Excede Sterile Suspension (Canada)

This page contains information on Excede Sterile Suspension for veterinary use.
The information provided typically includes the following:
  • Excede Sterile Suspension Indications
  • Warnings and cautions for Excede Sterile Suspension
  • Direction and dosage information for Excede Sterile Suspension

Excede Sterile Suspension

This treatment applies to the following species:
Manufacturer: Zoetis

ceftiofur crystalline free acid sterile injectable suspension

Veterinary Use Only

DESCRIPTION: EXCEDE® Sterile Suspension is a ready-to-use formulation that contains ceftiofur crystalline free acid, the designation for 7 - [[2 - (2 - Amino - 4 - thiazolyl) - 2 - (methoxyimino)acetyl]amino] - 3 - [[(2 - furanylcarbonyl)thio]methyl] - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct-2-ene 2-carboxylic acid.

Ceftiofur crystalline free acid 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, resulting from inhibition of cell wall synthesis.

Each mL contains 200 mg ceftiofur equivalents (as ceftiofur crystalline free acid).

Figure 1: The chemical structure of ceftiofur crystalline free acid

INDICATIONS: EXCEDE Sterile Suspension is indicated for the treatment of Bovine Respiratory Disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni (formerly Haemophilus somnus) in beef and non-lactating dairy cattle.

DOSAGE: Administer as a single subcutaneous (SC) injection in the middle third of the posterior aspect of the ear of cattle at a dosage of 6.6 mg ceftiofur equivalents (CE) per kg body weight (1.5 mL per 45 kg body weight).

Most animals will respond to treatment within three to five days. If no improvement is observed, the diagnosis should be reevaluated.

Table 1: Dosing Schedule for EXCEDE Sterile Suspension

Weight (kg)

Weight (lb)

Dose Volume (mL) at 6.6 mg/kg

45

100

1.5

90

200

3.0

135

300

4.5

180

400

6.0

225

500

7.5

270

600

9.0

320

700

10.5

360

800

12.0

410

900

13.5

450

1000

15.0

ADMINISTRATION: Shake well before using. EXCEDE Sterile Suspension is to be administered as a single SC injection in the middle third of the posterior aspect of the ear only, with no more than 10 mL administered per ear. When the full contents of the syringe have been administered correctly, a SC bleb of EXCEDE Sterile Suspension will appear. As with all injectables, apply pressure to the needle insertion point when withdrawing the needle, massaging toward the base of the ear and applying pressure to the site of injection to prevent leak-back and bleeding.

Proper injection technique should be used when administering EXCEDE Sterile Suspension; including adjusting the needle insertion point to avoid major blood vessels, previous implants, ear tags and ear tag holes (see Figure 2) and using a needle of suitable gauge, length and bevel (16 gauge, 1 inch long, 45° bevel). Special care should be taken to avoid inadvertent intra-arterial injection as it has been associated with a high risk of sudden death in cattle.

Figure 2: Diagram of the approximate locations of the major arteries of the posterior aspect of the ear and the recommended needle insertion locations: Site A primary injection site, Site B secondary injection site.

Proper Injection Technique

- Shake bottle vigorously for at least 30 seconds before using. If the bottle is left sitting for more than 5 minutes, shake again to re-suspend the formulation.

- Proper restraint of the animal in a chute is essential.

- The head must be completely immobilized (e.g., with a halter.)

- Avoid using in highly excited animals.

- The injection site should be clean (i.e., free from crusty debris, dirt or manure).

- The ear should be clipped, if necessary, to help locate the injection site and avoid blood vessels. Blood vessels on the posterior aspect of the ear must be clearly visible prior to injection.

- Do not use this product unless blood vessels are clearly visible as injection of EXCEDE Sterile Suspension in the arteries of the ear is likely to cause death.

- If the ears are frostbitten and/or any other reason that prevents injection into the middle third of the ear, EXCEDE Sterile Suspension should not be used.

- A needle with a 45° bevel must be used as it is less likely to penetrate a blood vessel than a standard, sharper needle with a 21-28° bevel. A syringe with an eccentric hub is preferable.

- The bevel of the needle should be facing away from the skin of the posterior aspect of the ear and the syringe should be held almost parallel to the ear, with the hub placed against the skin.

- The needle (1 inch long; 16 gauge) should be inserted at the junction of the middle and outer third of the ear to ensure correct product deposition in the middle third of the ear. Avoid bending the ear when inserting the needle.

- The full length of the one-inch needle should be inserted under the skin.

- Avoid implanting (growth promoting implants) and injecting (EXCEDE Sterile Suspension) in the exact same location. Select an injection location at least one finger width from an implant or tag.

- If the animal moves and the skin is penetrated, relocate the new injection to avoid product leakage.

