CATTLE PRODUCTS AND SERVICES - Zoetis · Antimicrobials 5 ALBON® Boluses (sulfadimethoxine)USES: Oral treatment of shipping fever complex, bacterial pneumonia, calf diphtheria and

CATTLEPRODUCTSAND SERVICES

U.S. BEEF AND DAIRY

ZOETIS CATTLE PRODUCTSANTIMICROBIALS

ADVOCIN® Sterile Injectable Solution (danofloxacin injection) . . . . . . . . . . . . . . . . . . . . . . . . . 5ALBON® Boluses (sulfadimethoxine) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5DRAXXIN® Injectable Solution (tulathromycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5DRAXXIN® 25 Injectable Solution (tulathromycin injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6EXCEDE® Sterile Suspension (ceftiofur crystalline free acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6EXCENEL® RTU EZ Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . . . 7LINCO-SPECTIN® Sterile Solution (lincomycin hydrochloride and spectinomycin sulfate tetrahydrate) . . 7LIQUAMYCIN® LA-200® (oxytetracycline) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8NAXCEL® Sterile Powder (ceftiofur sodium) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

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CALF SCOURS VACCINES, TREATMENTS AND SUPPORTCALF-GUARD® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9ENTROLYTE® H .E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9RE-SORB® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9SCOURGUARD® 4K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10SCOURGUARD® 4KC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10TERRAMYCIN® Scours Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

CLOSTRIDIAL VACCINESONE SHOT ULTRA® 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11ONE SHOT ULTRA® 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11ULTRABAC® 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12ULTRABAC® 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12ULTRABAC® 7/SOMUBAC® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12ULTRABAC® CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12ULTRACHOICE® CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13ULTRACHOICE® 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13ULTRACHOICE® 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

FOOTBATHHOOF-TECTM Copper-Shot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TECTM Organic Footbath Concentrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TECTM Organic Topical Spray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TECTM Copper-Cutter Dry Mix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TECTM Copper-Free Dry Mix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TEC Complete® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14HOOF-TECTM 1000 Footbath Concentrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

GENETICSCLARIFIDE®/CLARIFIDE® Ultra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15CLARIFIDE® Plus/CLARIFIDE® Ultra Plus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Genetic Condition Testing - beef cattle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16HD 50K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16i50K® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16GeneMax® Advantage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17GeneMax® Focus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17PredicGENTM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18SireTRACE® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

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GROWTH IMPLANTSSYNOVEX® C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19SYNOVEX® H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19SYNOVEX® S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19SYNOVEX CHOICE® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19SYNOVEX PLUS® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20SYNOVEX® ONE FEEDLOT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20SYNOVEX® ONE GRASS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

MASTITIS PREVENTION AND TREATMENTDry CowALBADRY PLUS® Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21ENVIRACOR® J-5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21ORBESEAL® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . 22Lactating CowPIRSUE® Sterile Solution (pirlimycin hydrochloride) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23SPECTRAMAST® LC Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . 23

ZOETIS CATTLE PRODUCTS

MEDICATED FEED ADDITIVESACTOGAINTM 45 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24AUREO S 700® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24AUREOMYCIN® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25BOVATEC® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25BOVATEC® 2 .2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26CHLORMAX® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26DECCOX® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27MGA® 200 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27MGA® 500 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

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RESPIRATORY-REPRODUCTIVE VACCINESBOVI-SHIELD GOLD® BVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33BOVI-SHIELD GOLD® IBR-BVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33BOVI-SHIELD GOLD® 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34BOVI-SHIELD GOLD® 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34BOVI-SHIELD GOLD FP® 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35BOVI-SHIELD GOLD FP® 5 L5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35BOVI-SHIELD GOLD FP® 5 VL5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36BOVI-SHIELD GOLD FP® 5 L5 HB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37BOVI-SHIELD GOLD ONE SHOT® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37BOVI-SHIELD GOLD FP® 5 VL5 HB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38BOVI-SHIELD® IBR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38CATTLEMASTER GOLD FP® 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39CATTLEMASTER GOLD FP® 5 L5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39CATTLEMASTER® 4+VL5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40INFORCETM 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40LEPTOFERM-5® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41ONE SHOT® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41ONE SHOT® BVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41ONE SHOT ULTRA® 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42ONE SHOT ULTRA® 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42PREGGUARD GOLD FP® 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43RESVAC® 4/SOMUBAC® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43SOMUBAC® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

