Excenel

Pharmacia and Upjohn Company

EXCENEL RTU EZ (ceftiofur hydrochloride) Sterile Suspension

FULL PRESCRIBING INFORMATION: CONTENTS*

• CAUTION
• EXCENEL DESCRIPTION
• INDICATIONS
  • Swine
  • Cattle
• EXCENEL DOSAGE AND ADMINISTRATION
  • Swine
  • Cattle
• EXCENEL CONTRAINDICATIONS
• WARNINGS
• RESIDUE WARNINGS
  • Swine
  • Cattle
• PRECAUTIONS
• CLINICAL PHARMACOLOGY
  • Swine
  • Cattle
• MICROBIOLOGY
• EFFECTIVENESS
  • Swine
  • Cattle
• ANIMAL SAFETY
  • Swine
  • Cattle
• TISSUE RESIDUE DEPLETION
  • Swine
  • Cattle
• STORAGE CONDITIONS
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL - 100 mL Vial Label

FULL PRESCRIBING INFORMATION

For intramuscular injection in swine.

For subcutaneous injection only in cattle. This product may be used in lactating dairy cattle.

Not for use in calves to be processed for veal.

CAUTION

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

EXCENEL DESCRIPTION

EXCENEL RTU EZ Sterile Suspension is a ready to use formulation that contains the hydrochloride salt of ceftiofur, which is a broad spectrum cephalosporin antibiotic. Each mL of this ready-to-use sterile suspension contains ceftiofur hydrochloride equivalent to 50 mg ceftiofur in a caprylic/capric triglyceride (Miglyol®) suspension.

Figure 1. Structure:

Chemical Name of Ceftiofur Hydrochloride: 5-Thia-1-azabicyclo[4,2.0]oct-2-ene-2-carboxylic acid, 7-[[(2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-3-[[(2-furanylcarbonyl)thio]methyl]-8-oxo-,hydrochloride salt [6R-[6α,7β(Z)]]-

INDICATIONS

Swine

EXCENEL RTU EZ Sterile Suspension is indicated for treatment/control of swine bacterial respiratory disease (swine bacterial pneumonia) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Salmonella Choleraesuis and Streptococcus suis.

Cattle

EXCENEL RTU EZ Sterile Suspension is indicated for treatment of the following bacterial diseases:

— Bovine respiratory disease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni.

— Acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus.

— Acute metritis (0 to 14 days post-partum) associated with bacterial organisms susceptible to ceftiofur.

EXCENEL DOSAGE AND ADMINISTRATION

Shake thoroughly prior to use. Visually assure contents are fully resuspended.

Swine

Administer intramuscularly at a dosage of 1.36 to 2.27 mg ceftiofur equivalents (CE)/lb (3.0 to 5.0 mg CE/kg) body weight (BW) (1 mL of sterile suspension per 22 to 37 lb BW). Treatment should be repeated at 24 hour intervals for a total of three consecutive days. Do not inject more than 5 mL per injection site.

Cattle

— For bovine respiratory disease and acute bovine interdigital necrobacillosis: administer by subcutaneous administration at the dosage of 0.5 to 1.0 mg CE/lb (1.1 to 2.2 mg CE/kg) BW (1 to 2 mL sterile suspension per 100 lb BW). Administer daily at 24 hour intervals for a total of three consecutive days. Additional treatments may be administered on Days 4 and 5 for animals which do not show a satisfactory response (not recovered) after the initial three treatments. In addition, for BRD only, administer subcutaneously 1.0 mg CE/lb (2.2 mg CE/kg) BW every other day on Days 1 and 3 (48 hour interval). Do not inject more than 15 mL per injection site.

Selection of dosage level (0.5 to 1.0 mg CE/lb) and regimen/duration (daily or every other day for BRD only) should be based on an assessment of the severity of disease, pathogen susceptibility and clinical response.

— For acute post-partum metritis: administer by subcutaneous administration at the dosage of 1.0 mg CE/lb (2.2 mg CE/kg) BW (2 mL sterile suspension per 100 lb BW). Administer at 24 hour intervals for five consecutive days. Do not inject more than 15 mL per injection site.

