TECHNICAL BULLETIN. Comparative Impact of Draxxin Arrival Metaphylaxis on BRD First-Treatment Success DRX December 2014.

Transcription

1 DRX TECHNICAL BULLETIN December 2014 Comparative Impact of Draxxin Arrival Metaphylaxis on BRD First-Treatment Success Zoetis Florham Park, NJ In 12 studies, 1-10 feedlot cattle that received Draxxin metaphylaxis demonstrated greater rates of initial BRD treatment success. T Summary A retrospective review of 12 metaphylaxis research studies 1-10 was conducted to compile data regarding the success of initial BRD treatment for feedlot/stocker cattle that had previously received arrival metaphylaxis with Draxxin (tulathromycin). Most studies compared Draxxin and a single other metaphylaxis product, but 4 studies evaluated 3 metaphylaxis treatment groups (Draxxin vs 2 other agents). Studies included in the data compilation were high-quality trials conducted by universities or veterinary research/consultant groups and often commissioned by Zoetis or other pharmaceutical companies. In each study, the Draxxin metaphylaxis treatment group generated a greater BRD first-treatment success rate than the comparative metaphylaxis agent(s). The success-rate advantages for Draxxin metaphylaxis (in absolute percentages) ranged from 1.0% 4 to 22.4%. 3 The consistent trend for favorable Draxxin metaphylaxis outcomes in regard to BRD first-treatment success is notable (any anecdotal field perceptions that suggest otherwise were not supported by any of the studies). he perpetual effort to reduce financial losses associated with bovine respiratory disease (BRD) has prompted many feedlot veterinarians and managers to universally employ metaphylaxis protocols where seemingly healthy animals are treated with an injectable antimicrobial upon arrival at the feedyard. This practice is based on wellestablished knowledge of BRD etiology, in that pathogen exposure associated with multi-source commingling in concert with shipping stress can often predispose cattle for BRD. By metaphylactically treating these arriving high-risk animals for subclinical or potential bacterial infections, respiratory health status is enhanced and rates of early BRD breaks can be greatly reduced. Though arrival metaphylaxis has been used for years, the strategy has received fresh interest due to the advent of newgeneration antimicrobial agents that offer extended durations of activity in cattle. These technological advancements have thus prompted the concept of a prolonged post-metaphylactic interval (PMI), which

2 Draxxin is approved for both treatment and control of BRD caused by the most common bacterial respiratory pathogens of cattle. Data from 12 studies 1-10 were compiled to evaluate BRD first-treatment success after arrival metaphylaxis with Draxxin vs other antimicrobials. refers to a period of time after antimicrobial metaphylaxis when no further treatment for BRD is administered. This management model is founded on the rationale that any additional treatment is often of little value if effective levels of an extended-duration medication are still resident in the animal. As a result, a PMI of 3 to 10 days is now often observed at many feedyards. Only after that time period has elapsed will cattle showing clinical signs of BRD be pulled for treatment, usually with a drug from a chemical class different than that used for metaphylaxis. Feedyard veterinarians are typically tasked with selection of the metaphylaxis antimicrobial, and several products are appropriate candidates (approved for the control of BRD in high-risk animals). Research studies reporting rates of postmetaphylaxis BRD incidence are usually consulted for guidance. However, another often overlooked criterion for metaphylaxis selection is the rate of first-treatment success after an initial BRD episode (occurring subsequent to the PMI). The ability of metaphylactically managed cattle to favorably respond to initial BRD treatment and rejoin penmates at the bunk is often a pivotal factor determining profit or loss, since BRD retreats and chronics can quickly elevate production costs and drain profit potential. The following offers a summary of research studies documenting first-treatment success rates for cattle that received arrival metaphylaxis with Draxxin. Draxxin Overview Draxxin (tulathromycin) Injectable Solution is a unique antibiotic for the control and treatment of BRD that conveniently delivers a full course of therapy in a single dose. Tulathromycin is a semi-synthetic macrolide compound developed by Zoetis scientists as a highly bioavailable, long-acting antimicrobial for treatment of BRD. 11 Administered as a single subcutaneous (SC) injection at 1.1 ml/100 lb body weight (2.5 mg/kg), Draxxin is indicated for the treatment of BRD associated with 4 of the most common bacterial respiratory pathogens of cattle: Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. These indications make Draxxin particularly well-suited for use in control programs for arriving feedlot cattle, when animals are experiencing stress due to transport, commingling, etc., and are at high risk of BRD pathogen exposure. Draxxin is also indicated for treatment of infectious bovine keratoconjunctivitis associated with Moraxella bovis, and bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii. Study Summary Process A review of available metaphylaxis research studies was conducted to compile data regarding the success of initial BRD treatment for feedlot/stocker cattle that had previously received arrival metaphylaxis with Draxxin vs animals dosed with another antimicrobial. Twelve studies were identified for inclusion in the retrospective data compilation, highquality trials conducted by universities or veterinary research/consultant groups and often commissioned by Zoetis or other pharmaceutical companies (Merck, Elanco, Merial) The trials varied in the number of animals/treatment group, pen numbers, and duration, but health results were usually tracked from arrival through finishing. Arrival metaphylaxis Day 0 (processing) 3-10 days post-metaphylaxis interval (PMI) DRAXXIN vs Micotil, Zactran, Zuprevo, Nuflor, or OTC Day st BRD treatment (as needed) End of Trt study Treat as needed for BRD. Note 1-treatment success. E XCEDE, Nuflor, A180, Baytril, or OTC Figure 1 General design of 12 studies that reported BRD first-treatment success rates for different arrival metaphylaxis treatment groups. 2