REPRODUCTIVE MANAGEMENTEAZI-BREED™ CIDR® Cattle Insert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31FACTREL® Injection (gonadorelin injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31LUTALYSE® Injection (dinoprost tromethamine injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32LUTALYSE® HighCon Injection (dinoprost tromethamine injection) . . . . . . . . . . . . . . . . . . . . . . . 32

PARASITICIDESDECTOMAX® 1% Injectable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29DECTOMAX® Pour-On . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29VALBAZEN® Suspension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

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OTHER VACCINE SOLUTIONSSRP® SALMONELLA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47SolidBac® Pinkeye IR/PR® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47ESCHERICHIA COLI BACTERIAL EXTRACT VACCINE with SRP® technology . . . . . . 47

PRESCRIBING INFORMATIONADVOCIN® Sterile Injectable Solution (danofloxacin injection) . . . . . . . . . . . . . . . . . . . . . . . . 50DRAXXIN® Injectable Solution (tulathromycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51DRAXXIN® 25 Injectable Solution (tulathromycin injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . 53EXCEDE® Sterile Suspension (ceftiofur crystalline free acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 EXCENEL® RTU EZ Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . . 59FACTREL® Injection (gonadorelin injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61LUTALYSE® Injection (dinoprost tromethamine injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62LUTALYSE® HighCon Injection (dinoprost tromethamine injection) . . . . . . . . . . . . . . . . . . . . . . . 64NAXCEL® Sterile Powder (ceftiofur sodium) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66PIRSUE® Sterile Solution (pirlimycin hydrochloride) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . 69SPECTRAMAST® LC Sterile Suspension (ceftiofur hydrochloride) . . . . . . . . . . . . . . . . . . . . . . 70

OTHER HEALTH MANAGEMENTTHERABLOAT® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

SERVICESPEOPLEFIRSTTM Human Capital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

RESPIRATORY-REPRODUCTIVE VACCINES CONTINUEDSPIROVAC® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44SPIROVAC® L5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44SPIROVAC® VL5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44STAYBRED® VL5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45TSV-2® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45VIBRIN® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5Antimicrobials

ALBON® Boluses (sulfadimethoxine)

USES:Oral treatment of shipping fever complex, bacterial pneumonia, calf diphtheria and foot rot .

SUPPLIED:5-g or 15-g scored boluses, 50 ct .

KEY FACTS:• Long-acting sulfonamide bolus .• Low dose provides rapid, sustained blood levels at higher

levels than most other long-acting sulfonamides .• Low toxicity .• Approved for use in lactating dairy cows .• Given at 25 mg/lb . body weight for first day, 12 .5 mg/lb .

for three to four subsequent days .

ALBON BOLUS has a 60 hour milk withhold period, and a pre-slaughter withdrawal time of seven days . Do not use in calves to be processed for veal . Treatment should not be continued beyond five days .

ANTIMICROBIALS

DRAXXIN® Injectable Solution (tulathromycin)

USES:For use in beef and nonlactating dairy cattle for the treatment and control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis . DRAXXIN® Injectable Solution is also indicated for the treatment of infectious bovine keratoconjunctivitis (IBK) associated with Moraxella bovis and foot rot associated with Fusobacterium necrophorum and Porphyromonas levii in beef and nonlactating dairy cattle .

For use in suckling calves, dairy calves and veal calves for the treatment of bovine respiratory disease associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis .

SUPPLIED:50-mL, 100-mL, 250-mL and 500-mL vials .

KEY FACTS:• Highly effective in the treatment and control of four major BRD-causing bacteria .

• Approved for the treatment of pinkeye and footrot .

• Provides up to 14 days of therapy in a single dose .

• Approved for treatment of BRD in suckling, veal and dairy calves .

IMPORTANT SAFETY INFORMATION:DRAXXIN has a pre-slaughter withdrawal time of 18 days . Do not use in female dairy cattle 20 months of age or older . Do not use in animals known to be hypersensitive to the product . See full Prescribing Information, attached .

ADVOCIN® Sterile Injectable Solution (danofloxacin injection)

USES:Treatment and control of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida .

SUPPLIED:100-mL and 250-mL vials .

KEY FACTS:• ADVOCIN® provides one more treatment and control

option for BRD in a subcutaneous, single dose at 2 mL/100 lb . of body weight .

