Excenel Sterile Powder (Canada)

Company: Zoetis

ceftiofur sodium powder for solution

Veterinary Use Only

broad-spectrum antibiotic

Sterile

DIN 00813567

Description

EXCENEL contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against Gram-positive and Gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro as a result of inhibition of cell wall synthesis.

Medicinal Ingredient: Each mL of reconstituted solution contains 50 mg ceftiofur (as ceftiofur sodium).

Preservative: Benzyl Alcohol 9 mg per mL (in the sterile diluent)

Non-medicinal ingredients:

Sterile Water for injection, 1 qs per mL

Monobasic Potassium Phosphate, 1.388 mg per mL

Sodium hydroxide, 10% qs to pH

Action

Ceftiofur sodium has demonstrated excellent in vitro and in vivo activity against Mannheimia haemolytica and Pasteurella multocida, two of the major pathogenic organisms associated with bovine respiratory disease (pneumonia, shipping fever). This drug has also demonstrated excellent in vitro and in vivo activity against Histophilus somni (Haemophilus somnus) and in vitro activity against Corynebacterium pyogenes, two other bacterial pathogens associated with bovine respiratory disease (BRD). Ceftiofur has demonstrated in vivo and in vitro activity against Fusobacterium necrophorum and Bacteroides melaninogenicus, two of the major pathogenic anaerobic bacteria associated with acute bovine interdigital necrobacillosis (foot rot, pododermatitis). Ceftiofur has excellent in vitro activity against Gram-negative pathogens such as Actinobacillus pleuropneumoniae, Salmonella choleraesuis, Pasteurella multocida and the Gram-positive pathogen Streptococcus suis, all of which singly or in combination can be associated with swine bacterial respiratory disease (swine bacterial pneumonia). Ceftiofur has also demonstrated excellent in vitro and in vivo activity against respiratory pathogens of horses. The drug was very active in vitro against Streptococcus zooepidemicus, S. equi, Streptococcus spp. and Pasteurella spp. isolated from patients with infections. Ceftiofur has demonstrated in vitro and in vivo activity against Mannheimia haemolytica, the major pathogenic bacterium associated with ovine respiratory disease (pneumonia). Ceftiofur has also demonstrated in vivo and in vitro activity against bacterial pathogens from dogs with urinary tract infections. Ceftiofur was more potent (in vitro) than other beta-lactam antibiotics against strains of Escherichia coli and Proteus mirabilis.

In addition, ceftiofur has excellent in vitro activity against other Gram-negative pathogens, such as Proteus vulgaris, Klebsiella pneumoniae, Salmonella typhimurium and some in vitro action against certain strains of Gram-positive pathogens such as Staphylococcus aureus, Staphylococcus xylosus, Staphylococcus simulans, Staphylococcus epidermidis, Streptococcus uberis and Streptococcus bovis. The clinical significance of these findings is not known. Clinical efficacy for the treatment of bovine respiratory disease has been demonstrated on the basis of well controlled multi-location clinical trials involving large numbers of cattle.

Ceftiofur sodium has demonstrated in vitro and in vivo activity against E. coli.

Excenel Sterile Powder Indications

Cattle and lactating dairy cattle:

For treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Haemophilus somnus. For the treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus.

Horses: For treatment of respiratory infections in horses associated with Streptococcus zooepidemicus.

Swine: For treatment of swine bacterial respiratory disease (swine bacterial pneumonia) associated with Actinobacillus pleuropneumoniae and Pasteurella multocida.

Lambs: For treatment of respiratory disease (pneumonia) in lambs associated with Mannheimia haemolytica.

Dogs: For the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis.

Excenel Sterile Powder Dosage And Administration

1 G

EXCENEL should be reconstituted by adding 20 mL of sterile diluent for EXCENEL to each 1 g vial. For ease in reconstitution use an 18 gauge needle or larger.

4 G

EXCENEL should be reconstituted by adding 80 mL of sterile diluent for EXCENEL to each 4 g vial.