- Inject slowly. In cold weather, keep at room temperature to improve syringeability and ease of administration.

- Watch for a SC bleb to develop. If a bleb does not form, stop immediately and move to a new injection site on the same ear, or inject the other ear.

- Reevaluate technique if significant bleeding or leakage occurs.

For additional guidance on the proper injection technique and on the availability of needles with a 45° bevel please contact Pfizer Animal Health, Pfizer Canada Inc. at toll-free 1-800-461-0917.

Clinical Pharmacology

Cattle: Ceftiofur administered as either ceftiofur sodium (EXCENEL® brand of ceftiofur sodium sterile powder), ceftiofur hydrochloride (EXCENEL® RTU brand of ceftiofur hydrochloride sterile suspension) or ceftiofur crystalline free acid (EXCEDE Sterile Suspension) is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Administration of ceftiofur to cattle as ceftiofur crystalline free acid provides effective concentrations of ceftiofur and desfuroylceftiofur-related metabolites in plasma above the MIC90 for BRD label pathogens Pasteurella multocida, Mannheimia haemolytica and Histophilus somni for generally not less than 150 hours (6 1/4 days) after a single administration (see Figure 3).

Figure 3: Average plasma concentration of ceftiofur- and desfuroylceftiofur-related metabolites after administration of EXCEDE Sterile Suspension at 6.6 mg CE/kg SC in the posterior aspect of the ear of cattle.

Table 2: Pharmacokinetic parameters measured after a single SC administration of 6.6 mg CE/kg body weight (BW) of EXCEDE Sterile Suspension in the posterior aspect of the ear of cattle are presented in the following table.

Pharmacokinetic Parameter

Mean Value ± Standard Deviation

Cmax (µg/mL)

6.90 ± 2.68

tmax (h)

12.1 ± 6.1

AUC 0-LOQ (µg•h/mL)

376 ± 66.1

t>0.2 (h)

183 ± 40.8

t1/2 (h)

62.3 ± 13.5

Cmax = maximum plasma concentration (in µg CE/mL)

tmax = the time after injection when Cmax occurs (in hours)

AUC0-LOQ = the area under the plasma concentration vs. time curve from time of injection to the limit of quantitation of the assay (0.15 µg CE/mL)

t>0.2 = the time plasma concentrations remain above 0.2 µg CE/mL (in hours)

t1/2 = terminal phase biological half life (in hours)

MICROBIOLOGY: Ceftiofur has demonstrated in vitro and in vivo activity against Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, the three major pathogenic bacteria associated with BRD.

A summary of minimum inhibitory concentrations (MIC) for various cattle pathogens is presented in Table 3. Isolates from 1988-1992 were obtained in the United States and Canada while isolates from 1997-1998 and 1998-2002 were obtained in the United States. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines.1

Table 3:

*Species

N

MIC Range
(µg/mL)

MIC90
(µg/mL)

Date tested

Mannheimia haemolytica

461

≤0.03-0.13

≤0.06

1988-1992

Pasteurella multocida

318

≤0.03-0.25

≤0.06

1988-1992

Histophilus somni

109

≤0.03-0.13

≤0.06

1988-1992

Mannheimia haemolytica

110

≤0.03-0.25

≤0.06

1997-1998

Pasteurella multocida

107

≤0.03-0.25

≤0.03

1997-1998

Histophilus somni

48

≤0.03-0.25

≤0.03

1997-1998

Mannheimia haemolytica

638

≤0.03-0.5

≤0.03

1998-2002

Pasteurella multocida

733

≤0.03-0.5

≤0.03

1998-2002

Histophilus somni

349

≤0.03-0.13

≤0.03

1998-2002

* Clinical isolates supported by clinical data and indications for use.

The minimum inhibitory concentration for 90% of the strains.

Ceftiofur breakpoints have been established for bacterial BRD pathogens for ceftiofur based on pharmacokinetic studies conducted with ceftiofur sodium and hydrochloride in cattle after a single intramuscular injection of 2.2 mg CE/kg BW in cattle, and the MIC and disk (30 µg) diffusion data. The following breakpoints are recommended by CLSI.

Zone Diameter (mm)

MIC (µg/mL)

Interpretation

≥21

≤2.0

(S) Susceptible

18-20

4.0

(I) Intermediate

≤17

>8.0

(R) Resistant

“Susceptible” or “S” indicates that the pathogen is likely to be inhibited by generally achievable blood concentrations after treatment with ceftiofur sodium, ceftiofur hydrochloride or ceftiofur crystalline free acid. “Intermediate” or “I” is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. “Resistant” or “R” indicates that the achievable drug concentrations are unlikely to be inhibitory and other therapy should be selected.

Standardized procedures1 require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strains. Ceftiofur sodium disks or powder reference standard are appropriate for both ceftiofur salts and ceftiofur crystalline free acid.

