Tobramycin

Uses and Indications

Tobramycin inhalation solution is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or >75% predicted, or patients colonized with Burkholderia cepacia.

Tobramycin ophthalmic solution, 0.3%, is a topical antibiotic indicated in the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany the use of tobramycin ophthalmic solution. Clinical studies have shown tobramycin to be safe and effective for use in children.

Limitations of Use

• Safety and efficacy of tobramycin inhalation solution have not been established in patients under 6 years of age or those with specific pulmonary function limitations.

• Monitoring of bacterial response is essential when using tobramycin ophthalmic solution.

Dosage and Administration

The recommended dosage of Tobramycin for oral inhalation in adults and pediatric patients aged 6 years and older is one single-dose ampule (300 mg) administered twice daily. 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. Doses should be taken as close to 12 hours apart as possible, but not less than 6 hours apart. Each 300 mg dose must be administered using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.

For Tobramycin ophthalmic solution, in cases of mild to moderate disease, 1 or 2 drops should be instilled into the affected eye(s) every 4 hours. In instances of severe infections, 2 drops should be instilled into the eye(s) hourly until improvement is observed, after which the treatment frequency should be reduced prior to discontinuation.

For Tobramycin injection, the recommended dosages for patients with normal renal function are as follows: adults with serious infections should receive 3 mg/kg/day in 3 equal doses every 8 hours, while those with life-threatening infections may receive up to 5 mg/kg/day in 3 or 4 equal doses, reducing to 3 mg/kg/day as clinically indicated. Pediatric patients over 1 week of age should receive 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses. For premature or full-term neonates aged 1 week or less, a maximum of 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

In patients with impaired renal function, after an initial loading dose of 1 mg/kg, subsequent dosages must be adjusted, either by administering reduced doses at 8-hour intervals or by maintaining normal doses at extended intervals. For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses, and the diluted solution should be infused over 20 to 60 minutes. Tobramycin for Injection should not be physically premixed with other drugs and must be administered separately according to the recommended dose and route.

Contraindications

Known hypersensitivity to any aminoglycoside is a contraindication for the use of tobramycin in all forms, including inhalation solutions, ophthalmic solutions, and injections. Tobramycin ophthalmic solution, 0.3%, is specifically contraindicated in patients with known hypersensitivity to any of its components.

Additionally, patients should be advised against wearing contact lenses if they exhibit signs and symptoms of bacterial ocular infection. The use of aminoglycosides, including tobramycin, has not been approved for intraocular and/or subconjunctival administration due to the risk of serious adverse effects, such as macular necrosis.

Warnings and Precautions

Bronchospasm Bronchospasm can occur with inhalation of tobramycin inhalation solution. If bronchospasm occurs, treat as medically appropriate.

Ototoxicity Tinnitus and hearing loss have been reported in patients receiving tobramycin inhalation solution. If these symptoms are noted, manage as medically appropriate, which may include discontinuing tobramycin inhalation solution.

Nephrotoxicity Tobramycin has been associated with nephrotoxicity as a class effect of aminoglycosides. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin inhalation solution.

Neuromuscular Disorders Aminoglycosides may aggravate muscle weakness due to a potential curare-like effect on neuromuscular function. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts, but mechanical assistance may be necessary.

Embryo-fetal Toxicity Aminoglycosides can cause fetal harm. Women who are pregnant or may become pregnant should be apprised of the potential hazard to the fetus.

Hypersensitivity Reactions Sensitivity to topically applied aminoglycosides may occur in some patients. The severity of hypersensitivity reactions can range from local effects to generalized reactions such as erythema, itching, urticaria, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a sensitivity reaction to tobramycin ophthalmic solution occurs, discontinue use.

Superinfection Risk As with other antibiotic preparations, prolonged use of tobramycin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Monitoring Requirements Patients should be monitored for auditory, vestibular, renal, and neuromuscular function. Audiograms, serum concentrations, and renal function should be assessed as appropriate, especially in patients with known or suspected dysfunction. Serum concentrations of tobramycin should be monitored through venipuncture, not finger prick blood sampling.

