Nebcin (Tobramycin Sulfate)

NEBCIN®

Lilly

Tobramycin Sulfate

Antibiotic

Action And Clinical Pharmacology: Like other aminoglycosides, the bactericidal activity of tobramycin is accomplished by specific inhibition of normal protein synthesis in susceptible bacteria, but at the present time, very little is known about this action. It is thought that inhibition of synthesis is due to an action on ribosomes that, in turn, causes bacterial misreading of messenger RNA.

Peak serum concentrations of tobramycin occur between 30 and 130 minutes after i.m. administration.

In patients with normal renal function, tobramycin administered every 8 hours does not accumulate in the serum. A serum half-life of about 2 hours was reported for patients with normal renal function while in patients with impaired renal function serum half-life of the drug ranged from 5 to 47 hours. Dosage for such patients must, therefore, be adjusted accordingly (see Dosage).

After i.v. administration, serum concentrations are similar to those following i.m. injection, and are dose-related.

Pediatric studies indicate that although the serum half-life in neonates was found to be 2 or 3 times longer than in adults, no accumulation of tobramycin occurred even after multiple doses of 4 mg/kg/day.

Tobramycin is eliminated almost exclusively by glomerular filtration; renal clearance is similar to that of endogenous creatinine. Ultrafiltration studies demonstrate that practically no serum protein binding occurs. In patients with normal renal function, up to 84% of the dose is recoverable from the urine in 8 hours and up to 93% in 24 hours.

Peak urine concentrations up to 100 g/mL have been observed after the i.m. injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily dose administered.

An inverse relationship exists between half-life and creatinine clearance, and the dosage schedule should be adjusted according to the degree of renal impairment. In patients undergoing hemodialysis, 25 to 70% of the administered dose may be removed, depending upon the duration of hemodialysis. Peritoneal dialysis was considered to be less efficient.

Tobramycin can be detected in tissues and body fluids after parenteral administration. Concentrations in bile ordinarily have been low, which suggests minimum biliary excretion. Tobramycin has been found in low and unpredictable concentrations in the cerebrospinal fluid following parenteral administration and would be inadequate against many gram negative organisms causing meningitis. It has also been found in sputum and in abscess fluids though possibly in nontherapeutic concentrations. Tobramycin crosses the placental membranes producing in 1 study a fetal serum half-life of 3.2 hours and a peak serum concentration of 1.2 g/mL.

Indications And Clinical Uses: Tobramycin may be indicated for the treatment of the following infections when caused by susceptible organisms: septicemia, complicated and recurrent urinary tract infections, lower respiratory infections, serious skin and soft tissue infections including burns and peritonitis and CNS infections caused by organisms resistant to antibiotics usually considered efficacious in these infections.

Nebcin is usually active against most strains of the following organisms in vitro and in clinical infections: P. aeruginosa; Proteus sp. (indole-positive and indole-negative), including P. mirabilis, M. morganii, P. rettgeri, and P. vulgaris; E. coli; Klebsiella-Enterobacter-Serratia group; Citrobacter sp.; Providencia sp.; Staphylococci, including S. aureus (coagulase-positive and coagulase-negative).

Tobramycin may be considered in serious staphylococcal infections when penicillin or other potentially less toxic drugs are contraindicated and when bacterial susceptibility testing and clinical judgment indicate its use.

Appropriate sensitivity studies should be performed to determine the susceptibility of the causative organism to tobramycin. Clinical judgement and anticipated bacteriological findings may permit the start of therapy before results of susceptibility studies are obtained.

Note: If susceptibility tests show that the causative organism is resistant to tobramycin, other appropriate therapy should be instituted.

Contra-Indications: Known hypersensitivity to tobramycin or any other aminoglycoside. Cross-allergenicity to other aminoglycosides has been established. tag_WarningWarnings

Manufacturers’ Warnings In Clinical States: Patients treated with tobramycin or other aminoglycosides should be under close clinical observation because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity.

Both vestibular and auditory toxicity can occur. Impairment of eighth nerve function is most likely in patients with preexisting renal damage, especially if the drug is administered for longer periods or in higher doses than those recommended. Patients with known or suspected impairment of renal function should be under close clinical observation, and renal and eighth nerve function should be monitored during therapy.

Such monitoring is also recommended during the treatment of patients in whom renal function is initially normal, but in whom oliguria or evidence of nitrogen retention (increasing BUN, NPN, or creatinine) develops during therapy. Evidence of developing impairment in renal, vestibular, and/or auditory function requires careful observance of dosage adjustments (see dosage chart). Discontinuation of the drug may be indicated.

Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mg/L should be avoided. Rising trough levels (above 2 mg/L) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity.

Concurrent and/or sequential use of other potentially neurotoxic and/or nephrotoxic drugs, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), amphotericin B, cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, requires careful monitoring. Other factors that may increase patient risk are advanced age and dehydration.

Tobramycin should not be used concurrently with potent diuretics because some diuretics themselves cause ototoxicity.

Tobramycin sulfate contains sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people.

Pregnancy: Safety for use in pregnancy has not been established. Animal and human studies have demonstrated that there is a maternal-fetal transfer of tobramycin. No reports to date have revealed teratogenic effects in humans. However, one study in guinea pigs using high doses (50 to 100 mg/kg) in the last 4 weeks of pregnancy revealed a low incidence of ototoxicity in the newborn.

Precautions: Neuromuscular block and respiratory paralysis have been reported in cats receiving very high doses of tobramycin (40 mg/kg). The possibility that these phenomena may occur in man should be considered if tobramycin is administered to patients who are also receiving general anesthesia and/or neuromuscular blocking agents such as succinylcholine and tubocurarine, or in patients with myasthenia gravis or Parkinson’s disease.

Tobramycin should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated, and if necessary, withdraw the drug.

Although not indicated for intraocular and/or subconjunctival use, there have been reports of macular necrosis following this type of injection of aminoglycosides, including tobramycin.

Adverse Reactions: Nephrotoxicity: Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, have been reported, especially in patients with a history of renal impairment who were treated for longer periods or with doses higher than those recommended.

Neurotoxicity: Adverse effects on both vestibular and auditory branches of the eighth-nerve have been reported, especially in patients on high dosage and/or prolonged therapy. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears and high frequency hearing loss.

Other adverse reactions that have been reported, and may be associated with tobramycin therapy, include increased serum transaminases (AST, ALT), increased alkaline phosphatase and increased serum bilirubin; anemia, granulocytopenia, and thrombocytopenia; fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache and lethargy. Local reaction at the injection site has been reported.

Symptoms And Treatment Of Overdose: Symptoms: The severity of the signs and symptoms following a tobramycin overdose are dependent on the dose administered, the patient’s renal function, state of hydration, and age and whether or not other medications with similar toxicities are being administered concurrently. Toxicity may occur in patients treated more than 10 days, given more than 5 mg/kg/day, children given more than 7.5 mg/kg/day, or patients with reduced renal function whose dose has not been appropriately adjusted.

Nephrotoxicity following the parenteral administration of an aminoglycoside is most closely related to the area under the curve of the serum concentration versus time graph. Nephrotoxicity is more likely if trough blood concentrations fail to fall below 2 mg/L and is also proportional to the average blood concentration. Patients who are elderly, have abnormal renal function, are receiving other nephrotoxic drugs, or are volume depleted are at greater risk for developing acute tubular necrosis. Auditory and vestibular toxicities have been associated with aminoglycoside overdose. These toxicities occur in patients treated longer than 10 days, in patients with abnormal renal function, in dehydrated patients, or in patients receiving medications with additive auditory toxicities. These patients may not have signs or symptoms or may experience dizziness, tinnitus, vertigo, and a loss of high-tone acuity as ototoxicity progresses. Ototoxicity signs and symptoms may not begin to occur until long after the drug has been discontinued.

Neuromuscular blockade or respiratory paralysis may occur following administration of aminoglycosides. Neuromuscular blockade, prolonged respiratory paralysis, and respiratory failure may occur more commonly in patients with myasthenia gravis or Parkinson’s disease. Prolonged respiratory paralysis may also occur in patients receiving decamethonium, tubocurarine, or succinylcholine. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.

If tobramycin were ingested, toxicity would be less likely because aminoglycosides are poorly absorbed from an intact gastrointestinal tract.

Treatment: The initial management in a tobramycin overdose is to assess respiration and if necessary to establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly if respiratory paralysis occurs.

Patients that have received an overdose of tobramycin and have normal renal function should be carefully hydrated to maintain a urine output of 3 to 5 mL/kg/hour. Fluid balance, creatinine clearance, and tobramycin plasma levels should be carefully monitored until the serum tobramycin level falls below 2 g/mL.

Patients in whom the elimination half-life is greater than 2 hours or whose renal function is abnormal may require more aggressive therapy. In such patients, hemodialysis may be beneficial.

Dosage And Administration: Tobramycin may be given i.m. or i.v. The i.v. dose is the same as the i.m. dose.

