Tobramycin

Description

TOBRAMYCIN INHALATION SOLUTION PAK contains tobramycin inhalation solution, USP, and the PARI LC PLUS Reusable Nebulizer. The tobramycin inhalation solution is a sterile, clear, slightly yellow, non-pyrogenic aqueous solution, with a pH adjusted to 6.0 and salinity specifically tailored for administration via the PARI LC PLUS Reusable Nebulizer. The chemical formula for tobramycin is C18H37N5O9, with a molecular weight of 467.52 g/mol.

Each single-use 5 mL ampule contains 300 mg of tobramycin and 11.25 mg of sodium chloride in sterile water for injection. The formulation is free of preservatives and utilizes sulfuric acid and sodium hydroxide for pH adjustment. Nitrogen is employed for sparging, and the osmolality of the inhalation solution ranges from 135 to 200 mOsmol/kg.

The PARI LC PLUS Reusable Nebulizer demonstrates specific performance characteristics when used with tobramycin inhalation solution, as measured using a Next Generation Impactor (NGI) at a continuous flow rate of 15 L/min under standard conditions (50% RH, 23°C). The delivered dose is 174 mg, with a fine particle dose of 97 mg for particles less than 5 μm. The nebulization time is approximately 13 minutes, with a mass median aerodynamic diameter of 4.3 μm and a geometric standard deviation of 2.2 μm.

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.

There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

Tobramycin inhalation solution is to be administered as one single-use ampule (300 mg/5 mL) via oral inhalation, twice daily. The dosing regimen consists of alternating periods of 28 days on the medication followed by 28 days off.

Doses should be taken as close to 12 hours apart as possible, but not less than 6 hours apart. It is important to note that the dosage is not adjusted based on patient weight.

Each 300 mg dose must be administered using the PARI LC PLUS Reusable Nebulizer in conjunction with the 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. Due to the potential for severe allergic reactions, administration in such cases 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 patient as medically appropriate.

Ototoxicity is a significant concern associated with the use of tobramycin inhalation solution, with reports of tinnitus and hearing loss in some patients. Should these symptoms arise, appropriate management should be initiated, which may include the discontinuation of tobramycin inhalation solution.

Nephrotoxicity is another potential risk linked to aminoglycosides, including tobramycin. If signs of nephrotoxicity develop, it is crucial to 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 professionals should exercise caution when prescribing this medication to pregnant individuals.

Side Effects

Patients receiving tobramycin inhalation solution may experience a range of adverse reactions. Common adverse reactions reported include increased cough, pharyngitis, increased sputum production, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion, and rash.

Serious adverse reactions associated with tobramycin inhalation solution include bronchospasm, which can occur upon inhalation and should be treated as medically appropriate if it arises. Ototoxicity, characterized by tinnitus and hearing loss, has also been reported; management may necessitate discontinuation of the medication if these symptoms are observed. Nephrotoxicity is a concern with aminoglycosides as a class, and if it develops, appropriate management strategies should be employed, including the potential discontinuation of tobramycin inhalation solution. Additionally, patients with neuromuscular disorders may experience exacerbated muscle weakness due to a curare-like effect on neuromuscular function; in cases of neuromuscular blockade, 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 risks of fetal harm. Patients with known hypersensitivity to any aminoglycoside should not use this medication. Signs and symptoms of acute toxicity from overdosage of intravenous tobramycin may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade.

Drug Interactions

Concurrent and/or sequential use of this drug with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential should be avoided to minimize the risk of adverse effects.

In particular, concomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended. The combination of these agents may enhance the toxicity of aminoglycosides, necessitating careful consideration of alternative therapies or close monitoring of renal function and auditory status if such combinations are deemed necessary.

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. Therefore, caution is advised when considering its use in this population. Further studies are needed to determine appropriate dosing and safety profiles for younger children.

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. 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 PAK in pregnant women to assess the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, it is important to note that systemic absorption of tobramycin following inhaled administration is expected to be minimal.

Pregnant women with cystic fibrosis may face additional risks, including an increased likelihood of preterm delivery. In animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, no adverse developmental outcomes were observed; however, ototoxicity was not evaluated in the offspring from these studies. Therefore, healthcare providers 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 for the indicated populations remains unknown. It is important to recognize 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.

Lactation

There are no data on the presence of tobramycin inhalation solution in either human or animal milk, nor on its 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 medication or from the underlying maternal condition.

Lactating mothers are advised to monitor the breastfed infant for signs of 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 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 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 may manifest through a range of signs and symptoms. Healthcare professionals should be vigilant for indications such as dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. These symptoms necessitate immediate medical attention and intervention.

It is important to note that the administration of tobramycin via inhalation leads to low systemic bioavailability, which may influence the clinical presentation of overdosage. Additionally, tobramycin is not significantly absorbed when administered orally, further emphasizing the importance of the route of administration in assessing potential toxicity.

Monitoring tobramycin serum concentrations can be a valuable tool in the evaluation of overdosage. Regular assessment of serum levels may assist healthcare professionals in determining the extent of exposure and guiding appropriate management strategies. In cases of suspected overdosage, prompt recognition and intervention are critical to mitigate potential adverse effects.

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

Postmarketing experience has identified reports of several adverse reactions associated with the use of tobramycin inhalation solution. These include hearing loss, tinnitus, and dizziness. Additionally, there have been reports of renal impairment linked to the use of this medication. Furthermore, cases of respiratory distress have been documented following administration of tobramycin inhalation solution.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use, prior to starting treatment. It is essential for patients to familiarize themselves with the Instructions for Use before beginning TOBRAMYCIN INHALATION SOLUTION PAK.

Patients must be instructed to use the tobramycin inhalation solution contained in TOBRAMYCIN INHALATION SOLUTION PAK exclusively with the PARI LC PLUS Reusable Nebulizer that is included in the package. This ensures proper administration and effectiveness of the medication.

Healthcare providers should counsel patients to promptly inform their physician if they experience any shortness of breath or wheezing following the administration of the tobramycin inhalation solution. Additionally, patients should be advised to report any occurrences of ringing in the ears, dizziness, or any changes in hearing, as these may indicate potential side effects.

It is also important for patients to disclose any history of kidney problems to their physician, as this may affect their treatment plan. Pregnant women should be specifically informed that aminoglycosides, including tobramycin, can lead to irreversible congenital deafness if administered during pregnancy.

Storage and Handling

Tobramycin inhalation solution is supplied in ampules and should be stored under refrigeration at a temperature range of 2-8°C (36-46°F). If refrigeration is not available, opened or unopened pouches of tobramycin inhalation solution may be stored at room temperature, not exceeding 25°C (77°F), for a maximum of 28 days. It is imperative 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.

Care should be taken to protect the ampules from intense light exposure. The solution is typically slightly yellow; however, it may darken with age 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

Laboratory tests for inhaled antibacterial products lack defined interpretive criteria. Clinicians can utilize in vitro antimicrobial susceptibility test methods, typically used for parenteral tobramycin therapy, to monitor the susceptibility of Pseudomonas aeruginosa isolated from cystic fibrosis patients. It is important to report any noted decreased susceptibility to the clinician. Notably, the susceptibility breakpoints established for parenteral tobramycin do not apply to aerosolized tobramycin inhalation solution, and the correlation between in vitro susceptibility test results and clinical outcomes with this therapy remains unclear. Additionally, a single sputum sample from a cystic fibrosis patient may reveal multiple morphotypes of P. aeruginosa, each potentially exhibiting different levels of susceptibility to tobramycin.

FDA Insert (PDF)

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

View full prescribing information (PDF)