Comparative Bioavailability Summary

The current CEFTIVAAN RTU EZ Sterile Suspension formulation replaces a previously approved formulation. The previously approved CEFTIVAAN 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 CEFTIVAAN 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 CEFTIVAAN RTU EZ Sterile Suspension at a dose of 2.27 mg CE/lb (5 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, AUC0-LOQ and Cmax, when each formulation was administered to swine IM at a dose rate of 2.27 mg CE/lb (5 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 AUC0-LOQ, Cmax, and t>0.2 when both products were administered by an intramuscular injection to swine at a dose rate of 5 mg CE/kg BW.

The effectiveness of injection site volumes greater than 5 mL to 15 mL was supported by a comparison of the length of time (hours) that plasma concentrations remained above 0.2 μg/mL (t>0.2) between injection site volumes less than or equal to 5 mL and injection site volumes greater than 5 mL to 12 mL. Statistical analysis allowed for an extrapolation of these findings to 15 mL per site. The pharmacokinetic data demonstrated that 5 mg/kg administered IM at injection volumes from greater than 5 mL to 15 mL resulted in acceptable t>0.2 for the indication.

Comparative Bioavailability Summary

The current CEFTIVAAN RTU EZ Sterile Suspension formulation replaces a previously approved formulation. The previously approved CEFTIVAAN 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 CEFTIVAAN 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 CEFTIVAAN 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, AUC0-LOQ and Cmax, when each formulation was administered to cattle IM or SC at a dose rate of 1 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 mg CE/lb (1.1 to 2.2 mg CE/kg) BW].

MICROBIOLOGY

CEFTIVAAN 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.