Gentocin Injectable Solution (100 mg) (Canada)

GENTOCIN Injectable Solution, gentamicin as sulfate USP, is a water soluble (bactericidal) antibiotic of the aminoglycoside group, derived from Micromonospora purpurea, an actinomycete.

GENTOCIN Injectable Solution 100 mg/mL is a sterile aqueous solution containing in each mL: Medicinal Ingredient: gentamicin sulfate USP equivalent to 100 mg gentamicin base; Non-Medicinal Ingredients: 10 mg benzyl alcohol as preservative, 2.4 mg sodium metabisulfite, 0.8 mg sodium sulfite anhydrous, and 0.1 mg edetate disodium.

Action

GENTOCIN Injectable Solution is a bactericidal antibiotic which affects bacterial growth by specific inhibition of normal protein synthesis in susceptible bacteria.

It is active against a wide variety of pathogenic gram-negative and gram-positive bacteria. Pseudomonas aeruginosa, Proteus species (both indole positive and indole negative), Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, and Staphylococcus species (including penicillin and methicillin-resistant strains).

In addition, gentamicin sulfate is active in vitro against species of Salmonella, Shigella, Serratia marcescens and Neisseria; certain species of Streptococcus including some strains which are sensitive to gentamicin. Only minimal activity has been found against Streptococcus faecalis and Diplococcus pneumoniae. Limited data suggest sensitivity of some strains of Mycoplasma. Most anaerobes (Species of Clostridium, Bacteroides, and Diphtheroids) are resistant.

The bactericidal concentration of gentamicin is usually one to four times the minimal inhibitory concentration. Gentamicin was over eight times more active in vitro at pH 7.5 than at pH 5.5, against several common urinary pathogens.

Gentamicin is excreted in an unchanged form, mainly by glomerular filtration. This results in high urinary concentrations of the antibiotic.

Clinical studies have shown that organisms previously sensitive to gentamicin have become resistant during therapy. Although this has occurred infrequently, the possibility should nevertheless be considered. There is evidence that cross resistance between gentamicin and the aminoglycoside antibiotics may occur since bacteria made resistant to aminoglycoside antibiotics artificially in the laboratory are also resistant to gentamicin; however, GENTOCIN Injectable Solution may be active against clinical isolates of bacteria resistant to other aminoglycosides. Conversely, organisms resistant to GENTOCIN Injectable Solution may be sensitive to other aminoglycoside antibiotics.

Gentocin Injectable Solution (100 mg) Indications And Clinical Uses

GENTOCIN Injectable Solution is clinically effective in infections due to susceptible gram-negative and gram-positive bacteria, including Pseudomonas aeruginosa, indole negative and indole positive Proteus species, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Arizona hinshawii, and Staphylococcus species. The use of GENTOCIN Injectable Solution is indicated in the treatment of infections caused by laboratory determined susceptible bacteria, with due regard for relative antibiotic toxicity. Therefore, the drug should be considered as follows:

Gentocin Injectable Solution (100 mg) Indication

	Route	Species
1) Urinary tract infections (cystitis and nephritis)	I.M./S.C.	Dogs and Cats
2) Bacteraemia/Septicaemia	I.M./S.C.	Dogs and Cats
3) Infected wounds	I.M./S.C.	Dogs and Cats
4) Soft tissue infections	I.M./S.C.	Dogs and Cats
5) Respiratory tract infections	I.M./S.C.	Dogs and Cats
6) Gastrointestinal tract infections	I.M./S.C.	Dogs and Cats
7) Scours (E. coli)	I.M.	1-3 day old piglets
8) Uterine infections
i. Bacterial infections of the uterus (metritis)	I.U./I.M.	Dogs
ii. Bacterial infections of the uterus (metritis)	I.U.	Horses
iii. Metritis and cervicitis associated with bacteria such as E. coli, S. aureus and Streptococcus species which are susceptible to gentamicin.	I.U.	Cows
The method of treatment of metritis associated with systemic involvement should be at the discretion of the attending veterinarian.
9) As an aid in the prevention of mortality in the first two weeks of life of 1 to 3 day old turkey poults due to Arizona hinshawii infections	S.C.
10) Prevention of early mortality caused by Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa, susceptible to gentamicin.	S.C.	One day old chicks

In the majority of cases bacteriologic cultures should be obtained initially, to identify the causative organism and to determine its sensitivity to GENTOCIN Injectable Solution. Sensitivity discs of 10 µg are available for this purpose.

GENTOCIN Injectable Solution should also be considered in Staphylococcal infections when other conventional anti-microbial therapy is inappropriate or when bacterial susceptibility testing and clinical judgment indicate its use.

If susceptibility tests indicate the causative organism is resistant to gentamicin, other anti-microbial therapy should be instituted.

Gentocin Injectable Solution (100 mg) Dosage And Administration

Intra-uterine

(a)

Horses

2.0 - 2.5 grams once per day for three to five days during estrus. Each dose should be diluted with 200-500 mL sterile physiological saline before aseptic uterine infusion. Although GENTOCIN Injectable Solution is not spermicidal, treatment should not be given the day of breeding.

