Tobramycin

Description

Tobramycin inhalation solution, USP is a sterile, clear, colorless to pale yellow aqueous solution that is non-pyrogenic, with pH and salinity adjusted. The chemical formula for tobramycin is C18H37N5O9, and it has a molecular weight of 467.52. The active ingredient, 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 4 mL ampule contains a 300 mg dose of tobramycin, along with sodium chloride and sulfuric acid in water for injection. Sulfuric acid and sodium hydroxide are utilized as necessary to adjust the pH to 5.0. Nitrogen is employed for sparging, filling, and pouching. The formulation is free from preservatives and is administered via a compressed air-driven reusable nebulizer.

Uses and Indications

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

Limitations of Use: Safety and efficacy have not been established in patients under the age of six years, in patients with a forced expiratory volume in one second (FEV1) less than 40% or greater than 80% predicted, or in patients colonized with Burkholderia cepacia.

Dosage and Administration

For oral inhalation only, the healthcare professional should administer the entire contents of one ampule twice daily. This regimen should be followed in repeated cycles of 28 days on the drug, succeeded by 28 days off the drug. It is essential to ensure proper inhalation technique to maximize drug delivery to the lungs.

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 inhalation solution. Monitoring parameters are essential; therefore, audiograms, serum concentration levels, and renal function should be assessed as appropriate to ensure patient safety and therapeutic efficacy.

It is critical to inform women of childbearing potential about the risks associated with aminoglycoside administration during pregnancy, as fetal harm may occur. Healthcare providers should ensure that patients are adequately apprised of the potential hazards to the fetus when considering treatment options.

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.

Serious adverse reactions may arise, necessitating caution in specific patient populations. Tobramycin inhalation solution should be prescribed with care to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction, as the aminoglycoside may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function. Additionally, bronchospasm has been reported following the inhalation of tobramycin, which requires monitoring.

There is a significant risk of fetal harm associated with the administration of aminoglycosides, including tobramycin, to pregnant women. Healthcare providers should inform women of childbearing potential about the potential risks to the fetus.

Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

In cases of overdosage, signs and 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. These potential effects underscore the importance of adhering to prescribed dosages and monitoring for adverse reactions.

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 increase the risk of adverse effects, particularly those related to renal function and auditory health.

Healthcare professionals are advised to monitor patients closely for signs of toxicity when tobramycin inhalation solution is used in conjunction with other drugs that may affect the nervous system, kidneys, or auditory pathways. Adjustments to dosage or treatment regimens may be necessary based on clinical judgment and patient response.

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. Caution is advised when considering the use of this medication in this age group, as clinical outcomes may differ from those observed in older children and adolescents.

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 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 tobramycin. 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 in pregnant patients may pose additional risks, including an increased likelihood of preterm delivery. Although animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis did not reveal adverse developmental outcomes, ototoxicity was not assessed in the offspring from these studies. It is important to note that no reproductive toxicology studies have been conducted with inhaled tobramycin. In the animal studies, subcutaneous doses of tobramycin up to 100 mg/kg/day in rats and 20 mg/kg/day in rabbits were not associated with adverse developmental outcomes; however, doses of 40 mg/kg/day or higher were severely maternally toxic in rabbits, preventing the evaluation of potential adverse developmental effects.

Lactation

There are no specific statements or considerations regarding nursing mothers or lactation in the provided drug insert text. Therefore, the effects of this medication on breastfed infants or its excretion in breast milk remain undetermined. Healthcare professionals should exercise caution and consider the potential risks and benefits when prescribing this medication to lactating mothers.

Renal Impairment

Caution should be exercised when prescribing tobramycin inhalation solution to patients with known or suspected renal dysfunction. It is important to monitor audiograms, serum concentration, and renal function as appropriate to ensure patient safety and therapeutic efficacy.

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. Symptoms may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

It is important to note that the administration of tobramycin via inhalation results in low systemic bioavailability, and tobramycin is not significantly absorbed when administered orally. Therefore, the risk of systemic toxicity from inhalation is minimal, but caution is warranted with intravenous use.

Monitoring tobramycin serum concentrations can be beneficial in assessing potential overdosage. 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, healthcare providers should consider the possibility of drug interactions that may alter drug disposition in cases of overdosage. This consideration is crucial for ensuring appropriate management and mitigating potential adverse effects.

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

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of tobramycin inhalation solution, reported voluntarily by patients and through surveillance programs.

