Tobramycin for Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Tobramycin for Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Bacteremia, Bacterial Infection, Bone infection (Osteomyelitis), Burns, External, Central Nervous System Infection (CNS Infection), Cystic Fibrosis, Endocarditis, Febrile Neutropenia, Intraabdominal Infection, Kidney Infections (Pyelonephritis), Meningitis, Peritonitis, Pneumonia, Sepsis, Shunt Infection, Skin or Soft Tissue Infection
Class: Aminoglycosides
Form: Liquid solution, Intramuscular (IM), Powder
Ingredients: Tobramycin sulfate, Edetate disodium, Sodium metabisulfite, Sodium hydroxide, Sulfuric acid

Pharmaceutical Information

Drug Substance

Proper Name: Tobramycin
Chemical Name: 

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-deoxystreptamine

Structural Formula:  
Molecular Formula: C18H37N5O9
Molecular Weight: 467.54
Description: Tobramycin is a white to off-white hygroscopic powder. It is a basic aminocyclitol aminoglycoside, freely soluble in water. A 10% solution in water has a pH of 9 to 11. Melting range = 172 – 178 °C.

Dosage Form

Composition

Tobramycin Injection, USP, 10 mg/mL

Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 10 mg, 0.1 mg edetate disodium, 5 mg phenol, 3.2 mg sodium metabisulfite in water for injection. May contain sodium hydroxide and/or sulfuric acid for pH adjustment.

Tobramycin Injection, USP, 40 mg/mL

Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 40 mg, 0.1 mg edetate disodium, 5 mg phenol, 3.2 mg sodium metabisulfite in water for injection. May contain sodium hydroxide and/or sulfuric acid for pH adjustment.

Tobramycin for Injection, USP, 1.2 g/vial

Tobramycin for Injection, USP Pharmacy Bulk Vials contain lyophilized tobramycin sulfate equivalent to 1.2 g tobramycin with no preservatives.

Reconstitution

Solutions for Reconstitution

Sterile Water for Injection

Table 1: Reconstitution Table for Pharmacy Bulk Vial
Vial Size Volume tobe added to vial Approximate Available Volume Approximate Average Concentration
1.2 g Powder (Pharmacy Bulk Vial) 30 mL 31.0 mL 40 mg/mL

Shake well until dissolved.

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

Solutions for IV Infusion

  • 5% Dextrose in Water
  • 0.9% Sodium Chloride Injection
Dilution of Tobramycin Injection, USP
Concentration Tobramycin Volume of Diluent
0.2 mg/mL 20 mg/2 mL (1 vial) 100 mL
0.4 mg/mL 20 mg/2 mL (1 vial) 50 mL
0.8 mg/mL 80 mg/2 mL (1 vial) 100 mL
1.6 mg/mL 80 mg/2 mL (1 vial) 50 mL

Stability of Solution

The Pharmacy Bulk Vial is intended for multiple dispensing for intravenous 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.

Reconstituted solution of Tobramycin for Injection, USP diluted with any of the solutions for i.v. infusion listed above in 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.

Tobramycin Injection, USP diluted with either of the solutions for i.v. infusion listed above in a concentration range of 0.2 mg/mL to 1.6 mg/mL should be used within twenty-four hours if kept at room temperature.

As with all parenteral drug products, intravenous admixture should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration whenever solution and container permit. Discard unused portion.

Storage

Tobramycin for Injection, USP should be stored at controlled room temperatures below 30 °C. Tobramycin for Injection, USP requires no refrigeration.

Tobramycin Injection, USP should be stored at controlled room temperature (15 °C to 30 °C). Multiple-dose vials. Discard unused portion 28 days after initial puncture.

Special Instructions

  • 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 intravenous admixture program.

Availability of Dosage Forms

Tobramycin is available in the following forms and package sizes:

C300502 Tobramycin Injection, USP, 10 mg/mL: Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 10 mg. Rubber stoppered vials of 2 mL for multiple use, packaged in cartons of 25 vials.
C300602 Tobramycin Injection, USP, 40 mg/mL: Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 40 mg. Rubber stoppered vials of 2 mL for multiple use, packaged in cartons of 25 vials.
C300604 Tobramycin Injection, USP, 40 mg/mL: Each mL of solutions contains:tobramycin sulfate equivalent to tobramycin 40 mg. Rubber stoppered vials of 4 mL for multiple use, packaged in cartons of 25 vials.
C300630 Tobramycin Injection, USP, 40 mg/mL: Each mL of solution contains: tobramycin sulfate equivalent to tobramycin 40 mg. Rubber stoppered vials of 30 mL for multiple use, packaged in cartons of 10 vials.
C300351 Tobramycin for Injection, USP, 1.2 g/vial: Each vial contains lyophilized tobramycin sulfate equivalent to 1.2 g of tobramycin, in 50 mL Pharmacy Bulk Vial, packaged in cartons of 6 vials.