EXCENEL CONTRAINDICATIONS

As with all drugs, the use of EXCENEL RTU EZ Sterile Suspension is contraindicated in animals previously found to be hypersensitive to the drug.

WARNINGS

NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN.

Penicillins and cephalosporins can cause allergic reactions in sensitized individuals. Topical exposures to such antimicrobials, including ceftiofur, may elicit mild to severe allergic reactions in some individuals. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the product with the skin, eyes, mouth and clothing.

Persons with a known hypersensitivity to penicillin or cephalosporins should avoid exposure to this product.

In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If allergic reaction occurs (e.g., skin rash, hives, difficult breathing), seek medical attention.

The material safety data sheet contains more detailed occupational safety information. To obtain a material safety data sheet (MSDS) please call 1-800-733-5500. To report any adverse event please call 1-800-366-5288.

RESIDUE WARNINGS

Swine

When used according to label indications, dosage and route of administration, treated swine must not be slaughtered for 4 days following the last treatment. Use of dosages in excess of those indicated or by unapproved routes of administration may result in illegal residues in edible tissues.

Cattle

When used according to label indications, dosage and route of administration, treated cattle must not be slaughtered for 3 days following the last treatment. When used according to label indications, dosage and route of administration, a milk discard time is not required. Uses of dosages in excess of those indicated or by unapproved routes of administration, such as intramammary, may result in illegal residues in edible tissues and/or milk. A withdrawal period has not been established in pre-ruminating calves. Do not use in calves to be processed for veal.

PRECAUTIONS

The effects of ceftiofur on cattle and swine reproductive performance, pregnancy and lactation have not been determined.

Subcutaneous injection in cattle and intramuscular injection in swine can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter.

CLINICAL PHARMACOLOGY

Swine

Ceftiofur administered as either ceftiofur sodium or ceftiofur hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Administration of ceftiofur to swine as either the sodium or hydrochloride salt provides effective concentrations of ceftiofur and desfuroylceftiofur metabolites in plasma above the lowest minimum inhibitory concentration to encompass 90% of the most susceptible isolates (MIC₉₀) for the labeled pathogens: Actinobacillus pleuropneumoniae, Pasteurella multocida, Streptococcus suis and Salmonella Choleraesuis for the 24 hour period between the dosing intervals. The MIC₉₀ for Salmonella Choleraesuis (1.0 µg/mL) is higher than the other three pathogens and plasma concentrations exceed this value for the entire dosing interval only after the 2.27 mg/lb (5.0 mg/kg) BW dose.

Comparative Bioavailability Summary

Comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or the revised EXCENEL RTU EZ Sterile Suspension were demonstrated in a comparative bioavailability pharmacokinetic (PK) study in swine. Following an intramuscular administration of EXCENEL RTU Sterile Suspension (reference article) or the revised EXCENEL RTU EZ Sterile Suspension (test article), the bioequivalence criteria were met for the AUC_0-LOQ, C_max, and T_>0.2 when both formulations were administered to swine at a dose rate of 2.27 mg CE/lb (5.0 mg CE/kg) BW.

In another comparative bioavailability PK study (previously reviewed under NADA 140-890), comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as NAXCEL Sterile Powder were demonstrated when each product was administered intramuscularly at the upper end of the label dose range [2.27 mg CE/lb (5.0 mg CE/kg) BW]. The bioequivalence criteria were met for the AUC_0-LOQ, C_max, and T_>0.2 when both products were administered by an intramuscular injection to swine at a dose rate of 5.0 mg CE/kg BW.

Figure 2. Average swine plasma concentrations of ceftiofur and desfuroylceftiofur metabolites following an intramuscular administration of 2.27 mg CE/lb (5.0 mg CE/kg) BW, as either EXCENEL RTU Sterile Suspension or the revised EXCENEL RTU EZ Sterile Suspension.

Cattle

Ceftiofur administered as either ceftiofur sodium or ceftiofur hydrochloride is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Administration of ceftiofur to cattle as either the sodium or hydrochloride salt provides effective concentrations of ceftiofur and desfuroylceftiofur metabolites in plasma above the MIC₉₀ for the label BRD pathogens Mannheimia haemolytica, Pasteurella multocida and Histophilus somni for at least 48 hours. The relationship between plasma concentrations of ceftiofur and desfuroylceftiofur metabolites above the MIC₉₀ in plasma and effectiveness has not been established for the treatment of bovine interdigital necrobacillosis (foot rot) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus.