3 In each study, arriving cattle at high risk for BRD received metaphylaxis with Draxxin (2.5 mg/kg) or label doses of another agent: Micotil (tilmicosin, Elanco); Zactran (gamithromycin, Merial); Zuprevo (tildipirosin, Merck); Nuflor (florfenicol, Merck); Oxytetracycline (OTC). Most studies compared Draxxin and a single other product, but 4 studies evaluated 3 metaphylaxis treatment groups (Draxxin vs 2 other agents). A PMI ranging from 3 to 10 days was a component of the arrival metaphylaxis protocol for most studies (Figure 1). Thereafter, cattle exhibiting clinical signs of BRD were pulled and treated according to standard criteria for each study/operation. The same BRD treatment protocol was used for each treatment group in a particular study, and the antimicrobial agent used for BRD therapy always differed from that used for metaphylaxis. Different antimicrobial agents were used for BRD treatment across the 12 studies, and included label doses of Excede (ceftiofur, Zoetis), Nuflor, A180 (danofloxacin, Zoetis), Baytril (enrofloxacin, Bayer), or OTC. For each study, the percent of BRD pulls that successfully responded to a single BRD treatment was extracted from the study report or publication (cattle requiring 2 or more BRD treatments were failures under these criteria). Outcomes were then compared for each metaphylaxis treatment group in the study (Draxxin metaphylaxis vs other-drug metaphylaxis). This analysis was based on the rationale that superior metaphylaxis should help reduce costly BRD retreats (enhanced respiratory health status can help reduce the severity of a BRD episode and, thus, encourage a favorable treatment response). Results The various designs, features, and outcomes for the 12 studies are summarized in Table 1. Notably, in each study, the Draxxin metaphylaxis treatment group generated a greater BRD first-treatment success rate than the comparative metaphylaxis In each study, 1-10 the Draxxin metaphylaxis treatment group generated a greater BRD first-treatment success rate than comparative agent(s). Table 1 Experiment designs and results for 12 studies that reported BRD first-treatment outcomes after arrival metaphylaxis. Avg. Avg. Approx. PMI (d) 1st-pull treatment success (%), by metaphylaxis drug source group (lb) (d) others drug Draxxin Micotil Zactran Zuprevo Nuflor OTC advant. Study Year Location Study hd(reps)/ start wt. duration Draxxin/ 1st-pull Draxxin A CO Zoetis 250 (5) /3 OTC 70.2% 60.0% 10.2% B ID Zoetis 250 (5) /3 OTC 73.6% 51.8% 21.8% C TX Zoetis 250 (5) /3 A % 55.1% 18.2% D Alberta Zoetis 3305 (10) /3 Nuflor 77.0% 61.5% 15.5% 61.2% 15.8% E KS KSU 146 (12) /3 Baytril 71.9% 49.5% 22.4% F Alberta Elanco 2247 (10) /5 Nuflor 90.0% 89.0% 1.0% G TX Cactus 787 (8) /3 Excede 95.0% 81.0% 14.0% H TX Zoetis 1184 (13) /10 Excede 74.5% 68.4% 6.1% I Alberta Merck 3358 (6) 550 close 3/3 na 79.3% J NM KSU / NMSU K TX Zoetis 457 (12) L KS/NE na = not available KSU / Merial 76.8% 2.5% 76.3% 3.0% 193 (10) na Excede 100.0% 97.4% 2.6% 98.5% 1.5% 10/ % 7.0% Excede 70.0% 10/3 59.0% 11.0% 1265 (17) na Nuflor 60.5% 58.5% 2.0% 3

4 Advantage of DRAXXIN metaphylaxis in first-pull treatment success (%) Study: Micotil Zactran Zuprevo Nuflor Figure 2 Advantage of Draxxin metaphylaxis vs other metaphylaxis agents in first-pull treatment success. A D E F G I J K H J L I K B C D 15.8 OTC First-treatment success advantages for Draxxin metaphylaxis ranged from 1.0% 4 to 22.4%. 3 Results of these 12 studies 1-10 further distinguish Draxxin as the choice antimicrobial for arrival metaphylaxis. agent(s). The success-rate advantages for Draxxin metaphylaxis (in absolute percentages) ranged from 1.0% (study F vs Micotil) to 22.4% (study E, also vs Micotil). These results suggest wide variability in the incidence and severity of BRD under the conditions of the various studies. Still, metaphylaxis with Draxxin consistently generated the best first-treatment success rates across the 12 studies. The Draxxin-metaphylaxis advantages relative to each of the other metaphylactic agents are summarized in Figure 2. A statistical analysis of these summarized outcomes was precluded because most studies did not statistically analyze specific data regarding BRD first-treatment results. However, the consistent trend for favorable Draxxin metaphylaxis outcomes in regard to BRD first-treatment success is notable (any anecdotal field perceptions that suggest otherwise were not supported by any of the studies). Conclusions Results of this retrospective review of 12 metaphylaxis research studies support the use of Draxxin for arrival metaphylaxis. In each study, feedlot cattle that received Draxxin metaphylaxis demonstrated greater rates of subsequent initial BRD treatment success than cattle that received some other metaphylactic agent. The consistently improved rates of initial BRD treatment success suggest that respiratory health status was enhanced in animals that received Draxxin metaphylaxis at arrival. These outcomes further differentiate Draxxin as the choice antimicrobial for arrival metaphylaxis. Draxxin offers feedlot veterinarians and managers the opportunity to help reduce medical expenses, performance losses, and input costs related to recurring BRD, thus helping optimize the profit potential of their operations. DRAXXIN IMPORTANT SAFETY INFORMATION: Draxxin has a pre-slaughter withdrawal time of 18 days. Do not use in dairy cattle 20 months of age or older. Do not use in animals known to be hypersensitive to the product. See full Prescribing Information. EXCEDE IMPORTANT SAFETY INFORMATION: As with all drugs, the use of Excede is contraindicated in animals with known allergy to ceftiofur or to the β-lactam group (penicillins and cephalosporins) of antimicrobials. Though safe in cattle when properly administered, inadvertent intra-arterial injection is possible and fatal. Excede has a pre-slaughter withdrawal time of 13 days in cattle. Do not use in calves to be processed for veal. See full Prescribing Information. 4