(b)

Dogs

4.4 mg/kg (2 mg/lb) body weight once a day for four days. Each dose should be diluted with 10 mL sterile physiological saline before aseptic uterine infusion.

(c)

Cows

200 mg one time only. The dose should be diluted with 16 mL sterile physiological saline solution before aseptic uterine infusion. Although GENTOCIN Injectable Solution is not spermicidal, treatment should not be given the day of breeding.

Intramuscular

(a)

Dogs And Cats

4.4 mg/kg (2 mg/lb) body weight twice the first day; 4.4 mg/kg (2 mg/lb) body weight once a day thereafter. Average duration of treatment in clinical studies was five to seven days.

Ordinarily, treatment should not be given for more than 7 to 10 days or be repeated unless required for serious infections not responsive to other agents. The decision to continue therapy with GENTOCIN Injectable Solution should be based on results of the sensitivity tests, clinical response of the patient, and consideration of relative antibiotic toxicity.

Results of in vivo and in vitro studies indicate that alkalinization of the urine may be a useful therapeutic adjunct. In clinical studies, a small percentage of animals experienced pain on administration.

(b)

Piglets

Each 1-3 day old piglet should be injected aseptically once intramuscularly with 5 mg of GENTOCIN Injectable Solution. To prepare 50 mL of 5 mg/mL solution, dilute 2.5 mL of GENTOCIN Injectable Solution 100 mg/mL with 47.5 mL of sterile physiological saline solution. Inject 1 mL per piglet.

Subcutaneous

(a)

Dogs And Cats

4.4 mg/kg (2 mg/lb) body weight twice the first day; 4.4 mg/kg (2 mg/lb) body weight once a day thereafter. Average duration of treatment in clinical studies was five to seven days.

(b)

Turkey Poults

Each turkey poult should be injected aseptically once subcutaneously in the neck with 1 mg of GENTOCIN Injectable Solution. To prepare 50 mL of 5 mg/mL solution, dilute 2.5 mL of GENTOCIN Injectable Solution 100 mg/mL with 47.5 mL of sterile physiological saline solution. Inject 0.2 mL per turkey poult.

(c)

Chicks

Each chick should be injected aseptically once subcutaneously in the neck with GENTOCIN Injectable Solution diluted with sterile physiological saline solution to provide 0.2 mg gentamicin in a 0.2 mL dose. This concentration can be provided by diluting GENTOCIN Injectable Solution as follows:

Gentocin - Injectable Solution

100mg/mL (mL)	Sterile Saline (mL)	No. Doses	Dose/ Chick (mL)
0.5	49.5	250	0.2
1.0	99.0	500	0.2
2.0	198.0	1,000	0.2
5.0	495.0	2,500	0.2
25.0	2,475.0	12,500	0.2

Ordinarily, treatment should not be given for more than 7 to 10 days or be repeated unless required for serious infections not responsive to other agents. The decision to continue therapy with GENTOCIN Injectable Solution should be based on results of the sensitivity tests, clinical response of the patient, and consideration of relative antibiotic toxicity.

Results of in vivo and in vitro studies indicate that alkalinization of the urine may be a useful therapeutic adjunct.

In clinical studies, a small percentage of animals experienced pain on administration.

Warning

This drug is not to be administered to horses that are to be slaughtered for use in food. For the following species, treated animals must not be slaughtered for use in food after the latest treatment with this drug for at least:

Cows	30 days
Piglets	42 days
Turkey Poults	63 days
Chickens	35 days

Contraindications

A history of hypersensitivity or toxic reactions to gentamicin are contraindications to its use.

Precaution: Pregnancy

Although studies in pregnant animals have not revealed teratogenic effects, caution should be exercised.

Ototoxicity

Gentamicin, in common with the antibiotics streptomycin, neomycin, and kanamycin, has produced ototoxicity in experimental animals and man. This adverse reaction which may be delayed in onset, is manifested primarily by damage to vestibular function. The reversibility of this adverse reaction is frequently contingent upon early recognition of potential ototoxicity. Complete damage has occurred mainly in humans who were uremic, had renal dysfunction, had prior therapy with ototoxic drugs, or received higher doses and longer courses of therapy than those recommended. In animals who have previously been treated with drugs likely to affect eighth cranial nerve function (e.g., streptomycin, neomycin, kanamycin, etc.) GENTOCIN Injectable Solution should be used with caution and with the understanding that toxic effects may be cumulative with these agents.

Nephrotoxicity

Nephrotoxicity, manifested by an elevated blood urea nitrogen or serum creatinine level or a decrease in the creatinine clearance may occur with GENTOCIN Injectable Solution. In most cases, these changes have been reversible when the drug has been discontinued. The administration of other potentially nephrotoxic agents prior to or in conjunction with GENTOCIN Injectable Solution may increase the risk of nephrotoxicity.

In animals with suspected or impaired renal function, daily serum determinations for GENTOCIN Injectable Solution should be carried out to avoid excessive and potentially toxic serum levels of GENTOCIN Injectable Solution.