Tobramycin for injection, usp pharmacy bulk vial does not contain any preservatives.

Vial stoppers do not contain natural rubber latex.

Microbiology

In vitro tests demonstrate that tobramycin is bactericidal and that it acts by inhibiting the synthesis of protein in bacterial cells.

Tobramycin is active against most strains of the following organisms:

  • Pseudomonas aeruginosa
  • Proteus sp. (indole-positive and indole-negative), including Proteus mirabilis, Morganella morganii, Providencia rettgeri, and Proteus vulgaris
  • Escherichia coli Klebsiella-Enterobacter-Serratia sp. Citrobacter sp.
  • Providencia sp.
  • Staphylococci, including Staphylococcus aureus (coagulase-positive and coagulase-negative).

Although most strains of enterococci demonstrate in vitro resistance, some strains in this group are susceptible. In vitro studies have shown that an aminoglycoside combined with an antibiotic which interferes with cell-wall synthesis affects some enterococcal strains synergistically. The combination of penicillin G and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of Enterococcus faecalis (formerly Streptococcus faecalis). However, this combination is not synergistic against other closely related organisms, e.g., Enterococcus faecium (formerly Streptococcus faecium). Speciation of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergism are therefore required.

Table 2: In Vitro Susceptibility of Microorganism to Tobramycin (Cumulative Percent of Strains inhibited in Broth or Agar-Dilution Studies)
I--------------------------------------------------MIC mg/L-----------------------------------I
Microorganism No. of strains 0.06 - 0.06 0.13 - 0.12 0.26 - 0.25 0.51 - 0.5 0.79 - 0.78 1.6 - 1.56 3.2 - 3.12 6.3 - 6.25 12.6 - 12.5 25
Ps. aeruginosa 2,888 6 18 40 63 70 91 96 97 98 99
Ps. aeruginosa (gentamicin-resistant) 153 12 18 27 30 35 46 59 71 80
Esch. coli 2,117 1 4 18 21 58 78 92 97 98
Proteus mirabills (indole-negative) 1,675 1 5 8 37 60 81 96 99
Proteus sp. (indole-positive 1,213 2 4 16 20 51 71 83 92 96
Proteus sp. (not specified) 76 1 12 12 42 97 100 100 100
Klebsiella sp. 1,244 3 5 20 47 50 86 94 97 99 99
Klebsiella- Enterobacter sp. 721 3 22 48 54 83 94 97 98 99
Enterobacter sp. 1,126 1 4 15 36 39 81 91 97 99 99
Serratia sp. 546 3 5 28 53 73 88 94
Providencia sp. 113 2 4 4 12 28 51 68 81
Chtrobacter sp. 167 1 5 19 19 73 93 98 98 99
Staph. aureus 2,013 11 28 42 70 73 87 93 96 99 99
Streptococcus faecalis (group D 448 1 2 2 3 4 14 38 61

* Inoculum did not exceed 105 organisms per mL in broth.

Susceptibility Plate Tests

If the Bauer-Kirby-Sherris-Turck method of disk susceptibility testing is used (Am. J. Clin. Pathol., 45:493, 1966), a disk containing 10 μg tobramycin should give a zone of inhibition of at least 15 mm when tested against a tobramycin susceptible bacterial strain and a zone of inhibition of 13 to 14 mm against strains of intermediate susceptibility, and a zone of inhibition of 12 mm or less against resistant organisms. The minimum inhibitory concentration correlates are < 4 mg/L for susceptibility and > 8 mg/L for resistance.

Pharmacology

Human Pharmacology

Peak serum concentrations of tobramycin occur between thirty and 130 minutes after intramuscular administration.

Table 3: Serum Concentrations After Single Intramuscular Doses
SERUM CONCENTRATION (mg/L)
DOSE 1/2 hr. 1 hr. 2 hr. 4 hr. 8 hr.
25 mg 1.14 0.8 0.56 0.26 0.01
50 mg 2.09 1.95 1.26 0.56 0.1
75 mg 2.71 2.68 1.86 0.9 0.2
100 mg 2.95 3.25 2.61 1.36 0.41
200 mg 9.63 8.99 7.70 4.33 0.94

In patients with normal renal function, tobramycin administered every eight 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 and Administration).

After intravenous administration, serum concentrations are similar to those following intramuscular injection, and are dose related.