• A four-day withdrawal time provides increased flexibility to treat animals during the entire feeding period .

• The single dose therapy provides convenience for all operations and requires less handling of cattle .

IMPORTANT SAFETY INFORMATION:Extra-label use of ADVOCIN in food-producing animals is prohibited . Do not use in cattle intended for dairy production or in calves to be processed for veal . ADVOCIN has a pre-slaughter withdrawal time of four days . See full Prescribing Information, attached .

6 Antimicrobials

DRAXXIN® 25 Injectable Solution (tulathromycin injection)

USES:A lower concentration of DRAXXIN® (tulathromycin injection) Injectable Solution for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis in suckling, dairy and veal calves .


KEY FACTS:• A lower concentration of DRAXXIN to treat BRD in

suckling, dairy and veal calves .

• More accurate and convenient dosing for smaller calves .

• Offers broad-spectrum treatment against all four major BRD-causing bacteria .

IMPORTANT SAFETY INFORMATION:DRAXXIN 25 has a pre-slaughter withdrawal time of 22 days in calves . Do not use in ruminating cattle . Do not use in animals known to be hypersensitive to the product . See full Prescribing Information, attached .

EXCEDE® Sterile Suspension (ceftiofur crystalline free acid)

USES: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 nonlactating dairy cattle that are at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni . EXCEDE 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 is also indicated for treatment of acute metritis (0-10 days postpartum) associated with bacterial organisms susceptible to ceftiofur in lactating dairy cattle .


KEY FACTS:• Approved for use in lactating dairy cows .

• Convenient, single-dose treatment protocol for BRD and foot rot .

• Zero milk discard means no trips to the hospital pen, maximizing performance and productivity from the fresh cow program .

• Two doses 72 hours apart are required for treatment of acute metritis .

• Advanced, sustained-release formulation provides extended therapy in a single dose versus multiple daily doses required for other treatments .

• Ready-to-use formulation .

• A single-dose treatment protocol improves antimicrobial treatment compliance .

• Unique base-of-ear site of administration contributes to better carcass quality .

• No milk withhold, 13 day pre-slaughter withdrawal .

IMPORTANT SAFETY INFORMATION: People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCEDE . EXCEDE is contraindicated in animals with known allergy to ceftiofur or to the β-lactam group (penicillins and cephalosporins) of antimicrobials . Inadvertent intra-arterial injection is possible and fatal . Do not use in calves to be processed for veal . Pre-slaughter withdrawal time is 13 days following the last dose . See full Prescribing Information, attached .

EXCENEL® RTU EZ Sterile Suspension (ceftiofur hydrochloride)

USES:Treatment of acute metritis (0-14 days postpartum) associated with bacterial organisms susceptible to ceftiofur . Treatment of bovine respiratory disease (BRD), shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni . EXCENEL RTU EZ is also indicated for the treatment of bovine foot rot (interdigital necrobacillosis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus .


KEY FACTS:• When used according to label directions, milk won’t

have to be discarded . No wasted milk ensures a better return on investment .

• Short, four-day pre-slaughter withdrawal time, one of the shortest withdrawal times of any treatment in its class .


• No special preparations, no mixing, no disruptions to the milking routine − ready to use right out of the bottle .

IMPORTANT SAFETY INFORMATION:People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to EXCENEL RTU EZ . Do not use in animals found to be hypersensitive to the product . Do not slaughter cattle for 4 days following last treatment . Do not use in calves to be processed for veal . See full Prescribing Information, attached .

LINCO-SPECTIN® Sterile Solution (lincomycin HCl and spectinomycin sulfate tetrahydrate)

USES:For use in semen extenders to protect against contamination .

SUPPLIED:20-mL vials .

KEY FACTS:• Dual antibiotic formulation protects

valuable bull semen, which is nonsterile when collected .

• Each mL contains 50 mg lincomycin HCl and 100 mg spectinomycin sulfate tetrahydrate .

• Not for drug use .

7Antimicrobials

LIQUAMYCIN® LA-200® (oxytetracycline)

USES:For use in the treatment of the following diseases in beef and dairy cattle; including suckling, dairy and veal calves: BRD due to Pasteurella spp . and Hemophilus (Histophilus) spp .; pinkeye caused by Moraxella bovis; foot rot and diptheria caused by Fusobacterium necrophorum; bacterial enteritis (scours, colibacillosis) caused by Escherichia coli; wooden tongue caused by Actinobacillus ligniersii; leptospirosis caused by Leptospira pomona; wound infections and acute metritis caused by staphylococci and streptococci organisms sensitive to oxytetracycline .