QC Strain

MIC (µg/mL)

Disk Zone Diameter (mm)

E. coli ATCC 25922

0.25-1

24-30

EFFICACY: The efficacy of EXCEDE Sterile Suspension was evaluated in several well-controlled clinical efficacy studies.

In a Mannheimia haemolytica challenge model study, EXCEDE Sterile Suspension administered as a single SC dose in the middle third of the posterior aspect of the ear was shown to be an effective treatment for induced bovine pneumonic pasteurellosis. All treatments were administered SC in the middle third of the posterior aspect of the ear. An EXCEDE Sterile Suspension dose range of 4.4 to 6.6 mg CE/kg was selected for further field testing.

A field dose confirmation study for the treatment of BRD evaluated the efficacy of single doses of 4.4 to 6.6 mg CE/kg BW for the treatment of the bacterial component of BRD under field conditions. All treatments were administered SC in the middle third of the posterior aspect of the ear. Cattle were clinically evaluated on days 2-4, 14 and 28 and were observed on all other study days. The 6.6 mg/kg EXCEDE Sterile Suspension dose significantly (P < 0.05) increased day 14 treatment success rate, defined as animals that did not require any ancillary treatment and had a rectal temperature of < 40°C, normal respiration index, and had no or mild depression on that day.

ANIMAL SAFETY: After parenteral administration, EXCEDE Sterile Suspension, ceftiofur sodium and ceftiofur hydrochloride accede to the same principal metabolite, desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate to evaluate the systemic safety of EXCEDE Sterile Suspension. Results from a five-day tolerance study conducted with ceftiofur sodium in normal feeder calves indicated that ceftiofur was well tolerated at 55 mg CE/kg/day for five consecutive days, approximately 8 times the label recommended dose of ceftiofur crystalline free acid (6.6 mg CE/kg). Ceftiofur administered parenterally had no adverse systemic effects.

In a 15-day safety/toxicity study, five steer and five heifer calves per group were administered ceftiofur sodium intramuscularly at 0 (vehicle control), 2.2, 6.6, 11 or 22 mg CE/kg/day. This represents up to 3.3 times the label recommended dose of EXCEDE Sterile Suspension of 6.6 mg CE/kg. There were no adverse systemic effects, indicating that ceftiofur has an adequate margin of safety when injected intramuscularly into feeder calves. Local tissue tolerance to subcutaneous injection of ceftiofur crystalline free acid in the posterior aspect of the ear of cattle was evaluated in a separate study.

In approximately 7,000 tested animals, nine animals have died following injection of EXCEDE Sterile Suspension. All deaths were within 30 minutes of the time of injection. The exact cause was confirmed in three animals. These deaths resulted from inadvertent intra-arterial injection of this oil-based suspension into one of the two major auricular (ear) arteries. Intra-arterial injection of EXCEDE Sterile Suspension at this location is believed to result in the delivery of the oil-based formulation to the brain through retrograde circulation resulting in embolism and death. Three additional cases of sudden death are likely to have resulted from inadvertent intravascular injection, for a total of six (out of nine) sudden death cases associated with inadvertent intravascular administration.

Since intra-arterial injection was confirmed in three animals that died following injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-arterial injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Two heifers (BW approximately 225 kg) were given a single 6.6 mg CE/kg bolus dose of EXCEDE Sterile Suspension in the middle auricular artery. Both heifers collapsed immediately and died within approximately eight minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will result in death and must be avoided.

As a subcutaneous injection in the ear may potentially result in inadvertent intravenous administration of an injectable product, the consequences of purposeful intravenous injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Three heifers and three steers (BW range 197-223 kg) were given a single 6.6 mg CE/kg bolus dose of EXCEDE Sterile Suspension in the jugular vein and were monitored for adverse effects following injection. One steer and one heifer had transient (2 - 5 minutes) increases in heart rate without any other untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile Suspension is an unacceptable route of administration.

A study was designed and conducted to specifically address tissue tolerance in cattle when EXCEDE Sterile Suspension was administered as a single SC injection into the middle third of the posterior aspect of the ear of cattle at the recommended dose of 6.6 mg CE/kg BW. Results from this study indicate that the SC injection of EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial increase in thickness is attributed to the space required for the volume of injected material. Additional increases in thickness were observed through day 14 after injection. After day 14 post injection ear thickness decreased in all animals. One animal carried an injected ear in a drooping position for 7 days post injection. At necropsy, SC areas of discoloration and some foci of hemorrhage were observed in ears of injected cattle. The discoloration was markedly reduced in size by the end of the study. No signs of irritation were observed on the edible portions of the carcass around the base of the ear.