Directions for Using Transfer Needle for Reconstitution:

1. Remove stopper overseal from diluent and sterile powder vials.

2. Hold transfer needle case by each end and twist slightly to break paper seal.

3. Pull plastic case apart which will expose the short end of the transfer needle. Insert through rubber stopper of diluent vial.

NOTE: It is imperative that the needle be placed in the diluent vial first. Entry into the sterile powder vial first will result in loss of vacuum and necessitate manual transfer of diluent.

4. Remove other end of plastic case from the transfer needle (needle will remain in the diluent vial).

5. Tipping diluent vial slightly, insert transfer needle through rubber stopper of the sterile powder vial. Quickly invert diluent vial over sterile powder vial. The vacuum should remove all liquid from the diluent vial. Should residual liquid remain in the diluent vial, this must be manually transferred to the sterile powder vial using an appropriate needle and syringe prior to use of the product.

6. Shake solution until complete reconstitution of powder occurs.

Rapid addition of diluent maintained at room temperature will give best results. Normally accepted aseptic technique should be followed during reconstitution to avoid microbial contamination.

A sterile needle and syringe should be used for each injection. Before withdrawing the solution from the bottle, disinfect the rubber cap on the bottle with suitable disinfectant, such as 70 percent alcohol. The injection site should be similarly cleaned with the disinfectant. Needles of 18 gauge and 1 to 1 1/2 inches long are adequate for intramuscular injections.

Administer intramuscular injections by directing the needle of suitable gauge and length into the neck of cattle, horses and swine. Avoid blood vessels and major nerves. Before injecting the solution, pull back gently on the plunger. If blood appears in the syringe, a blood vessel has been entered; withdraw the needle and select a different site. No more than 10 mL should be injected per site.

Cattle and Lactating Dairy Cattle: Reconstituted EXCENEL should be administered by intramuscular injection to cattle at the dosage of 1.0 mg ceftiofur per kg of body weight (1.0 mL per 50 kg body weight). Treatment should be repeated every 24 hours for a total of three treatments. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recovered) after the initial three treatments.

Horses: Reconstituted EXCENEL should be administered by intramuscular injection to horses at a dosage of 2.0 mg ceftiofur per kg of body weight (2.0 mL per 50 kg body weight) and repeated every 24 hours. Treatments should be continued for 48 hours after symptoms have disappeared. If no response is observed within 4 - 5 days, the diagnosis should be re-evaluated.

Swine: Reconstituted EXCENEL should be administered by intramuscular injection to swine at the dosage of 3.0 mg ceftiofur per kg of body weight (1 mL per 17 kg body weight). Treatment should be repeated every 24 hours for a total of three treatments.

Lambs: Reconstituted EXCENEL is to be administered by intramuscular injection at the dosage of 2.0 mg/kg body weight. Treatment should be repeated at 24 hour intervals for a total of three treatments. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recovered) after the initial three treatments.

Dogs: Reconstituted EXCENEL should be administered by subcutaneous injection at a dosage of 2.0 mg ceftiofur per kg of body weight (0.2 mL per 5 kg body weight). Treatment should be repeated at 24-hour intervals for 5 - 14 days.

Contraindications

As with all drugs, the use of EXCENEL is contraindicated in animals previously found to be hypersensitive to the drug. In the event of a hypersensitivity reaction following the administration of this drug, immediate appropriate therapy should be instituted.

CAUTIONS

1. The use of ceftiofur sodium in cattle may result in some signs of immediate and transient local pain at the injection site. If no improvement is seen within 3 - 5 days, redetermine the diagnosis.

2. The administration of antibiotics to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this drug and initiate appropriate therapy.

3. Since safety in breeding swine has not been determined, use in animals intended for breeding is not recommended.

4. For horses, safety in breeding animals and suckling foals (under 6 months of age) has not been established.

5. Reversible thrombocytopenia and anemia have occasionally been observed in dogs treated with ceftiofur for prolonged periods. Thus, the use of this drug is contraindicated in animals with pre-existing signs of these conditions. Prolonged therapy (greater than 14 days) should be undertaken only with appropriate evaluation and monitoring of hematologic values.