5 (tulathromycin) Injectable Solution Antibiotic 100 mg of tulathromycin/ml For use in beef cattle (including suckling calves), non-lactating dairy cattle (including dairy calves), veal calves, and swine. Not for use in female dairy cattle 20 months of age or older. CAUTION: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION DRAXXIN Injectable Solution is a ready-to-use sterile parenteral preparation containing tulathromycin, a semi-synthetic macrolide antibiotic of the subclass triamilide. Each ml of DRAXXIN contains 100 mg of tulathromycin as the free base in a 50% propylene glycol vehicle, monothioglycerol (5 mg/ml), with citric and hydrochloric acids added to adjust ph. DRAXXIN consists of an equilibrated mixture of two isomeric forms of tulathromycin in a 9:1 ratio. Structures of the isomers are shown below. Figure 1. The chemical names of the isomers are (2R,3S,4R,5R,8R,10R, 11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C-methyl-3-Ο-methyl- 4-C-[(propylamino) methyl]-α-l-ribo-hexopyrano-syl]oxy]- 2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11- [[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]-oxy]-1-oxa-6-azacyclopentadecan-15-one and (2R,3R,6R, 8R,9R,10S,11S,12R)-11-[[2,6-dideoxy-3-C-methyl-3-Οmethyl-4-C-[(propylamino)methyl]-α-L-ribo-hexopyrano-syl] oxy]-2-[(1r,2r)-1,2-dihydroxy-1-methylbutyl]-8-hydroxy- 3,6,8,10,12-pentamethyl-9-[[3,4,6-trideoxy-3-(dimethylamino)- β-d-xylo-hexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13- one, respectively. INDICATIONS Beef and Non-Lactating Dairy BRD DRAXXIN Injectable Solution is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis; and for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. IBK DRAXXIN Injectable Solution is indicated for the treatment of infectious bovine keratoconjunctivitis (IBK) associated with Moraxella bovis. Foot Rot DRAXXIN Injectable Solution is indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii. Suckling Calves, Dairy Calves, and Veal Calves BRD - DRAXXIN Injectable Solution is indicated for the treatment of BRD associated with M. haemolytica, P. multocida, H. somni, and M. bovis. DRAXXIN Injectable Solution is indicated for the treatment of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae; and for the control of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae in groups of pigs where SRD has been diagnosed. DOSAGE AND ADMINISTRATION Inject subcutaneously as a single dose in the neck at a dosage of 2.5 mg/kg (1.1 ml/100 lb) body weight (BW). Do not inject more than 10 ml per injection site. Table 1. DRAXXIN Dosing Guide Animal Weight Dose Volume (Pounds) (ml) Inject intramuscularly as a single dose in the neck at a dosage of 2.5 mg/kg (0.25 ml/22 lb) BW. Do not inject more than 2.5 ml per injection site. Table 2. DRAXXIN Dosing Guide Animal Weight Dose Volume (Pounds) (ml) CONTRAINDICATIONS The use of DRAXXIN Injectable Solution is contraindicated in animals previously found to be hypersensitive to the drug. WARNINGS FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. NOT FOR USE IN CHICKENS OR TURKEYS. RESIDUE WARNINGS intended for human consumption must not be slaughtered within 18 days from the last treatment. Do not use in female dairy cattle 20 months of age or older. intended for human consumption must not be slaughtered within 5 days from the last treatment. PRECAUTIONS The effects of DRAXXIN on bovine reproductive performance, pregnancy, and lactation have not been determined. Subcutaneous injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter. The effects of DRAXXIN on porcine reproductive performance, pregnancy, and lactation have not been determined. Intramuscular injection can cause a transient local tissue reaction that may result in trim loss of edible tissue at slaughter. ADVERSE REACTIONS In one BRD field study, two calves treated with DRAXXIN at 2.5 mg/kg BW exhibited transient hypersalivation. One of these calves also exhibited transient dyspnea, which may have been related to pneumonia. In one field study, one out of 40 pigs treated with DRAXXIN at 2.5 mg/kg BW exhibited mild salivation that resolved in less than four hours. CLINICAL PHARMACOLOGY At physiological ph, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than hydrophobic media. This solubility profile is consistent with the extracellular pathogen activity typically associated with the macrolides. 