Tobramycin

Uses and Indications

Tobramycin inhalation solution is indicated for the management of patients with cystic fibrosis who are infected with Pseudomonas aeruginosa.

Limitations of Use: The safety and efficacy of tobramycin inhalation solution have not been established in patients without cystic fibrosis or in those with infections caused by organisms other than Pseudomonas aeruginosa.

Dosage and Administration

For oral inhalation only. Healthcare professionals should administer the entire contents of one ampule twice daily by oral inhalation. This regimen should be followed in repeated cycles of 28 days on the drug, succeeded by 28 days off the drug.

Contraindications

Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Use in these patients may lead to severe allergic reactions.

Warnings and Precautions

Caution should be exercised when prescribing tobramycin inhalation solution to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction. The use of aminoglycosides, including tobramycin, may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function, necessitating careful consideration in patients with pre-existing conditions.

Healthcare professionals should be vigilant for the possibility of bronchospasm occurring with the inhalation of tobramycin. Patients should be monitored for respiratory symptoms, and appropriate measures should be taken to manage any adverse reactions.

Regular monitoring of audiograms, serum concentration levels, and renal function is recommended to ensure patient safety and to mitigate the risk of toxicity. These parameters should be assessed as appropriate based on the individual patient's clinical status and treatment regimen.

It is important to inform women of childbearing potential about the risks associated with aminoglycoside administration during pregnancy, as fetal harm may occur. Healthcare providers should counsel patients regarding the potential hazards to the fetus and consider alternative therapies when appropriate.

Side Effects

Patients receiving tobramycin inhalation solution may experience a range of adverse reactions. Common adverse reactions observed include decreased forced expiratory volume, rales, increased red blood cell sedimentation rate, and dysphonia.

In addition to these common reactions, there are important considerations regarding the safety profile of tobramycin inhalation solution. Caution should be exercised when prescribing this medication to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction, as the use of aminoglycosides may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function. Furthermore, bronchospasm has been reported following the inhalation of tobramycin.

It is also critical to note that the administration of aminoglycosides, including tobramycin, during pregnancy may result in fetal harm. Healthcare providers should inform women of childbearing potential about the potential risks to the fetus associated with this medication.

Drug Interactions

Concurrent and/or sequential use of tobramycin inhalation solution with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential is contraindicated. This precaution is essential to mitigate the risk of additive toxic effects that may compromise patient safety.

Specifically, tobramycin inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The combination of these medications may exacerbate the risk of adverse effects related to the aforementioned toxicities.

Healthcare professionals are advised to closely monitor patients receiving tobramycin inhalation solution, particularly when considering the use of other drugs with similar toxic profiles. Adjustments to dosage or treatment regimens may be necessary based on individual patient response and the presence of any concomitant medications.

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 with cystic fibrosis who are under six years of age. Therefore, caution is advised when considering the use of this medication in this age group.

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 on the use of tobramycin inhalation solution in pregnant women to inform a drug-associated 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 advised 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 indicated populations remains unknown; however, 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.

Cystic fibrosis may pose additional risks during pregnancy, including an increased likelihood of preterm delivery. Although no reproductive toxicology studies have been conducted specifically with inhaled tobramycin, 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, subcutaneous 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 nonclinical reproductive toxicity studies involving tobramycin.

Healthcare professionals should weigh the potential benefits against the risks when considering the use of tobramycin in pregnant patients, particularly those with cystic fibrosis.

Lactation

There are no data on the presence of tobramycin in either human or animal milk, nor on the effects on the breastfed infant or milk production following oral inhalation of tobramycin inhalation solution. 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 child 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

Tobramycin is primarily excreted unchanged in the urine, and renal function is expected to significantly affect the exposure of tobramycin. The risk of adverse reactions to this drug may be greater in patients with impaired renal function. Patients with serum creatinine levels greater than 2 mg/dL and blood urea nitrogen (BUN) levels exceeding 40 mg/dL have not been included in clinical studies, and there are no data available to support a recommendation for or against dose adjustment in this population.

For patients with renal dysfunction or those receiving concomitant parenteral tobramycin, serum concentrations should be monitored at the discretion of the treating physician. Caution is advised when prescribing tobramycin inhalation solution to patients with known or suspected renal dysfunction. Additionally, audiograms, serum concentrations, and renal function should be monitored as appropriate to ensure patient safety.