Table 4: Intravenous Dose Infused Over 30 – 45 Minutes
SERUM CONCENTRATION (mg/L)
DOSE 1/4 hr. 1/2 hr. 1 hr. 2 hr. 4 hr. 6 hr.
1 mg/kg 3.80 5.50 3.85 2.38 1.04 0.52
1.5 mg/kg 4.85 6.02 5.28 2.96 1.72 0.90

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 percent of the dose is recoverable from the urine in eight hours and up to 93 percent in twenty-four hours.

Peak urine concentrations up to 100 mg/L have been observed after the intramuscular 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 percent 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 non-therapeutic concentrations. Tobramycin crosses the placental membranes producing in one study a fetal serum half-life of 3.2 hours and a peak serum concentration of 1.2 mg/L.

Toxicology

Acute Toxicity

The acute toxicity of parenterally administered tobramycin was related to immediate CNS effects. Death often occurred within a few minutes after an intravenous dose and 20 minutes to 2 hours after subcutaneous administration. In a few rats and one guinea pig, delayed deaths were attributed to renal injury.

The intravenous LD50 values ranged from 53 to 107 mg/kg for mice and 131 to 134 mg/kg for rats; while the subcutaneous LD50 values were 416 to 484 mg/kg for mice and 928 to 1028 mg/kg for rats.

Tobramycin was no more toxic in newborn rats than in rats of 5 to 6 weeks of age, but it was slightly more toxic to 3 month old animals.

Two dogs were treated with subcutaneous doses of 100 and 200 mg/kg. No effect was observed with the 100 mg dose. Retching and tremors occurred after the administration of the 200 mg dose. The animals appeared normal after 3 hours. Two dogs tolerated single intravenous doses of 100 mg/kg with emesis as the only observed sign of toxicity.

Two cats received subcutaneous doses of 200 mg/kg of tobramycin which produced marked CNS effects that persisted for more than 5 hours. Both animals appeared normal on the following day. An intravenous dose of 50 mg/kg in three cats produced a short-term ataxia. A dosage of 100 mg/kg caused convulsions and death.

Subacute Toxicity

Rats

In a study using 10 animals/sex/dose, rats given 30 daily subcutaneous doses of 30, 60, or 120 mg/kg of tobramycin survived, with the exception of 1 of 20 of the 120 mg/kg dosage group. There were no significant changes in appearance or behavior. The 120 mg/kg regimen caused a slight retardation of growth in the females.

A slight renal toxicity was noted at all doses by virtue of an increase in SGOT, increased renal weights, and the histologic finding of a slight to moderate regeneration of renal cortical tubular epithelium. These effects were dose dependent.

In a similar study, rats tolerated 14 daily intravenous doses of 20 - 80 mg/kg of tobramycin with no adverse effects other than those associated with CNS effects after rapid injection. Six of 10 of the animals of the 80 mg/kg group died shortly after tobramycin administration. The hematologic and blood chemistry data of the surviving animals were unaffected. The relative renal weights of the tobramycin-dosed animals were significantly greater than control. The effect was dose dependent.

No drug-related tissue changes were noted in rats of the 20 mg/kg group. A slight regeneration of renal cortical tubular epithelium was detected in 1 of 20 animals given 40 mg/kg and most of those given 80 mg/kg. It was concluded that the only hazard in administration of tobramycin by the intravenous route rather than by the subcutaneous route is that a too rapid intravenous injection can cause convulsions and death.

Dogs

A study using 4 dogs for each daily intramuscular dose was carried out for 28 days. The appearance, behaviour, hematology, and blood chemistry were unaffected by doses of 3.75 to 15 mg/kg. Histologic examination of the tissue revealed that a slight renal injury, as evidenced by the finding of a mild regeneration of the cortical tubular epithelium, had occurred at the upper dose.

In a further study with 4 dogs, a daily dose of 30 mg/kg was tolerated for 2 weeks with no apparent ill effects; but thereafter, anorexia, weight loss, hypoactivity, and a general CNS depression were noted. Two animals were killed during the fourth week because of morbidity. Renal tubular necrosis accompanied by regeneration of the tubular epithelium was noted in all animals of the 30 mg/kg group.

Dogs had a reduced tolerance for tobramycin dosage regimens of longer duration. In a study using 2 dogs/sex/dose for 90 days, a daily intramuscular dose of 3.75 or 7.5 mg/kg of tobramycin caused no changes in appearance, behavior, or body weight, but 2 of 4 dogs on the 7.5 mg/kg dose had a mild degree of renal cortical tubular epithelial regeneration or a mild reparative nephrosis.

A daily dose of 15 mg/kg of tobramycin was well tolerated by 2 of 4 dogs. The other 2 dogs of this group had marked appetite suppression, weight loss, and marked elevations in BUN and SGOT. One of these dogs became deaf on day 49. This dog also showed evidence of tobramycin accumulation. A mild to moderate reparative nephrosis and inflammatory reactions at the injection sites represented the only histologic evidence of tobramycin injury.