Emergency Medical Help Get emergency medical help if signs of an allergic reaction occur, such as hives, difficulty breathing, or swelling of the face, lips, tongue, or throat.

Stop Taking and Call Your Doctor Instructions Patients should stop taking tobramycin and call their doctor if they experience severe diarrhea (watery or bloody) that may occur 2 months or more after the last dose, or if they notice symptoms of ototoxicity or nephrotoxicity.

Side Effects

Most Common Adverse Reactions

• Increased cough

• Pharyngitis

• Increased sputum

• Dyspnea

• Hemoptysis

• Decreased lung function

• Voice alteration

• Taste perversion

• Rash

• Hypersensitivity

• Localized ocular toxicity, including:

  • Lid itching

  • Swelling

  • Conjunctival erythema

These reactions occur in less than three of 100 patients treated with tobramycin ophthalmic solution.

Serious Adverse Reactions

• Bronchospasm: Can occur with inhalation of tobramycin inhalation solution. Treat as medically appropriate if it occurs.

• Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin. If noted, manage as medically appropriate, including potentially discontinuing tobramycin.

• Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin.

• Neuromuscular Disorders: Aminoglycosides may aggravate muscle weakness due to a potential curare-like effect on neuromuscular function. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts, but mechanical assistance may be necessary.

• Embryo-fetal Toxicity: Aminoglycosides can cause fetal harm.

Additional Adverse Reactions or Important Notes

• Postmarketing Experience: Additional adverse reactions identified from post-marketing use include:

  • Anaphylactic reaction

  • Stevens-Johnson syndrome

  • Erythema multiforme

• Acute Toxicity: Signs and symptoms of acute toxicity from overdosage of intravenous (IV) tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. Acute toxicity should be treated with immediate withdrawal of tobramycin, and baseline tests of renal function should be undertaken.

• Known Hypersensitivity: Patients with known hypersensitivity to any aminoglycoside should not use tobramycin.

• Caution: Prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Drug Interactions

Concurrent and/or sequential use of tobramycin, including its inhalation solution and formulations such as Bethkis and Tobi, with other drugs that possess neurotoxic, nephrotoxic, or ototoxic potential should be avoided. This caution extends to the use of aminoglycosides alongside other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides, to mitigate the risk of ototoxicity and nephrotoxicity.

Concomitant administration of tobramycin with potent diuretics, such as ethacrynic acid and furosemide, is not recommended due to the potential for enhanced aminoglycoside toxicity through alterations in serum concentrations. Additionally, the use of urea or intravenous mannitol alongside tobramycin should also be avoided for similar reasons.

Monitoring of serum calcium, magnesium, and sodium levels is advised during therapy with tobramycin, as these electrolytes can be affected. Prolonged concentrations of tobramycin above 12 mcg/mL should be avoided to prevent ototoxicity and nephrotoxicity, and rising trough levels above 2 mcg/mL may indicate tissue accumulation, necessitating dosage adjustments.

Neuromuscular blockade may occur in patients receiving tobramycin, particularly if they are also being treated with neuromuscular blocking agents. Furthermore, tobramycin can cause fetal harm when administered to a pregnant woman, as it crosses the placenta.

Pediatric Use

The safety and efficacy of tobramycin inhalation solution have not been established in pediatric patients under 6 years of age, and its use is not indicated in children younger than 6 years. Similarly, safety and effectiveness of tobramycin ophthalmic solution and other formulations have not been established in pediatric patients below the age of 2 months.

Clinical studies have demonstrated that tobramycin is safe and effective for use in children; however, specific data regarding its use in patients under 6 years of age, particularly those with cystic fibrosis, is lacking. In Phase 3 studies of TOBI Podhaler, patients aged 6 years and older were included, with no dosage adjustments required based on age. Adverse events in pediatric patients were similar to those observed in adults, although dysgeusia was reported more frequently in younger patients aged 6 to 19 years compared to those 20 years and older.

Overall, caution is advised when considering the use of tobramycin formulations in pediatric populations, particularly in those under 6 years of age and those below 2 months.