1 Markedly higher tulathromycin concentrations are observed in the lungs as compared to the plasma. The extent to which lung concentrations represent free (active) drug was not examined. Therefore, the clinical relevance of these elevated lung concentrations is undetermined. Although the relationship between tulathromycin and the characteristics of its antimicrobial effects has not been characterized, as a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens. 2 They also tend to exhibit concentration independent killing; the rate of bacterial eradication does not change once serum drug concentrations reach 2 to 3 times the minimum inhibitory concentration (MIC) of the targeted pathogen. Under these conditions, the time that serum concentrations remain above the MIC becomes the major determinant of antimicrobial activity. Macrolides also exhibit a post-antibiotic effect (PAE), the duration of which tends to be both drug and pathogen dependent. In general, by increasing the macrolide concentration and the exposure time, the PAE will increase to some maximal duration. Of the two variables, concentration and exposure time, drug concentration tends to be the most powerful determinant of the duration of PAE. Tulathromycin is eliminated from the body primarily unchanged via biliary excretion. 1 Carbon, C Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27: Nightingale, C.J Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16: Following subcutaneous administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulathromycin is rapidly and nearly completely absorbed. Peak plasma concentrations generally occur within 15 minutes after dosing and product relative bioavailability exceeds 90%. Total systemic clearance is approximately 170 ml/hr/kg. Tulathromycin distributes extensively into body tissues, as evidenced by volume of distribution values of approximately 11 L/kg in healthy ruminating calves. 3 This extensive volume of distribution is largely responsible for the long elimination half-life of this compound [approximately 2.75 days in the plasma (based on quantifiable terminal plasma drug concentrations) versus 8.75 days for total lung concentrations (based on data from healthy animals)]. Linear pharmacokinetics are observed with subcutaneous doses ranging from 1.27 mg/kg BW to 5.0 mg/kg BW. No pharmacokinetic differences are observed in castrated male versus female calves. 3 Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either subcutaneous or intravenous injection. Following intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (T max ~0.25 hour). Subsequently, the drug rapidly distributes into body tissues, achieving a volume of distribution exceeding 15 L/kg. The free drug is rapidly cleared from the systemic circulation (CL systemic = 187 ml/hr/kg). However, it has a long terminal elimination half-life (60 to 90 hours) owing to its extensive volume of distribution. Although pulmonary tulathromycin concentrations are substantially higher than concentrations observed in the plasma, the clinical significance of these findings is undetermined. There are no gender differences in swine tulathromycin pharmacokinetics. MICROBIOLOGY Tulathromycin has demonstrated in vitro activity against Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis, four pathogens associated with BRD; against Moraxella bovis associated with IBK; and against Fusobacterium necrophorum and Porphyromonas levii associated with bovine foot rot. The MICs of tulathromycin against indicated BRD and IBK pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A2). The MICs against foot rot pathogens were also determined using methods recommended by the CLSI (M11-A6). All MIC values were determined using the 9:1 isomer ratio of this compound.

6 BRD - The MICs of tulathromycin were determined for BRD isolates obtained from calves enrolled in therapeutic and at-risk field studies in the U.S. in In the therapeutic studies, isolates were obtained from pre-treatment nasopharyngeal swabs from all study calves, and from lung swabs or lung tissue of saline-treated calves that died. In the at-risk studies, isolates were obtained from nasopharyngeal swabs of saline-treated non-responders, and from lung swabs or lung tissue of salinetreated calves that died. The results are shown in Table 3. IBK - The MICs of tulathromycin were determined for Moraxella bovis isolates obtained from calves enrolled in IBK field studies in the U.S. in Isolates were obtained from pre-treatment conjunctival swabs of calves with clinical signs of IBK enrolled in the DRAXXIN and saline-treated groups. The results are shown in Table 3. Foot Rot - The MICs of tulathromycin were determined for Fusobacterium necrophorum and Porphyromonas levii obtained from cattle enrolled in foot rot field studies in the U.S. and Canada in Isolates were obtained from pre-treatment interdigital biopsies and swabs of cattle with clinical signs of foot rot enrolled in the DRAXXIN and saline-treated groups. The results are shown in Table 3. Table 3. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from field studies evaluating BRD and IBK in the U.S. and from foot rot field studies in the U.S. and Canada. Indicated Date No. of MIC 50 ** MIC 90 ** MIC range pathogen isolated isolates (μg/ml) (μg/ml) (μg/ml) Mannheimia haemolytica to 64 Pasteurella multocida to 64 Histophilus somni to 4 Mycoplasma bovis to > 64 Moraxella bovis to 1 Fusobacterium 0.25 necrophorum to > 128 Porphyromonas 0.25 levii to > 128 * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. In vitro activity of tulathromycin has been demonstrated against Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae. The MICs of tulathromycin against indicated SRD pathogens were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A and M31-A3). MICs for Haemophilus parasuis were determined using Veterinary Fastidious Medium and were incubated up to 48 hours at 35 to 37 C in a CO 2 -enriched atmosphere. All MIC values were determined using the 9:1 isomer ratio of this compound. Isolates obtained in 2000 and 2002 were from lung samples from saline-treated pigs and non-treated sentinel pigs enrolled in Treatment of SRD field studies in the U.S. and Canada. Isolates obtained in 2007 and 2008 were from lung samples from saline-treated and DRAXXIN-treated pigs enrolled in the Control of SRD field study in the U.S. and Canada. The results are shown in Table 4. Table 4. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from field studies evaluating SRD in the U.S. and Canada. Indicated Date No. of MIC 50 ** MIC 90 ** MIC range pathogen isolated isolates (μg/ml) (μg/ml) (μg/ml) Actinobacillus to 32 pleuropneumoniae to 32 Haemophilus 0.25 parasuis to > 64 Pasteurella to > 64 multocida to 2 Bordetella bronchiseptica to 8 * The correlation between in vitro susceptibility data and clinical effectiveness is unknown. ** The lowest MIC to encompass 50% and 90% of the most susceptible isolates, respectively. EFFECTIVENESS BRD In a multi-location field study, 314 calves with naturally occurring BRD were treated with DRAXXIN. Responses to treatment were compared to saline-treated controls. A cure was defined as a calf with normal attitude/activity, normal respiration, and a rectal temperature of 104 F on Day 14. The cure rate was significantly higher (P 0.05) in DRAXXIN-treated calves (78%) compared to saline-treated calves (24%). There were two BRD-related deaths in the DRAXXIN-treated calves compared to nine BRD-related deaths in the saline-treated calves. Fifty-two DRAXXIN-treated calves and 27 saline-treated calves from the multi-location field BRD treatment study had Mycoplasma bovis identified in cultures from pre-treatment nasopharyngeal swabs. Of the 52 DRAXXIN-treated calves, 37 (71.2%) calves were categorized as cures and 15 (28.8%) calves were categorized as treatment failures. Of the 27 salinetreated calves, 4 (14.8%) calves were categorized as cures and 23 (85.2%) calves were treatment failures. A Bayesian meta-analysis was conducted to compare the BRD treatment success rate in young calves (calves weighing 250 lbs or less and fed primarily a milk-based diet) treated with DRAXXIN to the success rate in older calves (calves weighing more than 250 lbs and fed primarily a roughage and grain-based diet) treated with DRAXXIN. The analysis included data from four BRD treatment effectiveness studies conducted for the approval of DRAXXIN in the U.S. and nine contemporaneous studies conducted in Europe. The analysis showed that the BRD treatment success rate in young calves was at least as good as the BRD treatment success rate in older calves. As a result, DRAXXIN is considered effective for the treatment of BRD associated with M. haemolytica, P. multocida, H. somni, and M. bovis in suckling calves, dairy calves, and veal calves. In another multi-location field study with 399 calves at high risk of developing BRD, administration of DRAXXIN resulted in a significantly reduced incidence of BRD (11%) compared to saline-treated calves (59%). Effectiveness evaluation was based on scored clinical signs of normal attitude/activity, normal respiration, and a rectal temperature of 104 F on Day 14. There were no BRD-related deaths in the DRAXXIN-treated calves compared to two BRD-related deaths in the saline-treated calves. Fifty saline-treated calves classified as non-responders in this study had Mycoplasma bovis identified in cultures of post-treatment nasopharyngeal swabs or lung tissue. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN against Mycoplasma bovis. A total of 166 calves were inoculated intratracheally with field strains of Mycoplasma bovis. When calves became pyrexic and had abnormal respiration scores, they were treated with either DRAXXIN (2.5 mg/kg BW) subcutaneously or an equivalent volume of saline. Calves were observed for signs of BRD for 14 days post-treatment, then were euthanized and necropsied. In both studies, mean lung lesion percentages were statistically significantly lower in the DRAXXIN-treated calves compared with saline-treated calves (11.3% vs. 28.9%, P = and 15.0% vs. 30.7%, P < ). IBK Two field studies were conducted evaluating DRAXXIN for the treatment of IBK associated with Moraxella bovis in 200 naturally-infected calves. The primary clinical endpoint of these studies was cure rate, defined as a calf with no clinical signs of IBK and no corneal ulcer, assessed on Days 5, 9, 13, 17, and 21. Time to improvement, defined as the first day on which a calf had no clinical signs of IBK in both eyes, provided that those scores were maintained at the next day of observation, was assessed as a secondary variable. At all time points, in both studies, the cure rate was significantly higher (P < 0.05) for DRAXXIN-treated calves compared to saline-treated calves. Additionally, time to improvement was significantly less (P < ) in both studies for DRAXXIN-treated calves compared to saline-treated calves. Foot Rot - The effectiveness of DRAXXIN for the treatment of bovine foot rot was evaluated in 170 cattle in two field studies. diagnosed with bovine foot rot were enrolled and treated with a single subcutaneous dose of DRAXXIN (2.5 mg/kg BW) or an equivalent volume of saline. were clinically evaluated 7 days after treatment for treatment success, which was based on defined decreases in lesion, swelling, and lameness scores. In both studies, the treatment success percentage was statistically significantly higher in DRAXXIN-treated calves compared with saline-treated calves (60% vs. 8%, P < and 83.3% vs. 50%, P = ). In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with DRAXXIN. Responses to treatment were compared to saline-treated controls. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104 F on Day 7. The treatment success rate was significantly greater (P 0.05) in DRAXXIN-treated pigs (70.5%) compared to saline-treated pigs (46.1%). M. hyopneumoniae was isolated from 106 saline-treated and non-treated sentinel pigs in this study. Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN against M. hyopneumoniae. Ten days after inoculation intranasally and intratracheally with a field strain of M. hyopneumoniae, 144 pigs were treated with either DRAXXIN (2.5 mg/kg BW) intramuscularly or an equivalent volume of saline. Pigs were euthanized and necropsied 10 days post-treatment. The mean percentage of gross pneumonic lung lesions was statistically significantly lower (P < ) for DRAXXIN-treated pigs than for saline-treated pigs in both studies (8.52% vs % and 11.31% vs %). The effectiveness of DRAXXIN for the control of SRD was evaluated in a multi-location natural infection field study. When at least 15% of the study candidates showed clinical signs of SRD, all pigs were enrolled and treated with DRAXXIN (226 pigs) or saline (227 pigs). Responses to treatment were evaluated on Day 7. Success was defined as a pig with normal attitude, normal respiration, and rectal temperature of < 104 F. The treatment success rate was significantly greater (P < 0.05) in DRAXXIN-treated pigs compared to saline-treated pigs (59.2% vs. 41.2%). ANIMAL SAFETY Safety studies were conducted in feeder calves receiving a single subcutaneous dose of 25 mg/kg BW, or 3 weekly subcutaneous doses of 2.5, 7.5, or 12.5 mg/kg BW. In all groups, transient indications of pain after injection were seen, including head shaking and pawing at the ground. Injection site swelling, discoloration of the subcutaneous tissues at the injection site and corresponding histopathologic changes were seen in animals in all dosage groups. These lesions showed signs of resolving over time. No other drug-related lesions were observed macroscopically or microscopically. An exploratory study was conducted in feeder calves receiving a single subcutaneous dose of 10, 12.5, or 15 mg/kg BW. Macroscopically, no lesions were observed. Microscopically, minimal to mild myocardial degeneration was seen in one of six calves administered 12.5 mg/kg BW and two of six calves administered 15 mg/kg BW. A safety study was conducted in preruminant calves 13 to 27 days of age receiving 2.5 mg/kg BW or 7.5 mg/kg BW once subcutaneously. With the exception of minimal to mild injection site reactions, no drug-related clinical signs or other lesions were observed macroscopically or microscopically. Safety studies were conducted in pigs receiving a single intramuscular dose of 25 mg/kg BW, or 3 weekly intramuscular doses of 2.5, 7.5, or 12.5 mg/kg BW. In all groups, transient indications of pain after injection were seen, including restlessness and excessive vocalization. Tremors occurred briefly in one animal receiving 7.5 mg/kg BW. Discoloration and edema of injection site tissues and corresponding histopathologic changes were seen in animals at all dosages and resolved over time. No other drug-related lesions were observed macroscopically or microscopically. STORAGE CONDITIONS Store at or below 25 C (77 F) HOW SUPPLIED DRAXXIN Injectable Solution is available in the following package sizes: 50 ml vial 100 ml vial 250 ml vial 500 ml vial NADA , Approved by FDA Distributed by: Zoetis Inc. Kalamazoo, MI To report a suspected adverse reaction or to request a safety data sheet call For additional information about adverse drug experience reporting for animal drugs, contact FDA at FDA-VETS or online at For additional DRAXXIN product information call: DRAXXIN or go to ZOA&P Made in Brazil Revised: February 2014

7 (Ceftiofur Crystalline Free Acid) Sterile Suspension For subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) in lactating dairy cattle. For subcutaneous injection in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) in beef and non-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 for disease prevention purposes; at unapproved doses; frequencies, durations, or routes of administration; and in unapproved major food producing species/ production classes. DESCRIPTION EXCEDE Sterile Suspension is a ready-to-use formulation that contains the crystalline free acid of ceftiofur, which is a broad spectrum cephalosporin antibiotic active against Gram- positive and Gramnegative bacteria including ß-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal, in vitro, resulting from inhibition of cell wall synthesis. Each ml of this ready-to-use sterile suspension contains ceftiofur crystalline free acid equivalent to 200 mg ceftiofur, in a caprylic/capric triglyceride (Miglyol ) and cottonseed oil based suspension. Figure 1. Structure of ceftiofur crystalline free acid: ADMINISTRATION ADMINISTRATION FOR THE MIDDLE THIRD OF THE EAR Shake well before using. Please read the complete package insert before administering EXCEDE Sterile Suspension subcutaneously in the posterior ear of cattle. Deposit as a single subcutaneous injection in the middle third of the posterior aspect of the ear, avoiding all blood vessels. See Figures 2 and 3. Adjust the needle insertion point to avoid any blood vessels, previous implants, ear tags or ear tag holes. Do not administer intra-arterially. Deliver the entire contents of the syringe. When administered correctly, a subcutaneous bleb of EXCEDE Sterile Suspension will appear. When withdrawing the needle, apply pressure to the needle insertion point, and massage toward the base of the ear. Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the middle third of the posterior aspect of the ear. Chemical name of ceftiofur crystalline free acid: 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 INDICATIONS EXCEDE Sterile Suspension is indicated for treatment of bovine respiratory disease (BRD, shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef, non-lactating dairy, and lactating dairy cattle. EXCEDE Sterile Suspension is also indicated for the control of respiratory disease in beef and non-lactating dairy cattle which are at high risk of developing BRD associated with M. haemolytica, P. multocida, and H. somni. EXCEDE Sterile Suspension is also indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Porphyromonas levii in beef, nonlactating dairy, and lactating dairy cattle. EXCEDE Sterile Suspension is also indicated for treatment of acute metritis (0-10 days post-partum) associated with bacterial organisms susceptible to ceftiofur in lactating dairy cattle. DOSAGE Treatment of BRD and bovine foot rot Administer as a single subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) to cattle at a dosage of 3.0 mg ceftiofur equivalents (CE)/lb (6.6 mg CE/kg) body weight (BW) (1.5 ml sterile suspension per 100 lb BW). In beef and non-lactating dairy cattle, EXCEDE Sterile Suspension may also be adminis tered as a single subcutaneous injection in the middle third of the posterior aspect of the ear at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Most animals will respond to treatment within three to five days. If no improvement is observed, the diagnosis should be reevaluated. Control of BRD Administer as a subcutaneous injection either in the middle third of the posterior aspect of the ear or in the posterior aspect of the ear where it attaches to the head (base of the ear) to beef and nonlactating dairy cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Clinical studies indicate that administration of EXCEDE Sterile Suspension is effective for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of devel oping BRD. One or more of the following factors typically characterizes calves on arrival at high risk of developing BRD. are from multiple farm origins, cattle have had extended transport times (that may have included few if any rest stops), ambient temperature change from origin to arrival of 30 F or more, cattle have had continued exposure to extremely wet or cold weather conditions, cattle have experienced excessive shrink or excessive arrival processing procedures (such as castration, dehorning). Treatment of Acute Metritis Administer as a subcutaneous injection in the posterior aspect of the ear where it attaches to the head (base of the ear) to lactating dairy cattle at a dosage of 3.0 mg CE/lb (6.6 mg CE/kg) BW (1.5 ml sterile suspension per 100 lb BW). Repeat this dose in the contra-lateral (opposite) ear approximately 72 hours following the initial dose. Table 1. Dosing Schedule for EXCEDE Sterile Suspension. Weight Dose Volume Weight Dose Volume (lb) (ml) (lb) (ml) Figure 3. Diagram of the approximate locations of the major arteries of the posterior ear and the recommended needle insertion locations. Administration of EXCEDE Sterile Suspension into ear arteries is likely to be fatal. locations for injections main ear arteries (avoid) large vein (avoid) ADMINISTRATION FOR BASE OF THE EAR In lactating dairy cattle the injection techniques for subcutaneous (SC) injection in the posterior aspect of the ear where it attaches to the head (base of the ear) can be made by the rostral or ventral injection techniques. In beef and non-lactating dairy cattle the SC injection in the base of the ear can be made by the rostral, ventral or toward the opposite eye injection techniques. Shake well before using. Please read the complete package insert before administering EXCEDE Sterile Suspension subcutaneously in the posterior aspect of the ear where it attaches to the head (base of the ear). The subcutaneous (SC) injection may be made using the toward the opposite eye, rostral, or ventral techniques. Hold the syringe and needle and insert the needle as described below. Deliver the entire contents of the syringe. Do not administer EXCEDE Sterile Suspension in the neck. Administration for the Base of the Ear: Toward the Opposite Eye Technique Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the direction of an imaginary line that would pass through the head toward the animal s opposite eye. See Figures 4 and 5. Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while maintaining this angle. See Figure 4. Figure 4. Subcutaneous administration of EXCEDE Sterile Suspension in the posterior aspect of the ear where it attaches to the head (base of the ear).

8 Figure 5. Injection location for the subcutaneous administration of EXCEDE Sterile Suspension in the posterior aspect of the ear where it attaches to the head (base of the ear). location for injection Administration for the Base of Ear: Toward the Same Eye Technique or Rostral Direction Hold the syringe and needle behind the ear to be dosed so the needle and syringe point in the direction of an imaginary line that would pass through the head toward the eye on the same side of the head. See Figures 5 and 6. Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while maintaining the needle position. See Figure 6. Figure 6. Diagram of head showing the direction for the base of ear injections administered rostrally toward the eye on the same side of the head into the loose skin in the caudal aspect of the base of the ear. Administration for Base of the Ear: Ventral Technique Hold the syringe and needle above the ear to be dosed so that the needle and syringe are pointing ventrally toward the base of the ear. The needle will be inserted into the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while pointing ventrally. Care should be taken to not insert the needle through the cartilage of the ear. See Figure 7. Insert the needle through the loose skin in the posterior aspect of the ear where it attaches to the head (base of the ear) while maintaining needle position. See Figure 7. Figure 7. Diagram of head showing the direction of base of ear injections when administered ventrally into the loose skin in the caudal aspect of the base of the ear. ANTIBACTERIAL WARNINGS Use of antibacterial drugs in the absence of a susceptible bacterial infection is unlikely to provide benefit to treated animals and may increase the risk of the development of drug-resistant bacteria. PRECAUTIONS 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. Following injection