Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution specifically formulated for administration by a compressed air driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9, with a molecular weight of 467.52 g/mol. 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 ampule contains 300 mg of tobramycin and 11.25 mg of sodium chloride in sterile water for injection. The pH of the solution is adjusted to 6.0 using sulfuric acid and sodium hydroxide, 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 include the lack of demonstrated safety and efficacy in patients under the age of 6 years, as well as in patients with forced expiratory volume in 1 second (FEV1) less than 25% or greater than 75% predicted. This drug is also not indicated for 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, 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 should 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 the medication.

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. Healthcare providers should exercise caution when prescribing this medication 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 following 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; 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.

In the event of overdosage, symptoms 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

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 geriatric patients are more likely to experience decreased renal function, it is advisable to monitor renal function closely in this population. This monitoring can help mitigate the risk of potential adverse effects associated with tobramycin therapy.

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 not well defined; 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. Ototoxicity was not assessed in offspring during non-clinical reproductive toxicity studies involving tobramycin.

Healthcare professionals should carefully consider these factors when prescribing tobramycin inhalation solution to pregnant patients or women of childbearing potential.

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 should be 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 of renal function is recommended to ensure patient safety and to guide therapeutic decisions.

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 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 the event of suspected overdosage, immediate action is required. The first step is the withdrawal of the tobramycin inhalation solution. Following this, it is essential to conduct baseline tests to assess renal function, as renal impairment may be a significant concern in cases of toxicity.

Healthcare providers are advised to contact the Regional Poison Control Center for guidance on effective treatment strategies in all instances of suspected overdosage. Additionally, hemodialysis may be considered as a supportive measure to facilitate 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 several adverse events reported voluntarily or through surveillance programs. Hearing loss, including ototoxicity characterized by ringing in the ears, has been documented. There is a potential risk of irreversible congenital deafness when administered to pregnant women.

Additionally, this medication belongs to a class of drugs known to cause kidney damage, and worsening kidney problems (nephrotoxicity) may occur, particularly in individuals with pre-existing kidney conditions. Severe breathing problems, such as bronchospasm, have also been reported.

Patients with neuromuscular disorders, including myasthenia gravis or Parkinson's disease, may experience worsening muscle weakness. The most frequently reported side effects include increased cough, loss or change in taste, coughing up blood, increased sputum production, voice changes, difficulty breathing, sore throat, rash, and decreased lung function.

Healthcare professionals are advised to monitor patients for these potential adverse effects and to provide guidance on reporting side effects to 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 encouraged 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 2°C to 8°C (36°F 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 Ritedose Pharmaceuticals, LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)