Comparative Bioavailability Summary

Comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or the revised EXCENEL RTU EZ Sterile Suspension were demonstrated in a comparative bioavailability PK study in cattle. Following a subcutaneous administration of EXCENEL RTU Sterile Suspension (reference article) or the revised EXCENEL RTU EZ Sterile Suspension (test article), the bioequivalence criteria were met for the AUC_0-LOQ and T_>0.2 when both products were administered by a subcutaneous injection of 1.0 mg CE/lb (2.2 mg CE/kg) BW.

In other comparative bioavailability PK studies in cattle (previously reviewed under NADA 140-890), comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as NAXCEL Sterile Powder were demonstrated when each product was administered intramuscularly or subcutaneously at the approved dose range of ceftiofur sodium [0.5 to 1.0 mg CE/lb (1.1 to 2.2 mg CE/kg) BW].

Figure 3: Average cattle plasma concentrations of ceftiofur and desfuroylceftiofur metabolites following a subcutaneous administration of 1.0 mg CE/lb (2.2 mg CE/kg) BW, as either EXCENEL RTU Sterile Suspension or the revised EXCENEL RTU EZ Sterile Suspension.

MICROBIOLOGY

EXCENEL RTU EZ Sterile Suspension is a ready-to-use formulation that contains the hydrochloride salt of ceftiofur. Ceftiofur is a broad-spectrum cephalosporin antibiotic active against Gram-positive and Gram-negative bacteria. Like other cephalosporins, ceftiofur is predominantly bactericidal in vitro, resulting in the inhibition of cell wall synthesis. In vitro activity of ceftiofur has been demonstrated against Actinobacillus pleuropneumoniae, Pasteurella multocida, and Salmonella Choleraesuis, three pathogens associated with swine respiratory disease. Similarly, in vitro activity of ceftiofur has been demonstrated against Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, the three major pathogens associated with bovine respiratory disease, and against Fusobacterium necrophorum and Bacteroides melaninogenicus, pathogenic anaerobic bacteria associated with bovine foot rot.

Utilizing data that included isolates from swine and cattle affected by respiratory disease, zone diameter and minimum inhibitory concentration (MIC) breakpoints were determined using standardized procedures from the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee of Clinical Laboratory Standards) M31-A2. The CLSI-accepted interpretive criteria for ceftiofur against these Gram-negative pathogens are shown in Table 3.

EFFECTIVENESS

Swine

Plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension following intramuscular administration in swine were compared and found to be bioequivalent for AUC_0-LOQ, C_max, and T_>0.2. Therefore, EXCENEL RTU EZ Sterile Suspension has the same effectiveness profile as previously established for EXCENEL RTU Sterile Suspension. Because the effectiveness of cephalosporin antibiotics is dependent upon time above MIC, EXCENEL RTU EZ Sterile Suspension is considered effective for the treatment/control of swine respiratory disease.

Cattle

Plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension following subcutaneous administration in cattle were compared and found to be bioequivalent for AUC_0-LOQ and T_>0.2. Therefore, EXCENEL RTU EZ Sterile Suspension has the same effectiveness profile as previously established for EXCENEL RTU Sterile Suspension. Because the effectiveness of cephalosporin antibiotics is dependent upon time above MIC, EXCENEL RTU EZ Sterile Suspension is considered effective for the labeled indications.

ANIMAL SAFETY

Swine

Plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension were demonstrated to be bioequivalent (see CLINICAL PHARMACOLOGY). After parenteral administration, both ceftiofur sodium (as NAXCEL Sterile Powder) and ceftiofur hydrochloride are rapidly metabolized to desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate for determining the systemic safety of EXCENEL RTU EZ Sterile Suspension. Results from a tolerance study (57 mg CE/lb BW per day for five consecutive days) and a toxicity study (2.27, 6.81, or 11.36 mg CE/lb BW per day for 15 consecutive days) conducted with ceftiofur sodium in healthy feeder pigs indicated that ceftiofur was safe.