6. In dogs, safety in breeding, pregnant, lactating and neonatal animals has not been established.

Warnings

Treated swine and lambs must not be slaughtered for use in food for at least 24 hours after the latest treatment with this drug. No meat withdrawal period or milk withholding time is required in cattle when treated according to the label. Do not use in calves to be processed for veal. This drug is not to be administered to horses that are to be slaughtered for use in food. Antimicrobial drugs, including penicillins and cephalosporins can cause allergic reactions in sensitized individuals. To minimize the possibility of such a reaction, users of such antimicrobial products, including ceftiofur, are advised to avoid direct contact of the product with the skin and mucous membranes. To limit the development of antimicrobial resistance:

● EXCENEL should not be used as a mass medication for cattle, swine or any other species.

● EXCENEL should only be used to treat individual animals as per the indications.

● The choice of EXCENEL as the most appropriate treatment should be confirmed by clinical experience supported where possible by pathogen culture and drug susceptibility testing.

● The extra-label drug use of EXCENEL is not recommended.

KEEP OUT OF REACH OF CHILDREN

Note

Cattle: Use of dosages in excess of those indicated may result in illegal residues in tissues and/or in milk. Residual drug concentrations in milk at all time intervals after last treatment (e.g., 3, 6, 9, 12, 24, etc. to 120 hours) are well below the published Safe Concentration of 1.0 ppm which has been established on the basis of extensive metabolism and toxicity data. Drug residues were not detectable by any of several screening assay procedures commonly used by the dairy industry. Assay procedures used were Delvotest P*, Bacillus stearothermophilus disk assay (BSDA) and the cylinder/plate (M. luteus) assay. Lower limits of detection for microbiologically active residues for these assays, respectively, were 0.05 ppm, 0.08 ppm and 0.015 ppm.

Animal Safety

Cattle:

Results from a 5-day tolerance study in normal feeder calves indicated that formulated ceftiofur sodium was well tolerated at over 55 times (55.0 mg/kg/day) the recommended dose of 1.0 mg/kg/day for 5 consecutive days. Ceftiofur sodium administered intramuscularly had no adverse systemic effects. Local effects of muscle irritation were detected after the last dose (5 consecutive daily doses) as evidenced by significantly elevated aspartate transaminase and creatine phosphokinase values. However, these transient elevated values returned to baseline values 9 days post-treatment.

In a 15-day safety/toxicity study, 5 steer and 5 heifer calves per group were intramuscularly administered formulated ceftiofur sodium at just over 0 (vehicle control), 2, 6, 10 and 20 times the maximum recommended dose of 1.0 mg/kg/day to determine the safety factor and to measure the muscle irritancy potential in the target species. There were no adverse systemic effects indicating that formulated ceftiofur sodium has a wide margin of safety when injected intramuscularly into feeder calves at over 22 times (22.0 mg/kg/day) the recommended dose for 3 times (15 days) the recommended 3 to 5 days of therapy. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at post treatment days 1, 3, 7 and 14.

Horses:

In a safety study, horses received a daily intramuscular injection of either 0 mg/kg/day (saline control), 2.2 mg/kg/day (50 mg/mL), 6.6 mg/kg/day (100 mg/mL), or 11.0 mg/kg/day (200 mg/mL) of an aqueous solution of ceftiofur sodium for 30 or 31 days. Ceftiofur sodium was well tolerated when administered intramuscularly to male and female horses at doses up to 11.0 mg/kg/day for 30 or 31 days. No clinical evidence of irritation was noted at any dose. The drug-related changes detected in this study were limited to a transient decrease in food consumption in horses receiving 6.6 or 11.0 mg/kg/day ceftiofur, and a general mild skeletal muscle irritation at the injection sites of ceftiofur treated horses evident only on gross and histopathological examination.