SUPPLIED:100-mL, 250-mL and 500-mL vials .

KEY FACTS:• Broad-spectrum oxytetracycline is effective against

various bacterial diseases .

• Ready to use . No mixing, refrigeration or special handling needed .

• One dose delivers three days of sustained therapy . Fewer injections mean less labor and animal stress .

• Beef-friendly subcutaneous (SC) option is available to minimize risk of carcass blemish .

• Approved for use in lactating dairy cows .

• Administered by SC or intravenous (IV) injection to beef and dairy cattle and calves, including pre-ruminating veal calves .

• Single dosage of 9 mg/lb . is recommended for treatment of bacterial pneumonia (shipping fever) associated with Pasteurella spp . and Histophilus spp . in calves and yearlings or infectious bovine keratoconjunctivitis (pinkeye) caused by Moraxella bovis . For treatment of foot rot and other indicated diseases, a dosage of 3-5 mg/lb . body weight per day is recommended .

Discontinue treatment with LIQUAMYCIN® LA-200® at least 28 days prior to slaughter . Discard milk for 96 hours after the last treatment . Do not exceed the highest recommended level of drug per pound of body weight per day .

NAXCEL® Sterile Powder (ceftiofur sodium)

USES:NAXCEL® is indicated for treatment of bovine respiratory disease (BRD), shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni . NAXCEL also is indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus .

SUPPLIED:20-mL, 1-g and 80-mL, 4-g vials .

KEY FACTS:• Fast and effective, reaches therapeutic

blood concentrations within minutes .

• Broad-spectrum — effective against a broad range of pneumonia pathogens, including those that produce beta-lactamase that deactivates penicillins such as ampicillin and amoxicillin .


• Has a flexible (12 mL per 100 lbs . body weight) low-volume dose via subcutaneous (SC) or intramuscular (IM) administration .

• Short pre-slaughter withdrawal — when used according to label directions, you have the confidence of a four-day meat withholding time

IMPORTANT SAFETY INFORMATION:People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to NAXCEL . NAXCEL has a pre-slaughter withdrawal time of four days . Do not use in animals found to be hypersensitive to the product . See full Prescribing Information, attached .

8 Antimicrobials

CALF-GUARD® Bovine Rota-Coronavirus Vaccine (Modified-Live Virus)

USES:For vaccination of healthy newborn calves or pregnant cows as an aid in preventing diarrhea (scours) caused by bovine rotavirus and coronavirus .

SUPPLIED:1-dose vials .

KEY FACTS:• For oral vaccination of newborn calves or intramuscular

(IM) vaccination of pregnant cows .

• Cow vaccination stimulates maternal antibodies, which are transferred to nursing calves via colostrum and milk .

• Aids in preventing two of the most prevalent forms of viral scours .

• Oral vaccination of calves with a single 3-mL dose should occur as soon as possible after birth and before ingestion of colostrum .

• Cows should receive two IM 3-mL doses administered three to six weeks apart during late pregnancy . Ideally, the second dose should be administered within 30 days prior to calving . Revaccinate cows annually with two doses during each subsequent pregnancy .

ENTROLYTE® H.E. (Oral Nutrient Powder for Calves)

USES:To provide a source of electrolytes and energy that are typically lost in cases of scours .

SUPPLIED:Twin 178-g pouches per packet, 20 packets per carton .

KEY FACTS:• High dextrose content provides more energy per dose

and ensures palatability .

• Provides a rapidly absorbed source of critical electrolytes lost as a result of calf scours .

• Easy to mix and use − powder dissolves quickly in warm water .

• Conveniently packaged in pre-measured twin-pouch packets for mixing in ½-gallon quantities .

• Contents of both pouches are mixed with ½-gallon (64 oz .) of warm water and given by nursing bottle or stomach tube .

CALF SCOURS VACCINES, TREATMENT AND SUPPORT

RE-SORB® (Oral Hydration Electrolyte Product for Scouring Calves)

USES:Fluid and electrolyte replacement associated with dehydration from diarrhea (scours) in calves .

