Equine & Livestock Product & Promotions Guide

(tulathromycin and ketoprofen injection) INJECTABLE SOLUTION For subcutaneous injection Antibiotic: 100 mg of Tulathromycin/mL Non-Steroidal Anti-inflammatory Drug: 120 mg Ketoprofen/mL CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian DESCRIPTION DRAXXIN KP (tulathromycin and ketoprofen injection) Injectable Solution is a ready to use sterile parenteral preparation containing tulathromycin, a semi-synthetic macrolide antibiotic of the subclass triamilide and ketoprofen a non-steroidal anti-inflammatory drug. ACTIVE INGREDIENTS: Each mL of DRAXXIN KP contains 100 mg of tulathromycin as a free base and 120 mg ketoprofen as a free acid in a 50% propylene glycol vehicle. INACTIVE INGREDIENTS: monothioglycerol (5 mg/mL), 2-pyrrolidone (70 mg/mL), citric acid (20 mg/mL) and sodium hydroxide/hydrochloric acid added to adjust pH. DRAXXIN KP contains an equilibrated mixture of two isomeric forms of tulathromycin in a 9:1 ratio and a racemic mixture of ketoprofen. The structures of the tulathromycin isomers and ketoprofen are shown below: Figure 1. Tulathromycin structures The chemical names of the tulathromycin 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- hexopyranosyl]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-Ο-methyl-4-C-[(propylamino) methyl]-α-L-ribo-hexopyranosyl]oxy]-2-[(1S,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. Figure 2. Ketoprofen Structure The chemical name of ketoprofen is 2-(3-Benzoylphenyl) propanoic acid. INDICATIONS Draxxin ® KP is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis, and control of pyrexia associated with BRD in beef steers, beef heifers, beef calves 2 months of age and older, beef bulls, dairy bulls, and replacement dairy heifers. Not for use in reproducing animals over one year of age, dairy calves, or veal calves. DOSAGE AND ADMINISTRATION Inject subcutaneously as a single dose in the neck at a dosage of 2.5 mg tulathromycin and 3 mg ketoprofen/kg (1.1 mL/100 lb) bodyweight (BW). Do not inject more than 10 mL per injection site. Use this product within 56 days of the first puncture and puncture a maximum of 20 times. If more than 20 punctures are anticipated, the use of automatic injection equipment or a repeater syringe is recommended. When using a draw-off spike or needle with bore diameter larger than 16 gauge, discard any product remaining in the vial immediately after use. Table 1. DRAXXIN KP Cattle Dosing Guide Animal Weight (lb) Dose Volume (mL) 150 1.7 200 2.3 250 2.8 300 3.4 350 4.0 400 4.5 500 5.7 600 6.8 700 8.0 800 9.1 900 10.2 1000 11.4 CONTRAINDICATIONS The use of DRAXXIN KP Injection is contraindicated in animals previously found to be hypersensitive to tulathromycin and ketoprofen. WITHDRAWAL PERIODS AND RESIDUE WARNINGS: Cattle must not be slaughtered for human consumption within 18 days following last treatment with this drug product. Not for use in female dairy cattle 1 year of age or older, including dry dairy cows; use in these cattle may cause drug residues in milk and/or in calves born to these cows or heifers. Not for use in beef calves less than 2 months of age, dairy calves, and veal calves. A withdrawal period has not been established for this product in pre-ruminating calves. USER SAFETY WARNINGS: NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. The Safety Data Sheet (SDS) provides more detailed occupational safety information. To obtain a Safety Data Sheet contact Zoetis Inc. at 1-888-963-8471. ANIMAL SAFETY WARNINGS and PRECAUTIONS The effects of DRAXXIN KP on bovine reproductive performance, pregnancy, and lactation have not been determined. Not for use in reproducing animals over one year of age because reproductive safety testing has not been conducted. Administration of tulathromycin and ketoprofen injection may result in injection site swelling that appears the day after treatment and may persist for at least 32 days post-injection. This may result in trim loss of edible tissue at slaughter. As a class, cyclo-oxygenase inhibitory NSAIDs (Ketoprofen) may be associated with gastrointestinal, hepatic and renal toxicity. Sensitivity to drug-associated adverse effects varies with the individual patient. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction. Use judiciously when renal impairment or gastric ulceration is suspected. Since many NSAIDs possess the potential to induce gastrointestinal ulceration, concomitant use of DRAXXIN KP with other anti-inflammatory drugs, such as other NSAIDs and corticosteroids, should be avoided or closely monitored. Discontinue use if fecal blood is observed. ADVERSE REACTIONS Repeated administration of NSAIDs can result in gastric or renal toxicity. Sensitivity to drug- associated adverse effects varies with the individual patient. Patients at greatest risk for toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with pre-existing gastric ulcers, renal, cardiovascular, and/or hepatic dysfunction. CONTACT INFORMATION: To report suspected adverse drug experiences, to obtain a Safety Data Sheet (SDS) or for technical assistance, contact Zoetis at (888) 963-8471. For additional information about adverse drug experience reporting for animal drugs, contact the FDA at 1-888-FDA-VETS or http://www.fda.gov/reportanimalae. CLINICAL PHARMACOLOGY Mechanism of Action Ketoprofen is a propionic acid derivate and nonsteroidal anti-inflammatory drug (NSAID) with anti- inflammatory, analgesic and antipyretic effects. Ketoprofen inhibits the activity of the enzymes cyclo-oxygenase I and II, resulting in a decreased formation of precursors of prostaglandins and thromboxanes. Ketoprofen also causes a decrease in the formation of thromboxane A2 synthesis, by thromboxane synthase, thereby inhibiting platelet aggregation. The principal mechanism of action of tulathromycin against bacteria involves direct inhibition of essential protein biosynthesis by selective binding to bacterial 50S ribosomal subunits. Tulathromycin acts by stimulating the dissociation of peptidyl-tRNA from the ribosome during the translocation process. Clinical Pharmacology In a GLP pharmacokinetic study, 60 cattle received one of 3 treatments: 2.5 mg tulathromycin/kg BW, 3 mg ketoprofen/kg BW or a combination of the two active ingredients (2.5 mg tulathromycin and 3 mg of ketoprofen/kg BW) via subcutaneous injection. Blood samples were obtained pre-dose and at 20 min, 40 min, 1, 1.5, 2, 3, 4, 6, 10, 24, 28, 32, 48, 52, 56, 72, 120, 168, 216, 264, 336, and 360 hours after dosing. The samples were analyzed using validated high- performance liquid chromatography-mass spectrometry (LC-MS/MS) methods for tulathromycin and ketoprofen concentrations. The rate of drug exposure was greater for the ketoprofen alone product. The mean [±standard deviation (SD)] maximum plasma concentration (Cmax) and time to Cmax (tmax) was 6451 (±1342) ng/mL and 0.83 (±0.53) hr, respectively for ketoprofen alone compared to a mean (±SD) Cmax and tmax of 2322 (±1505) ng/mL and 4.0 (±2.93) hr, respectively, for ketoprofen in the combination product. However, the extent of drug exposure was slightly greater and terminal half life (t1/2) was longer for ketoprofen in the combination product. The mean (±SD) area under the drug concentration- time curve between times 0 and the last quantifiable concentration (AUC0-t(last)) was 26458 (±3605) ng*hr/mL for ketoprofen in the combination product and 23106 (±3500) for ng*hr/mL for ketoprofen alone. Similarly, the mean t 1/2 was 6.84 (±2.09) hr for ketoprofen in the combination product and 2.86 (±1.09) hr for ketoprofen alone. Although the mean (±SD) Cmax of tulathromycin in the combination group (373 (±105) ng/mL) was less than tulathromycin alone (653 (±261) ng/mL), based on mean (±SD) AUC0-t(last), the combination (13647 (±2577) ng*hr/mL) and tulathromycin alone (14088 (±4408) ng*hr/mL) groups had similar tulathromycin bioavailability. Tulathromycin half life was also similar between the combination (93.3 (±27.9) hr) and tulathromycin alone (98.7 (±23.1) hr) groups.

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