Injection site tissue tolerance and resolution were evaluated after administration of EXCENEL RTU EZ Sterile Suspension by intramuscular injection to 12 young pigs at 2.27 mg CE/lb BW once daily for three consecutive days. Each injection was administered in a different location on the neck, and injection sites alternated between the left and right sides. General health and injection sites were evaluated through 14 days after the last treatment. No test article-related health issues were observed. Mild swelling was present in all pigs on the day after each injection. Firmness (associated with swelling) was also reported in most early post-treatment observations. By the end of the study, only three injection sites had visible swelling or firmness noted.

Cattle

Plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or as EXCENEL RTU EZ Sterile Suspension were demonstrated to be bioequivalent (see CLINICAL PHARMACOLOGY). After parenteral administration, both ceftiofur sodium (as NAXCEL Sterile Powder) and ceftiofur hydrochloride are rapidly metabolized to desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate for determining the systemic safety of EXCENEL RTU EZ Sterile Suspension. Results from a tolerance study (25 mg CE/lb BW per day for five consecutive days) and a toxicity study (1, 3, 5, or 10 mg CE/lb BW per day for 15 consecutive days) conducted with ceftiofur sodium in healthy feeder calves indicated that ceftiofur was safe.

Injection site tissue tolerance and resolution were evaluated after administration of EXCENEL RTU EZ Sterile Suspension by subcutaneous injection to 12 calves at 2.2 mg CE/kg BW once daily for five consecutive days. Each injection was administered in a different location on the neck, and injection sites alternated between the left and right sides. General health and injection sites were evaluated through 29 days after the last treatment. No test article-related health issues were observed. Injection site reactions consisted of firmness and swelling at the injection sites. Injection site swelling was most prominent the day after injection but showed substantial regression by the following week. At the end of the study, mild swelling was still present at all injection sites.

TISSUE RESIDUE DEPLETION

Swine

Radiolabeled residue metabolism studies established tolerances for ceftiofur residues in swine kidney, liver and muscle. The tolerances for ceftiofur residues are 0.25 ppm in kidney, 3.0 ppm in liver and 2.0 ppm in muscle.

A pivotal tissue residue decline study was conducted in swine. In this study, pigs received 2.27 mg of ceftiofur per lb body weight (5 mg of ceftiofur per kg body weight) per day for three consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as kidney, liver and muscle by 4 days after dosing. These data collectively support a 4-day pre-slaughter withdrawal period in swine when used according to label directions.

Cattle

A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. A separate study established the tolerance for ceftiofur residues in milk. The tolerances for ceftiofur residues are 0.4 ppm in kidney, 2.0 ppm in liver, 1.0 ppm in muscle and 0.1 ppm in milk.

A pivotal tissue residue decline study was conducted in cattle. In this study, cattle received a subcutaneous injection of 1.0 mg of ceftiofur per lb body weight (2.2 mg of ceftiofur per kg body weight) for five consecutive days. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in kidney and muscle by 3 days after dosing. These data collectively support a 3-day pre-slaughter withdrawal period in cattle when used according to label directions.

STORAGE CONDITIONS

Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect from freezing. Store upright. Shake thoroughly prior to use. Visually assure contents are fully resuspended.

HOW SUPPLIED

EXCENEL RTU EZ Sterile Suspension is available in 100 mL vials.

NADA 141-288, Approved by FDA

U.S. Patent Nos. 4,902,683; 5,736,151

April 2008

820 893 000
694103

PRINCIPAL DISPLAY PANEL - 100 mL Vial Label

100 mL

EXCENEL ^® RTU EZ
(ceftiofur hydrochloride)
Sterile Suspension

Equivalent to
50 mg per mL
ceftiofur

For intramuscular injection in swine.

For subcutaneous injection only in cattle. This
product may be used in lactating dairy cattle.

Not for use in calves to be processed for veal.

Caution: Federal (USA) law restricts this drug to use
by or on the order of a licensed veterinarian.

For Use in Animals Only

NADA 141-288, Approved by FDA

Pfizer