Neuromuscular Blocking Action

Neuromuscular blockage and respiratory paralysis have been reported in the cat receiving high doses (40 mg/kg) of gentamicin. The possibility of these phenomena occurring should be considered if gentamicin is administered to animals receiving general anesthesia and/or neuromuscular blocking agents such as succinylcholine or tubocurarine. Neuromuscular blocking action by gentamicin in animals may be antagonized by neostigmine or calcium.

Superinfections

As with other antibiotics, treatment with gentamicin may occasionally result in overgrowth of non-sensitive organisms. If superinfection occurs, appropriate measures should be taken.

Side Effects

In humans, adverse reactions have been confined mainly to disturbances in equilibrium and veterinarians should be aware of this possibility.

Symptoms And Treatment Of Overdose

In the event of overdosage or toxic reactions, peritoneal dialysis or hemodialysis will aid in the removal of GENTOCIN Injectable Solution from the blood.

Pharmacology

When gentamicin is administered intramuscularly, peak serum concentrations, bactericidal for susceptible bacteria, occur between 30 and 90 minutes after injection: effective concentrations persist for six to eight hours.

Minimal amounts of gentamicin are absorbed following oral administration. Therefore oral administration is not recommended for treatment of systemic infections. About 25-30% of the administered dose of gentamicin in bound by serum protein: it is released as the drug is excreted, GENTOCIN Injectable Solution is excreted principally in the urine by glomerular filtration. After initial administration to humans with normal renal function, 30-100% of the gentamicin is recoverable in the urine in 24 hours. Renal clearance of GENTOCIN Injectable Solution is similar to that of endogenous creatinine.

Gentamicin has been found in the cerebrospinal fluid after intramuscular injection: however, concentrations have been low and may be inadequate for treatment of certain central nervous system infections.

Gentamicin has also been found in the sputum, pleural fluid and peritoneal cavity. Gentamicin crosses the peritoneal as well as the placental membrane.

GENTOCIN Injectable Solution at considerably higher doses than normally recommended, like other aminoglycoside antibiotics, causes neuromuscular blockage in animals. This phenomenon is antagonized by neostigmine or calcium (See precaution).

Toxicology

GENTOCIN Injectable Solution has been shown to affect vestibular and renal functions in animals and man. Chronic administration of 5 mg/kg for 50 days in dogs, 10 mg/kg for 40 days in cats and 20 mg/kg for 24 days in rats resulted in mild toxicity in some animals studied. Higher toxic doses resulted in renal and vestibular function damage which appeared to be dose related. In humans the only serious side effect to date has been damage to the eighth cranial nerve predominantly the vestibular branch. Proteinuria, a rise in blood urea nitrogen or serum creatinine have also occurred. These findings have usually reverted to normal when the drug was discontinued.

No toxicity was observed in neonatal pigs injected with gentamicin at three times the recommended dose for twice the recommended treatment period. No adverse effects were reported during clinical studies in piglets up to three days of age.

During clinical evaluation no visible signs of toxicity were noted with GENTOCIN Injectable Solution doses as high as 10 mg per poult subcutaneously. The LD50 for day old turkey poults is calculated to be 27.8 mg per male poult and 40.5 mg per female poult.

Compatibility

GENTOCIN Injectable Solution should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

Storage

Store between 2° and 25°C. Protect from freezing.

Dosage Forms

GENTOCIN Injectable Solution 100 mg/mL is packaged in 100 mL multiple dose vials containing 100 mg/mL of gentamicin base in an aqueous solution of a pH of 4.5 for parenteral administration.

Bibliography

1. Weinstein. M.J. & al. Gentamicin, a new broad spectrum antibiotic complex. Antimicrobial Agents and Chemotherapy. 1963, p. 1-7.

2. Black J. & al. Pharmacology of gentamicin a new broad spectrum antibiotic. Antimicrobial Agents and Chemotherapy- 1963, p. 138-147.

3. Finland, M. Gentamicin: Antibacterial activity. clinical pharmacology, and clinical applications. Medical Times 97:161-74.

4. Cox, C.E. Gentamicin, Medical Clinics of North America 54:1305-1315.

5. Sager, F.C. Management and medical treatment of uterine disease. J.A.V.M.A. 153 1567-1569.

6. Peterson, FB. & al. Studies on the pathogenesis of endometritis in the mare. Proc. 151h Ann. Conv. A.A. of E.P. Dec. 69. p. 279-282.

7. Hughes, J.F. & al. The occurrence of Pseudomonas in the reproductive tract of mares and its effect on fertility. The Cornell Veterinarian. Vol. LVI, No. 4, Oct. 66, p. 595-610.

8. Berkman. RH. et al. Gentamicin new broad spectrum antibiotic for treatment of canine urinary tract infections. Schering Corporation. Animal Health Research Centre, Feb. 71.

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Assignment of original copyright by SCHERING CORPORATION.

^® Registered trademark of Schering-Plough Canada Inc.

03-0239INS

S.2260A 07.2005

Nac No.

12080510