Adults: Patients with normal renal function: 1 mg/kg every 8 hours, for a total of 3 mg/kg/day. Mild to moderate infections of the lower urinary tract have responded to doses of 2 to 3 mg/kg/day administered once daily. When renal tissue is involved or in serious infections, especially when there are signs of systemic involvement, 2 or 3 equally divided doses are recommended.

The usual dosage for patients weighing more than 60 kg is 80 mg (2 mL) every 8 hours. For patients weighing 60 kg or less, the usual dosage is 60 mg (1.5 mL) every 8 hours.

In patients with life threatening infections, dosages up to 5 mg/kg/day may be administered in 3 or 4 equal doses. This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored.

Children: 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses.

Neonates (1 week of age or less): Dosage up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours (see Precautions).

The usual duration of treatment is 7 to 10 days. A longer course of therapy may be necessary in difficult and complicated infections. Monitoring of renal, auditory, and vestibular functions is advisable in these cases because neurotoxicity is more likely to occur when treatment is extended for longer than 10 days.

Patients with Impaired Renal Function: Serum tobramycin concentrations should be monitored during therapy.

Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with lower doses administered at 8 hour intervals or with normal doses at prolonged intervals (see Table I). Both regimens should be based on the BUN, the serum creatinine or the creatinine clearance of the patient, because these values correlate with the half-life of tobramycin.

Adjusted dose at 8-hour intervals (Regimen I): An appropriately reduced dosage range can be found in Table I for any patient for whom the BUN, creatinine clearance or serum creatinine values are known. The choice of dose within the indicated range should be based on the severity of the infection, the sensitivity of the pathogen, and individual patient considerations, especially renal function.

Both of these regimens are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. The appropriate dosage schedules derived from either regimen should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.

Dosage in Moderate to Marked Obesity: The appropriate dose may be calculated by using the patient’s estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

I.V. Administration: This route is recommended when the i.m. route is not feasible, e.g. in the presence of shock, hematologic disorders, severe burns or reduced muscle mass.

The concentration of Nebcin in solution should not normally exceed 1 mg/mL for either adults or children. The solution should be infused over a period of 20 to 60 minutes. When it is necessary to restrict the volume of solution infused, a more concentrated solution may be used; however, it is important that the infusion time exceed 5 minutes to prevent excessively high serum concentrations. A volume control set is recommended for this administration.

Note: Nebcin should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

Shake well until dissolved.

The Pharmacy Bulk Vial is intended only for i.v. infusion (by single puncture for multiple dispensing).

Solutions for I.V. Infusion: 5% Dextrose in water; 10% Dextrose in water; 0.9% Sodium Chloride Injection; 5% Dextrose and 0.9% Sodium Chloride; Ringer’s Solution; Lactated Ringer’s Solution.

Stability of solution: Storage: Nebcin diluted with any of the solutions for i.v. infusion listed above in a concentration range of 1 mg/mL to 0.2 mg/mL should be used within 24 hours if kept at room temperature and 36 hours if stored under refrigeration. The Pharmacy Bulk Vial is intended for multiple dispensing for i.v. use employing a single puncture. Following reconstitution, the solution should be dispensed and diluted for use within 8 hours. Any unused reconstituted solution should be discarded after 8 hours.

Nebcin should be stored at controlled room temperatures below 30°C. Nebcin injection requires no refrigeration.

Special Instructions: Pharmacy Bulk Vials: Pharmacy Bulk Vials contain no preservatives. Care must be taken to minimize the potential for inadvertent introduction of microorganisms during manipulation in the hospital environment. The availability of the Pharmacy Bulk Vial is restricted to hospitals with a recognized i.v. admixture program.

Availability And Storage: Injection: 10 mg: Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 10 mg (pediatric). Rubber stoppered vials of 2 mL.

40 mg: Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 40 mg. Rubber stoppered vials of 2 mL.

Pharmacy Bulk Vials: Pharmacy Bulk Vial (7040), equivalent to sterile tobramycin 1.2 g powder, and equivalent to tobramycin 1.2 g in 30 mL of solution at a concentration of 40 mg/mL, for single puncture multiple dispensing. Rubber stoppered vials of 30 mL.

Pharmacy Bulk Vial (7090), equivalent to 1.2 g liquid for multiple puncture and dispensing. Rubber stoppered vials of 30 mL.

Nonmedicinal ingredients: edetate disodium, phenol, sodium bisulfite and water for injection.

NEBCIN® Lilly Tobramycin Sulfate Antibiotic

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