Excenel

Zoetis Inc

EXCENEL RTU EZ Ceftiofur Hydrochloride Sterile Suspension

FULL PRESCRIBING INFORMATION: CONTENTS*

• CAUTION
• EXCENEL DESCRIPTION
• INDICATIONS
• EXCENEL DOSAGE AND ADMINISTRATION
  • Cattle:
• EXCENEL CONTRAINDICATIONS
• WARNINGS
• RESIDUE WARNINGS:
• PRECAUTIONS
• CLINICAL PHARMACOLOGY
• MICROBIOLOGY
• EFFECTIVENESS
• ANIMAL SAFETY
• TISSUE RESIDUE DEPLETION
• STORAGE CONDITIONS
• HOW SUPPLIED
• PRINCIPAL DISPLAY PANEL - 100 ML Vial Label
• PRINCIPAL DISPLAY PANEL - 250 ML Vial Label

FULL PRESCRIBING INFORMATION

For intramuscular injection in swine.
For intramuscular and subcutaneous injection 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. Federal law prohibits extra-label use of this drug in cattle and swine for disease prevention purposes; at unapproved doses, frequencies, durations, or routes of administration; and in unapproved major food producing species/production classes.

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, 2.50 mg polyoxyethylene sorbitan monooleate (polysorbate 80), 6.5 mg water for injection in a caprylic/capric triglyceride (Miglyol® 812) 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 well before using.

Swine: Administer intramuscularly at a dosage of 1.36 to 2.27 mg ceftiofur equivalents (CE)/lb (3 to 5 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 intramuscular or subcutaneous administration at the dosage of 0.5 to 1 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 intramuscularly or subcutaneously 1 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 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 intramuscular or subcutaneous administration at the dosage of 1 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

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) or to report any adverse event please call 1-888-963-8471.

For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/AnimalVeterinary/SafetyHealth.

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 4 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.

Intramuscular and 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.

The current EXCENEL RTU EZ Sterile Suspension formulation replaces a previously approved formulation. The previously approved EXCENEL RTU EZ product was a reformulation of another ceftiofur hydrochloride injectable product, EXCENEL RTU Sterile Suspension (NADA 140-890). Comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension or the reformulated EXCENEL RTU EZ Sterile Suspension were demonstrated in a comparative two-treatment, two-period crossover relative bioavailability study in swine. Products were administered via intramuscular (IM) injection into the neck, using alternating sides during periods 1 and 2. A summary of average plasma pharmacokinetic (PK) parameters in swine after a single IM administration of EXCENEL RTU Sterile Suspension and EXCENEL RTU EZ Sterile Suspension at a dose of 2.27 mg CE/lb (5.0 mg CE/kg) BW is provided in Table 1.

The standard bioequivalence (BE) criteria, based upon the exponentiated 90% confidence bounds about the ratio of treatment means, were met for the pivotal bioequivalence parameters, AUC_0-LOQ and C_max, when each formulation was administered to swine IM at a dose rate of 2.27 mg CE/lb (5.0 mg CE/kg) BW (Table 2).

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.

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.

The current EXCENEL RTU EZ Sterile Suspension formulation replaces a previously approved formulation. The previously approved EXCENEL RTU EZ product was a reformulation of another ceftiofur hydrochloride injectable product, EXCENEL RTU Sterile Suspension (NADA 140-890). Comparable plasma concentrations of ceftiofur administered as EXCENEL RTU Sterile Suspension and the reformulated EXCENEL RTU EZ Sterile Suspension were demonstrated in two comparative two-treatment, two-period crossover relative bioavailability studies in cattle. Products were administered via intramuscular (IM) or subcutaneous (SC) injection, using alternating sides of the neck during periods 1 and 2. A summary of average plasma pharmacokinetic (PK) parameters in cattle after a single IM and SC administration of EXCENEL RTU Sterile Suspension and EXCENEL RTU EZ Sterile Suspension at a dose of 1.0 mg CE/lb (2.2 mg CE/kg) BW is provided in Table 3.

The standard bioequivalence (BE) criteria, based upon the exponentiated 90% confidence bounds about the ratio of treatment means, were met for the pivotal bioequivalence parameters, AUC_0-LOQ and C_max, when each formulation was administered to cattle IM or SC at a dose rate of 1.0 mg CE/lb (2.2 mg CE/kg) BW (Table 4).

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 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].

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 5.