In a tolerance study, horses received a single daily intravenous infusion of either 0 (saline), 22.0 or 55.0 mg/kg/day of an aqueous solution (50 mg/mL) of ceftiofur for 10 days. The results indicated that ceftiofur administered intravenously at a dose of 22.0 or 55.0 mg/kg/day apparently can change the bacterial flora of the large intestine leading to inflammation of the large intestine with subsequent diarrhea and other clinical signs (loose feces, eating bedding straw, dehydration, rolling or colic and a dull, inactive demeanor). Decreased food consumption, a loss of body weight, hematologic changes related to acute inflammation and stress, and serum chemistry changes related to decreased food consumption and diarrhea were also associated with treatment at these doses. The adverse effects were most severe a few days after dosing was initiated and tended to become less severe towards the end of the 10-day dosing period.

Swine:

Results from a 5-day tolerance study in normal feeder pigs indicated that formulated ceftiofur was well tolerated when administered at 125.0 mg/kg (more than 40 times the recommended daily dosage of 3.0 mg/kg of body weight) for 5 consecutive days. Ceftiofur sodium administered intramuscularly to pigs produced no overt adverse signs of toxicity.

To determine the safety factors and to measure the muscle irritancy potential in swine, a safety/toxicity study was conducted. Five barrows and 5 gilts per group were intramuscularly administered formulated ceftiofur sodium at 0, 5.0, 15.0 and 25.0 mg/kg of body weight for 15 days which is 0, 1.66, 5 and 8.33 times the recommended dose of 3.0 mg/kg of body weight/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects indicating that formulated ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the recommended dose of 3.0 mg/kg/day for 3 days or at levels up to 8.33 times the recommended dose for 5 times the recommended length of treatment. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at post treatment days 1, 2, 3 and 4. By day 10 post injection the muscle reaction was subsiding and at day 15 post injection there was little evidence of muscle damage in any of the pigs in any of the treatment groups.

Lambs:

In a 15-day safety/toxicity study in sheep, 3 wether and 3 ewe lambs per group were given formulated ceftiofur sodium by the intramuscular route 0 (sterile water vehicle), 1, 3 or 5 times the recommended dose of 2.0 mg/kg/day for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in lambs. Based on examination of injection sites from study days 9, 11, 13 and 15, a low incidence of visual changes and histopathologic findings of a mild, reversible inflammation from all groups including the controls indicated that the formulation is a slight muscle irritant.

Dogs:

Ceftiofur sodium was well tolerated at the therapeutic dose and is safe for the treatment of urinary tract infections in dogs. In clinical studies, ceftiofur was well tolerated by dogs at the recommended level (2.0 mg/kg) for 5 - 14 days. In the acute study, minimal inflammation at the injection site was noted when administered subcutaneously for 42 consecutive days. One of four females also developed thrombocytopenia (15 days) and anemia (36 days). Thrombocytopenia and anemia also occurred at the 3X and 5X dose levels. In the reversibility phase of the study (5X dose), the thrombocytopenia reversed within 8 days, and of the two anemic animals, the male recovered within 6 weeks and the female was sacrificed due to the severity of the anemia.

In the 15-day tolerance study in dogs, exaggerated high subcutaneous doses of 25 and 125 times the recommended therapeutic dose produced a progressive and dose-related thrombocytopenia, with some dogs also exhibiting anemia and bone marrow changes. The hematopoietic changes noted in dogs treated with ceftiofur were similar to those associated with long-term cephalosporin administration in dogs and humans. The hematopoietic effects are not expected to occur as a result of recommended therapy.

STORAGE

1. Store unreconstituted product at a temperature between 15 and 30°C.

2. Store reconstituted product at a temperature between 2 and 8°C for up to 7 days, between 15 and 30°C for up to 12 hours, or frozen for up to 8 weeks. Although some breakage may occur with the frozen product, thaw by immersing the vial in hot, running tap water until a clear, ice-free solution is obtained and then use according to label. Do not freeze and thaw reconstituted product more than once.

3. Colour of cake may vary from off-white to tan and does not affect potency.

4. Protect from light.

Presentation

EXCENEL is available in 1 g and 4 g vials.

Zoetis is a trademark and Excenel is a registered trademark of Zoetis or its licensors, used under license by Zoetis Canada Inc.

Zoetis Canada Inc., Kirkland QC H9H 4M7

1627-11-3

40024482

CPN: 1198286.7