental outcomes, although doses of 40 mg/kg/day or higher were associated with severe maternal toxicity in rabbits, preventing the evaluation of potential adverse effects on development.

Healthcare professionals should exercise caution when prescribing tobramycin to pregnant patients and consider the potential risks and benefits in the context of the individual patient's health status and the severity of the condition being treated.

Lactation

There are no specific statements regarding nursing mothers or lactation 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 about 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 clinical trials for this medication. Consequently, there is no available information regarding 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 warranted based on clinical judgment.

Overdosage

Acute toxicity resulting from an overdosage of intravenous (IV) tobramycin can manifest through various 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.

While tobramycin administered by inhalation leads to low systemic bioavailability, it is important to note that the drug is not significantly absorbed when taken orally. Therefore, monitoring tobramycin serum concentrations can be a useful tool 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.

Additionally, healthcare providers should consider the possibility of drug interactions that may alter drug disposition in cases of overdosage. In certain situations, 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

Tobramycin inhalation solution has been associated with reports of hearing loss. Additionally, there have been observations of airway narrowing in patients receiving this treatment. It is important to note that tobramycin inhalation solution belongs to a class of drugs known to potentially cause kidney damage. Furthermore, the use of aminoglycosides during pregnancy has been linked to the risk of irreversible congenital deafness in the offspring. These events have been 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 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 these symptoms may indicate hearing loss associated with the use of tobramycin inhalation solution.

Patients with a history of kidney problems should be encouraged 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 result in irreversible congenital deafness if 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 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 tobramycin inhalation solution is not used beyond the expiration date indicated on the bottom of the ampule when stored under refrigeration, or beyond 28 days when kept at room temperature. Care should be taken to protect the ampules from intense light exposure.

The solution in the ampule may appear slightly yellow, and while it may darken with age if not stored in the refrigerator, this color change does not affect the quality of the product as long as it is maintained within the recommended storage conditions.

Additional Clinical Information

Patients with known or suspected renal dysfunction, or those taking concomitant nephrotoxic drugs while using tobramycin inhalation solution, should have their serum concentrations of tobramycin and renal function assessed at the discretion of their treating physician. Additionally, patients who are pregnant or become pregnant during treatment with tobramycin inhalation solution should be informed of the potential risks to the fetus.

In postmarketing experience, there have been reports of hearing loss among patients receiving tobramycin inhalation solution.

FDA Insert (PDF)

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

View full prescribing information (PDF)