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 and C_max. 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 intramuscular or subcutaneous administration in cattle were compared and found to be bioequivalent for AUC_0-LOQ and C_max. 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: Evaluation of target animal safety in swine was based on a PK comparison between the reformulated EXCENEL RTU EZ Sterile Suspension and EXCENEL RTU Sterile Suspension. Ceftiofur administered to swine as the reformulated EXCENEL RTU EZ Sterile Suspension at a dose of 5 mg CE/kg BW by IM injection was demonstrated to be bioequivalent to a corresponding IM injection of EXCENEL RTU Sterile Suspension based upon comparability of their respective AUC_0-LOQ and C_max values (see EFFECTIVENESS section). Because of the demonstrated blood level bioequivalence, this study confirms the systemic safety of the reformulated EXCENEL RTU EZ Sterile Suspension in swine when administered by IM injection at a dose of 5 mg CE/kg BW for three consecutive days.

Injection site tissue tolerance and resolution were evaluated after administering EXCENEL RTU EZ Sterile Suspension by intramuscular injection to 8 young pigs with at least the maximum proposed volume of 5 mL per injection site 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 42 days after the first treatment. No test articlerelated health issues were observed. Mild swelling, erythema, and firmness was observed in a very small number of occasions (≤ 2% of total observations). No swelling was observed from 3 days after the last injection through the end of the study. Grossly visible discoloration of the injection site and histopathologic changes consistent with inflammation were noted in treated pigs necropsied 7 days or 14 days after injection.

Cattle: Evaluation of target animal safety in cattle was based on two PK studies comparing the reformulated EXCENEL RTU EZ Sterile Suspension and EXCENEL RTU Sterile Suspension (one study comparing IM administration and one study comparing SC administration). In both studies, ceftiofur, when administered to cattle at a dose of 2.2 mg CE/kg BW of the reformulated EXCENEL RTU EZ Sterile Suspension, was demonstrated to be bioequivalent to a 2.2 mg CE/kg BW dose of EXCENEL RTU Sterile Suspension (see EFFECTIVENESS section). Because of the demonstrated blood-level bioequivalence, these studies confirm systemic safety of the reformulated EXCENEL RTU EZ Sterile Suspension when administered either IM or SC at a dose of 2.2 mg CE/kg BW for five consecutive days.

Injection site tissue tolerance and lesion resolution were evaluated after administration of the reformulated EXCENEL RTU EZ Sterile Suspension by intramuscular and subcutaneous injections to 16 growing cattle (8 cattle for each route) at the maximum volume of 15 mL per injection site, 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 necropsy (up to 42 days after the first dose). Animals were euthanized on Day 7, 14, 28, or 42 (two calves at each time point). No test article-related health issues were observed. Injection site reactions consisted of firmness and swelling at the injection sites. Injection site swelling was observed in 4/1030 (0.4%) of IM injection site observations and in 606/1029 (58.9%) of SC injection site observations. Swelling progressively decreased over time, and was still present in both animals injected SC that were necropsied on Day 42. Grossly visible discoloration of the injection site and/or histopathologic changes consistent with inflammation were noted through Day 42 in SC and IM 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 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.

Two pivotal tissue residue decline studies were conducted in cattle. Cattle received either a subcutaneous injection or intramuscular injection of 1.0 mg of ceftiofur per lb body weight (2.2 mg per kg body weight). In both studies, ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as the kidney and muscle by 4 days after dosing. These data collectively support a 4-day pre-slaughter withdrawal period when used according to label directions.

STORAGE CONDITIONS

Store at controlled room temperature 20° to 25°C (68° to 77°F); excursions permitted 15° to 40°C (59° to 104°F). Protect from freezing. Shake well before using. Contents should be used within 42 days after the first dose is removed.

HOW SUPPLIED

EXCENEL RTU EZ Sterile Suspension is available in 100 mL and 250 mL vials.

NADA 141-288, Approved by FDA

Revised: March 2013

Distributed by:
Zoetis Inc.
Kalamazoo, MI 49007

14080900

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 intramuscular and subcutaneous injection 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. Federal law prohibits
extra-label use of this drug in cattle and swine for disease
prevention purposes; at unapproved doses, frequencies,
durations, or routes of administration; and in unapproved
major food producing species/production classes.

For Use in Animals Only

NADA 141-288, Approved by FDA

zoetis

14081001
1528000

LOT/EXP

PRINCIPAL DISPLAY PANEL - 250 ML Vial Label

250 ML

EXCENEL ^® RTU EZ
Ceftiofur Hydrochloride
Sterile Suspension

Equivalent to
50 MG PER ML CEFTIOFUR

For intramuscular injection in swine.
For intramuscular and subcutaneous injection 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. Federal law
prohibits extra-label use of this drug in cattle and swine
for disease prevention purposes; at unapproved doses,
frequencies, durations, or routes of administration; and
in unapproved major food producing species/production
classes.

For Use in Animals Only

NADA 141-288, Approved by FDA

zoetis

14081301
1538000

LOT/EXP