Geriatric Use

Clinical studies of tobramycin inhalation solution did not include patients aged 65 years and over. Tobramycin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in elderly patients, particularly those with impaired renal function. Elderly patients are more likely to have decreased renal function, which may not be evident in routine screening tests such as BUN or serum creatinine; therefore, a creatinine clearance determination may be more useful.

Monitoring of renal function during treatment with tobramycin is particularly important in geriatric patients, as they may be at a higher risk of developing nephrotoxicity and ototoxicity. Factors contributing to these risks include rising trough levels, excessive peak concentrations, dehydration, concomitant use of other neurotoxic or nephrotoxic drugs, and cumulative dose. Dose reduction may be required for patients with impaired renal function, and peak and trough serum levels should be measured periodically to ensure adequate levels and avoid potentially toxic levels.

No overall differences in safety or effectiveness have been observed between elderly and younger patients. However, due to the increased likelihood of renal impairment in elderly patients, careful monitoring and potential dose adjustments are recommended.

Pregnancy

Aminoglycosides, including tobramycin, have been associated with potential fetal harm. Literature indicates that the use of streptomycin, another aminoglycoside, during pregnancy can lead to total, irreversible, bilateral congenital deafness. While there are no adequate and well-controlled studies in pregnant women regarding tobramycin, systemic absorption following inhaled administration is expected to be minimal.

Animal reproduction studies involving subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis did not reveal adverse developmental outcomes; however, ototoxicity was not assessed in the offspring. It is important to advise pregnant patients of the potential risks to the fetus.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is approximately 2% to 4% and 15% to 20%, respectively. Additionally, cystic fibrosis may increase the risk of preterm delivery.

Given the lack of human data and the potential risks, tobramycin should be used during pregnancy only if clearly needed, and healthcare providers should carefully consider the benefits and risks before prescribing this medication to pregnant patients.

Lactation

Tobramycin is present in human milk, although the systemic absorption following inhaled administration is expected to be minimal, which may reduce the potential for excretion into breast milk. Limited published data indicate that tobramycin may alter the intestinal flora of breastfed infants.

Due to the potential for adverse reactions in nursing infants, healthcare providers should advise lactating mothers to consider whether to discontinue breastfeeding or the medication, weighing the importance of the drug to the mother against potential risks to the infant. Monitoring of breastfed infants for symptoms such as loose or bloody stools and candidiasis (thrush, diaper rash) is recommended.

Caution should be exercised when administering tobramycin inhalation solution to nursing mothers, particularly given the lack of specific data on its effects in this population. The developmental and health benefits of breastfeeding should be considered alongside the mother's clinical need for tobramycin and any potential adverse effects on the breastfed child.

Renal Impairment

Patients with renal impairment should be prescribed tobramycin with caution due to the potential for nephrotoxicity associated with aminoglycosides. It is essential to monitor renal function, serum concentrations, and audiograms as appropriate.

Tobramycin is primarily excreted unchanged in the urine, and renal function is expected to significantly affect its exposure. 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 to support specific dosing recommendations for this population. Therefore, careful consideration should be given when treating these patients.

Monitoring of peak and trough serum concentrations is recommended to ensure adequate therapeutic levels while avoiding toxicity. Rising trough levels above 2 mcg/mL may indicate tissue accumulation, necessitating dosage adjustments or discontinuation of therapy. Additionally, urine should be evaluated for signs of renal impairment, such as decreased specific gravity and increased protein excretion.

In patients with known or suspected renal dysfunction, the prescribing of tobramycin inhalation solution should be approached with caution. Advanced age and dehydration may further increase the risk of nephrotoxicity. It is also advised to avoid concurrent use of other neurotoxic or nephrotoxic agents, including potent diuretics, which may exacerbate the risk of adverse effects.

Overall, close clinical observation and appropriate monitoring are critical for patients with renal impairment receiving tobramycin to mitigate the risk of nephrotoxicity and ensure patient safety.