Ototoxicity, characterized by complaints of hearing loss or tinnitus, has been noted among patients receiving treatment. It is recommended that physicians consider conducting an audiogram at baseline, especially for individuals at increased risk of auditory dysfunction. Patients reporting tinnitus or hearing loss during therapy should be referred for audiological assessment. Additionally, vestibular toxicity may present as vertigo, ataxia, or dizziness.

Bronchospasm has been reported following the inhalation of tobramycin. Patients are advised to inform their healthcare provider immediately if they experience symptoms such as shortness of breath with wheezing, coughing, or chest tightness.

Nephrotoxicity and neuromuscular disorders are potential adverse reactions associated with aminoglycosides, including tobramycin. Patients may experience worsening kidney function, necessitating blood and urine tests to monitor renal health during treatment. Furthermore, individuals with pre-existing muscle weakness, such as those with myasthenia gravis or Parkinson's disease, may experience exacerbated muscle weakness.

Patients should be informed of these risks and advised to report any concerning symptoms to their healthcare provider promptly.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use. It is important to inform patients that information regarding the long-term efficacy and safety of tobramycin inhalation solution is limited, particularly in patients with severe cystic fibrosis (FEV < 40% predicted).

Patients must be instructed to complete a full 28-day course of tobramycin inhalation solution, even if they begin to feel better. After this 28-day therapy, they should discontinue the use of tobramycin inhalation solution for the next 28 days, followed by a resumption of therapy for the next 28 days on and 28 days off cycle.

For patients who are taking multiple inhaled medications and/or performing chest physiotherapy, it is essential to advise them on the correct order of administration. Tobramycin inhalation solution should be taken last in the sequence.

Patients should be informed that tobramycin inhalation solution is intended for use with the PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor. They should be directed to refer to the manufacturer's instructions for the proper care and use of the nebulizer and compressor.

It is crucial to inform patients about the potential for ototoxicity, which may present as hearing loss or tinnitus. Physicians should consider conducting an audiogram at baseline, especially for patients at increased risk of auditory dysfunction. If patients report tinnitus or hearing loss during therapy, they should be referred for audiological assessment. Additionally, patients should be reminded that vestibular toxicity may manifest as vertigo, ataxia, or dizziness.

Patients should be made aware that bronchospasm can occur with the inhalation of tobramycin. They should also be informed of the adverse reactions associated with aminoglycosides, including nephrotoxicity and neuromuscular disorders. Monitoring of hearing, serum concentrations of tobramycin, and renal function may be necessary during treatment.

It is important to inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman. Patients should be advised to inform their healthcare provider if they are pregnant, become pregnant, or plan to become pregnant.

In the event that a dose of tobramycin inhalation solution is missed, patients should be instructed to take the prescribed dose as soon as possible if there are at least 6 hours until the next scheduled dose. If less than 6 hours remain, they should not take the missed dose and should resume their usual dosing schedule.

Patients should be encouraged to contact their healthcare provider if they have any questions regarding their treatment.

Storage instructions should be clearly communicated: tobramycin inhalation solution ampules should be stored in a refrigerator (36°F to 46°F or 2°C to 8°C). However, if refrigeration is not available, the foil pouches (opened or unopened) may be stored at room temperature (up to 77°F/25°C) for up to 28 days. Patients should also be informed that tobramycin inhalation solution is light sensitive; unopened ampules should be returned to the foil pouch and should not be exposed to intense light.

Finally, patients should be cautioned against using tobramycin inhalation solution if it appears cloudy, contains particles, or has been stored at room temperature for more than 28 days. They should also not use the solution beyond the expiration date stamped on the ampule.

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 unavailable, the solution may be stored at room temperature, not exceeding 25°C (77°F), for a maximum of 28 days. It is essential that the 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.

To protect the ampules from intense light, they should remain in their foil pouch until use. The solution is typically colorless to pale yellow; 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 has been stored according to the specified guidelines.

Additional Clinical Information

The clinical microbiology laboratory is advised to provide cumulative results of in vitro susceptibility tests for antimicrobial drugs utilized in local hospitals and practice areas. These periodic reports should detail the susceptibility profiles of both nosocomial and community-acquired pathogens, assisting physicians in selecting the most effective antimicrobial therapies for their patients.

In postmarketing experience, clinical trials of tobramycin inhalation solution did not reveal any trends in the treatment-emergent isolation of other bacterial respiratory pathogens, such as Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, or Staphylococcus aureus, when compared to placebo. However, a slight increase in the isolation of Candida spp in sputum was noted at the conclusion of the treatment cycle with tobramycin inhalation solution.

FDA Insert (PDF)

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

View full prescribing information (PDF)