The daily intravenous administration of 7.5, 15 or 30 mg/kg of tobramycin for 2 dogs/sex/dose over 14 days caused no changes in appearance or behavior except for a single emetic episode in one dog of the 30 mg/kg group. Blood serum concentrations of tobramycin one hour after intravenous injection were similar to those found one hour after intramuscular administration. The hematologic and blood chemistry parameters were not altered significantly. A slight to moderate proteinuria was detected in one or two dogs of each dosage regimen, and a slight glucosuria occurred in one animal of the 15 mg/kg group. There was no histologic evidence of tissue injury. It seems probable, however, on the basis of the results of intramuscular administration of similar doses, that renal injury would occur with more prolonged intravenous dosage.

Cats

In a study using 2 animals/sex/dose, cats were given daily subcutaneous doses of 25 or 50 mg/kg. The 25 mg/kg dose was tolerated by 4 cats for 65 doses with no apparent vestibular injury. Haemorrhagic cystitis and urinary tract blockage due to urolithiasis in one male cat were considered unrelated to the drug, but co-existent renal cortical tubular necrosis with epithelial regeneration in the same cat were probably drug-related. One other cat had slight regeneration of renal cortical tubular epithelium. The 50 mg/kg/day dosage was poorly tolerated by all 4 cats. One cat was sacrificed after 25 doses, and another after 40 doses, because of poor physical condition. Tobramycin administration was terminated for the other 2 cats of this group on day 40. All 4 animals had severe vestibular injury. The 2 cats sacrificed during treatment had moderate renal tubular necrosis. A lack of histological evidence of renal injury in the 2 cats that were sacrificed 34 days after a 40 dose treatment, plus the finding of regenerative cortical tubular epithelium in animals killed during treatment suggested that moderate renal injury, occurring as the result of tobramycin administration, may be reversible.

In a second study, 6 cats received tobramycin in a dosage of 35 mg/kg/day causing a marked reduction in PRN times in all six cats within 20 to 47 days.

Guinea Pigs

In a study using guinea pigs, a daily 50 mg/kg dose of tobramycin had no effect on growth or on auditory function in a 4-week period. A 100 mg/kg dose caused a 25% retardation of growth, as compared with controls. No hearing impairment was noted at 2 weeks, but some loss was detected at 4 weeks.

In a further study, daily doses of 150 to 200 mg/kg markedly depressed growth and was lethal to 40% of the animals within 6 weeks. Cochlear injury that occurred in 40% of the surviving animals was verified by electrophysiologic and histopathologic methods.

Teratology and Reproduction

Daily subcutaneous administration of tobramycin given in 50 and 100 mg/kg doses to rats (30 animals/sex/dose) during all phases of the reproductive cycle, had no adverse effect on fertility or reproductive performance, nor did it affect the progeny.

In a further study, pregnant rats were given subcutaneous doses of 50 and 100 mg/kg of tobramycin from gestation days 14 through 20. Reparative nephrosis was detected in 6 of 25 of the 50 mg/kg group and 22 of 25 of the 100 mg/kg group at necropsy. There was no adverse effect on reproduction indices, nor on the growth of the progeny.

Daily subcutaneous doses of 20 or 40 mg/kg of tobramycin were given to pregnant rabbits (15 animals/dose) during organo-genesis and early fetal development (gestation days 6 – 18).

A marked anorexia and weight loss occurred in several animals; 3 of the 20 mg/kg group and 13 of the 40 mg/kg group died or aborted prior to gestation day 28. Drug-induced renal injury was evident in most of the animals that received the antibiotic. Fetal development appeared normal in all of the dams, including those that died or aborted. No drug-related abnormalities were detected in any of the progeny. It was concluded that daily subcutaneous doses as great as 40 mg/kg were not teratogenic in the rabbit, despite marked maternal toxicity.

A 25 to 200 mg/kg daily dose of tobramycin to mice during the period of organogenesis produced no embryocidal or teratogenic effect.

Daily doses of tobramycin 100 mg/kg/day administered to pregnant guinea pigs in early gestation, from the beginning of the second week to the end of the fifth week, resulted in hearing loss and histological damage to the six mothers. The litters born to these females, however, showed no hearing loss or damage to the inner ear. In contrast, when tobramycin was administered at 50 or 100 mg/kg daily to females in the terminal four weeks of gestation, one of eighteen newborn animals had pinna reflex loss at 20,000 Hz and four of thirty-eight had unilateral, incomplete loss of outer hair cells at the basal end of the cochlea.