Hepatic Impairment

Patients with hepatic impairment do not have specific dosage adjustments, special monitoring, or precautions outlined for the use of Tobramycin in any of its formulations, including solutions, ophthalmic solutions, inhalation solutions, and drops. The available data does not provide any information regarding the impact of hepatic impairment on the pharmacokinetics or safety profile of Tobramycin. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing Tobramycin to patients with liver problems, as no specific guidelines are available to inform treatment decisions in this population.

Overdosage

Signs and symptoms of acute toxicity from an overdose of tobramycin, particularly when administered intravenously, may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. The severity of these symptoms can depend on factors such as the dose, renal function, hydration state, age, and concurrent medications that may have similar toxicities. Toxicity is more likely to occur in adults receiving more than 5 mg/kg/day or in children receiving more than 7.5 mg/kg/day. Nephrotoxicity is particularly concerning if trough blood concentrations do not fall below 2 mcg/mL.

In the event of an overdose, immediate withdrawal of the tobramycin inhalation solution is recommended, and baseline tests of renal function should be conducted. Patients should be adequately hydrated to maintain a urine output of 3 to 5 mL/kg/hr, and fluid balance, creatinine clearance, and tobramycin plasma levels should be monitored until serum levels fall below 2 mcg/mL. For patients with an elimination half-life greater than 2 hours or those with abnormal renal function, hemodialysis may be beneficial in removing tobramycin from the body.

In all cases of suspected overdosage, it is essential for healthcare providers to contact the Regional Poison Control Center for the most current treatment information. Additionally, the possibility of drug interactions that may alter drug disposition should be considered. For tobramycin administered via inhalation, it is noted that systemic bioavailability is low, and oral administration does not significantly absorb the drug.

For tobramycin ophthalmic solution, while specific overdosage information is limited, treatment should be symptomatic and supportive. Clinically apparent signs and symptoms may include punctate keratitis, erythema, increased lacrimation, edema, and lid itching, which can resemble adverse reactions seen in some patients.

Nonclinical Toxicology

Carcinogenesis

A two-year inhalation toxicology study was conducted in rats to assess the carcinogenic potential of tobramycin inhalation solution. 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 rats, which is significantly higher than the average serum levels of 1 mcg/mL observed in cystic fibrosis patients during clinical trials. The study found no drug-related increase in the incidence of any type of tumor.

Mutagenesis

Tobramycin has been evaluated 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. Additionally, tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Impairment of Fertility

Subcutaneous administration of tobramycin at doses up to 100 mg/kg did not affect mating behavior or result in impairment of fertility in both male and female rats. Furthermore, reproduction studies conducted in three types of animals at doses up to 33 times the normal human systemic dose revealed no evidence of impaired fertility or harm to the fetus. However, it is important to note that there are no adequate and well-controlled studies in pregnant women, and the use of tobramycin during pregnancy should be considered only if clearly needed due to the potential risks.

Storage and Handling

Tobramycin is supplied in various forms, including inhalation solutions and ophthalmic solutions. The inhalation solution is typically packaged in ampules or pouches, while the ophthalmic solution is available in plastic dropper bottles.

Tobramycin inhalation solution should be stored under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). If refrigeration is unavailable, opened or unopened pouches may be stored at room temperature (up to 25ºC/77ºF) for a maximum of 28 days. It is important to note that the solution should not be used beyond the expiration date stamped on the ampule when stored under refrigeration or beyond 28 days when stored at room temperature. The ampules should be protected from intense light, and unopened ampules should be returned to the foil pouch to maintain light protection. The solution in the ampule may appear slightly yellow and can darken with age if not refrigerated; however, this color change does not indicate a loss of quality as long as the product is stored under the recommended conditions.

For the ophthalmic solution, it should be stored at temperatures between 2ºC to 25ºC (36ºF to 77ºF). After opening, the ophthalmic solution can be used until the expiration date on the bottle. It is essential to keep the container tightly closed and protect it from excessive heat.

In summary, proper storage conditions are crucial for maintaining the efficacy and safety of tobramycin products, and adherence to the specified temperature ranges and handling instructions is recommended.