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

In clinical trials, no overdoses have been reported with tobramycin inhalation solution. However, healthcare professionals should remain vigilant regarding the potential for acute toxicity associated with intravenous tobramycin overdosage.

Signs and Symptoms of Overdosage Acute toxicity from intravenous tobramycin may manifest through various symptoms, including dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. These symptoms necessitate prompt recognition and management.

Pharmacokinetics Considerations It is important to note that administration of tobramycin by inhalation results in low systemic bioavailability, and the drug is not significantly absorbed following oral administration. Consequently, monitoring tobramycin serum concentrations can be beneficial in assessing potential overdosage.

Management Recommendations In all instances of suspected overdosage, it is imperative for physicians to contact the Regional Poison Control Center to obtain guidance on effective treatment strategies. Additionally, clinicians should consider the possibility of drug interactions that may alter drug disposition, which could complicate the management of an overdose situation.

Nonclinical Toxicology

A two-year inhalation toxicology study in rats was conducted to evaluate the carcinogenic potential of an inhaled solution of tobramycin. During the study, rats were exposed to 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, which is 35 times the average exposure 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 types.

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 impact mating behavior or result in impairment of fertility in either male or female rats.

Postmarketing Experience

During postapproval use of tobramycin inhalation solution, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ear and labyrinth disorders have included hearing loss and tinnitus.

Skin and subcutaneous tissue disorders reported include hypersensitivity, pruritus, urticaria, and rash.

Nervous system disorders have encompassed aphonia and dysgeusia.

Respiratory, thoracic, and mediastinal disorders have included bronchospasm and oropharyngeal pain.

Metabolism and nutrition disorders have been characterized by decreased appetite.

Patient Counseling

Healthcare providers should inform patients that tobramycin inhalation solution is intended for oral inhalation only. The recommended dosage for patients aged six years and older is one single-dose ampule (300 mg/4 mL) administered twice daily by oral inhalation. This regimen should follow a cycle of 28 days on the medication, followed by 28 days off. It is important to take doses as close to 12 hours apart as possible, but not less than 6 hours apart.

Patients should be advised on what to do if they miss a dose. They can take the missed dose as soon as possible, provided it is within 6 hours of the next scheduled dose. If less than 6 hours remain before the next dose, they should wait until the next scheduled dose.

The administration of tobramycin inhalation solution requires the use of a hand-held PARI LC PLUS Reusable Nebulizer with a PARI Vios Air compressor. Patients should be instructed that the inhalation process will take approximately 15 minutes and should continue until sputtering from the nebulizer output has occurred for at least one minute. It is crucial to inform patients that the solution should not be diluted or mixed with dornase alfa or any other medications in the nebulizer. Additionally, tobramycin inhalation solution is not suitable for subcutaneous, intravenous, or intrathecal administration.

Patients should be cautioned against using the solution if it appears cloudy, contains particles, or has been stored at room temperature for more than 28 days. Healthcare providers should exercise caution when prescribing this medication to patients with known or suspected auditory or vestibular dysfunction.

For patients with known or suspected renal dysfunction, or those taking concomitant nephrotoxic drugs, healthcare providers should consider obtaining serum concentrations of tobramycin and laboratory measurements of renal function at their discretion. Furthermore, patients receiving both tobramycin inhalation solution and parenteral aminoglycoside therapy should be monitored for potential toxicities associated with aminoglycosides, and serum tobramycin levels should be checked as clinically appropriate.

Pregnant women should be informed of the potential risks to a fetus associated with the use of tobramycin inhalation solution. Additionally, it may cause alterations in intestinal flora; therefore, breastfeeding women should monitor their infants for symptoms such as loose or bloody stools and candidiasis (thrush, diaper rash). Further instructions on the administration of tobramycin inhalation solution are available in the Patient’s Instructions for Use.

Storage and Handling

Tobramycin inhalation solution, USP is supplied in ampules that 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 pouches, whether opened or unopened, may be stored at room temperature, not exceeding 25°C (77°F), 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. The ampules must be protected from intense light; therefore, unopened ampules should be returned to their foil pouch to shield them from light exposure.

The solution within the ampule is typically colorless to 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 solution has been 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 Teva Pharmaceuticals USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)