The local tolerance of the ear of cattle to a single SC injection of EXCEDE Sterile Suspension was also evaluated in a large multilocation field efficacy study. None of the 1924 animals treated with EXCEDE Sterile Suspension were removed from this trial due to ear irritation although swelling was noted at some injection sites. Leak back and/or bleeding from the injection site was observed immediately after administration in approximately 5% of the 960 animals treated at the recommended dose of 6.6 mg CE/kg BW. It was concluded that administration of EXCEDE Sterile Suspension in the middle third of the posterior aspect of the ear was well tolerated and was acceptable under feedlot conditions.

A study evaluated the 56-day feedlot performance of beef steers administered EXCEDE Sterile Suspension alone, EXCEDE Sterile Suspension with a growth promoting implant, growth promoting implant alone or neither product in a total of 207 Angus and Angus cross-bred steers. The administration of EXCEDE Sterile Suspension in the posterior aspect of the ear with growth promoting implants did not adversely affect feedlot cattle performance, as measured by average daily gain and feed efficiency, when compared to cattle that received only the growth promoting implant. Administration of EXCEDE Sterile Suspension in the middle third of the posterior aspect of the ear with or without growth promoting implants was well tolerated by cattle. However, the location of injection or implantation should be adjusted slightly within the boundaries of the middle third of the posterior aspect to avoid implanting and injecting in the exact same location.

ADVERSE EFFECTS: During the conduct of clinical studies, nine out of approximately 7,000 animals died suddenly following administration of EXCEDE Sterile Suspension in the ear. Three of these deaths were confirmed to be the result of inadvertent intra-arterial injection. Three additional cases of sudden death are likely to have resulted from inadvertent intravascular injection, for a total of six (out of nine) sudden death cases associated with inadvertent intravascular administration. No other adverse systemic events were noted for either the antibiotic or formulation during any of the clinical and target animal safety studies.

REPORTING SUDDEN DEATH CASES: Veterinarians should report any suspected adverse drug reaction, including deaths occurring within 60 minutes of product administration and deaths preceded by recumbency and neurological signs, to Pfizer Animal Health, Pfizer Canada Inc. at toll free 1-800-461-0917. Non-veterinarians should report any suspected adverse drug reaction, including cases of sudden death, to their veterinarian.

Warning

- Treated cattle must not be slaughtered for use in food for at least 3 days after the latest treatment with this drug.

- Do not use in dairy cows 20 months of age or older.

- Use of dosages in excess of those indicated or administration by unapproved routes such as subcutaneous in the neck, intramuscular or intramammary may lead to illegal residues.

- Do not use in veal calves. The withdrawal period has not been established in pre-ruminating calves.

- 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 potential development of antimicrobial resistance:

- EXCEDE Sterile Suspension should not be used as a mass medication for feedlot cattle.

- EXCEDE Sterile Suspension should only be used for treating individual cases of bovine respiratory disease.

- The choice of EXCEDE Sterile Suspension as the most appropriate treatment should be confirmed by clinical experience supported where possible, by pathogen culture and drug susceptibility testing.

- The extra-label use of EXCEDE Sterile Suspension is not recommended.

- Not for human use.

- KEEP OUT OF REACH OF CHILDREN.

Contraindications

The use of EXCEDE Sterile Suspension is contraindicated in animals previously found to be hypersensitive to the drug.

CAUTION: Administration of EXCEDE Sterile Suspension into the arteries of the ear is likely to result in sudden death to the animal.

Following subcutaneous injection in the middle third of the posterior aspect of the ear, thickening and swelling (characterized by aseptic cellular infiltrate) of the ear may occur./ As with other parenteral injections, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence.

Storage

Store at a temperature between 15° and 25°C. Once broached, contents should be used within 12 weeks.

PRESENTATION: EXCEDE Sterile Suspension is available in a 100 mL vial.

DIN 02292149

1Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals; Proposed Standard. CLSI Document M31-A (ISBN 1-56238-377-9). CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1832, 1999.

® Registered trade-mark of Pharmacia & Upjohn Company LLC; Pfizer Canada Inc., licensee.

Pfizer Animal Health, Pfizer Canada Inc., Kirkland QC H9J 2M5

804 061 001

694073

NAC No.: 11983363

ZOETIS CANADA
17,300 TRANS-CANADA HIGHWAY, KIRKLAND, QC, H9J 2M5
Order Desk:   800-663-8888
Technical Services Canada:   800-461-0917
Technical Services USA:   800-366-5288
Website:   www.zoetis.ca
Every effort has been made to ensure the accuracy of the Excede Sterile Suspension information published above. However, it remains the responsibility of the readers to familiarize themselves with the product information contained on the Canadian product label or package insert.

Copyright © 2014 North American Compendiums. Updated: 2014-04-11

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