in the posterior aspect of the ear where it attaches to the head (base of the ear), areas of discoloration and signs of inflammation may persist at least 13 days post administration resulting in trim loss of edible tissue at slaughter. Injection of volumes greater than 20 ml, in the middle third of the ear, may result in open draining lesions in a small percentage of cattle. The effects of ceftiofur on bovine reproductive performance, pregnancy, and lactation have not been determined. ADVERSE EFFECTS Intra-arterial injection may occur during administration of EXCEDE Sterile Suspension via middle third of the ear injection or base of the ear injection directed towards the opposite eye. Intra-arterial injection of EXCEDE Sterile Suspension is likely to result in sudden death of the animal. During the conduct of clinical studies, there was a low incidence of acute death (see ANIMAL SAFETY) confirmed to be the result of inadvertent intra-arterial injection. No other adverse systemic effects were noted for either the antibiotic or formulation during any of the clinical and target animal safety studies. CLINICAL PHARMACOLOGY Ceftiofur administered as either ceftiofur sodium (NAXCEL Sterile Powder), ceftiofur hydrochloride (EXCENEL RTU Sterile Suspension), or ceftiofur crystalline free acid (EXCEDE Sterile Suspension) is metabolized rapidly to desfuroylceftiofur, the primary metabolite. Subcutaneous administration of ceftiofur crystalline free acid, either in the middle third of the posterior aspect of the ear (middle third of the ear, MOE) of beef and non-lactating dairy cattle, or in the posterior aspect of the ear where it attaches to the head (base of the ear, BOE) of beef, non-lactating dairy, and lactating dairy cattle, provides therapeutic concentrations of ceftiofur and desfuroylceftiofur-related metabolites in plasma above the lowest minimum inhibitory concentration to encompass 90% of the most susceptible isolates (MIC 90 ) for the labeled BRD pathogens, Pasteurella multocida, Mannheimia haemolytica and Histophilus somni, for generally not less than 150 hours after a single administration (See Figure 8). Single Dose Regimen The pharmacokinetic parameters for the two subcutaneous locations of injection (MOE and BOE) are found in Table 2. Statistical analyses of the data from these two subcutaneous injection sites (MOE and BOE) demonstrate that they are therapeutically equivalent. Figure 8. Average (n=12/group) plasma concentrations of ceftiofur and desfuroylceftiofur-related metabolites after administration of EXCEDE Sterile Suspension at 3.0 mg CE/lb (6.6 mg CE/kg) BW via subcutaneous injection into one of two different locations of the ear, middle third of the ear (MOE ) and base of the ear (BOE ) in beef cattle as well into the base of the ear (BOE Lactating) in lactating dairy cattle. Concentration of ceftiofur and its metabolites (μg/ml) CONTRAINDICATIONS As with all drugs, the use of EXCEDE Sterile Suspension is contraindicated in animals pre viously found to be hypersensitive to the drug. WARNINGS FOR USE IN ANIMALS ONLY. 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. Sensitization of the skin may be avoided by wearing protective gloves. 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 or to report any adverse event please call Intra-arterial injection may occur during administration of EXCEDE Sterile Suspension via middle third of the ear injection or base of the ear injection directed towards the opposite eye. Intra-arterial injection of EXCEDE Sterile Suspension is likely to result in sudden death of the animal. RESIDUE WARNINGS Following label use as either a single-dose or 2-dose regimen, a 13-day pre-slaughter withdrawal period is required after the last treatment. Following label use as either a single-dose or 2-dose regimen, no milk discard period is required for this product. Use of dosages in excess of 3.0 mg CE/lb (6.6 mg CE/kg) BW or administration by unap proved routes (subcutaneous injection in the neck or intramuscular injection) may cause violative residues. A withdrawal period has not been established for this product in pre-ruminating calves. Do not use in calves to be processed for veal. Day Table 2. Average (n = 12/group) pharmacokinetic parameters for ceftiofur and desfuroylceftiofur metabolites calculated after a single subcutaneous administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension in either the middle third of the ear or the base of the ear. Pharmacokinetic Beef - Middle Beef - Base of Dairy Cow - Parameter Third of the Ear the Ear Base of the Ear Mean Value ± Mean Value ± Mean Value ± Standard Standard Standard Deviation Deviation Deviation C max (μg CE/mL) 6.90 ± ± ± 1.65 t max (h) 12.0 ± ± ± 8.02 AUC 0-LOQ (μg h/ml) 376 ± ± ± 85.5 t >0.2, model (h) 183 ± 40.8 NE NE t >0.2, nca (h) 246 ± ± ± 35.7 t1/2 (h) 62.3 ± ± ± 9.84 C max (μg CE/mL) = maximum plasma concentration (in μg CE/mL). t max (h) = the time after injection when C max occurs (in hours). AUC 0-LOQ (μg h/ml) = 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, model (h) = the time plasma concentrations remain above 0.2 μg CE/mL (in hours), estimated using compartmental pharmacokinetic techniques. t >0.2, nca (h) = the time plasma concentrations remain above 0.2 μg CE/mL (in hours), estimated using noncompartmental pharmacokinetic techniques. t 1/2 (h) = terminal phase biological half life (in hours) NE = Not estimated Two-Dose Regimen A two-dose regimen of 6.6 mg CE/kg BW administered 72 hours apart is required for the treatment of acute metritis in lactating cows. The mean plasma concentration vs. time profile for ceftiofur and desfuroylceftiofur-related metabolites for the 2-dose regimen in 12 cows is shown in Figure 9 below. The pharmacokinetic parameters for the 2-dose regimen are provided in Table 3.