SUPPLIED:2 .26-oz . (64-g) double-sided packets in boxes of 12 and buckets of 72 .

KEY FACTS:• Rapidly replenishes lost electrolytes and fluids in the

scouring calf .

• Oral dosing permits fluid replacement at first signs of scours .

• Easy to mix, dissolves rapidly, stays in solution .

• Palatable formula tastes good, avoids stress of tube feeding .

• Contents of one packet (both sides) are added to 2 quarts of water and fed as 2 quarts of solution twice daily for two days (four feedings) .

9Calf Scours Vaccines, Treatment and Support

SCOURGUARD® 4KC Bovine Rota-Coronavirus Vaccine (Killed Virus) Clostridium Perfringens Type C-Escherichia Coli Bacterin-Toxoid

USES:Used for vaccination of healthy, pregnant cows and heifers as an aid in preventing diarrhea in their calves caused by bovine rotavirus (serotypes G6 and G10), bovine coronavirus, enterotoxigenic strains of E. coli having the K99 pili adherence factor and Clostridium perfringens Type C .

SUPPLIED:10- and 50-dose vials .

KEY FACTS:• It is the first and only vaccine with label protection for

both rotavirus G6 and G10 serotypes .*

• It significantly (P < 0 .05) increases antibody concentrations to rotavirus G10 in the colostrum .1

• Compared with unvaccinated controls, SCOURGUARD has been shown to reduce mortality caused by E. coli by 95% .

• Administer two IM doses approximately three weeks apart to pregnant cows, with the second dose given three to six weeks before calving .

*As indicated by USDA label claims .1 Data on file, Study Report No . 2134H-60-02-010, Zoetis Inc .

SCOURGUARD® 4K Bovine Rota-Coronavirus Vaccine (Killed Virus) Escherichia Coli Bacterin

USES:Used for vaccination of healthy, pregnant cows and heifers as an aid in preventing diarrhea in their calves caused by bovine rotavirus (serotypes G6 and G10), bovine coronavirus and enterotoxigenic strains of Escherichia coli (E. coli) having the K99 pili adherence factor .


KEY FACTS:• It is the first and only vaccine with label protection for

both rotavirus G6 and G10 serotypes .*

• Helps protect calves from scours .

• Compared with unvaccinated controls, SCOURGUARD has been shown to reduce mortality caused by E. coli by 95 percent .

• Administer two IM doses approximately three weeks apart to pregnant cows, with second dose given three to six weeks before calving .

*As indicated by USDA label claims .

TERRAMYCIN® Scours Tablets (oxytetracycline hydrochloride)

USES:Oral antibiotic for control and treatment of bacterial enteritis and pneumonia in beef and dairy calves .

SUPPLIED:Boxes of 24 and 100 tablets (250 mg/tablet) .

KEY FACTS:• For antibacterial treatment of shipping fever complex

caused by Pasteurella multocida and enteritis (scours) caused by E. coli (colibacillosis) and Salmonella typhimurium in beef and dairy calves .

• Readily absorbed from digestive tract .

• Dosage is 1 or 2 tablets per 100 pounds of body weight every 12 hours for up to four consecutive days .

TERRAMYCIN has a pre-slaughter withdrawal time of 7 days . Do not use in lactating dairy cattle . Do not use in calves to be processed for veal .

10 Calf Scours Vaccines, Treatment and Support

ONE SHOT ULTRA® 7 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D-Mannheimia Haemolytica Bacterin-Toxoid

USES:Aids in the prevention of diseases caused by the clostridial agents indicated above and bovine pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 .


KEY FACTS:• Helps prevent seven clostridial diseases (including

diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .

• Helps protect against the primary cause of respiratory death in cattle, shipping fever and pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 .

• Produces leukotoxoid and whole-cell antibody responses, helping provide protection needed to withstand Mannheimia haemolytica challenge .

• Contains STIMUGEN®, a patented, water-soluble adjuvant that enhances the immune response with minimal risk of injection-site reactions .

• No age restrictions on use .

• Subcutaneous (SC) dose is 2 mL followed by a second 2-mL dose of ULTRACHOICE® 7 four to six weeks later .

ONE SHOT ULTRA® 8 Clostridium Chauvoei-Septicum-Haemolyticum- Novyi-Sordellii-Perfringens Types C & D- Mannheimia Haemolytica Bacterin-Toxoid



KEY FACTS:• Helps prevent eight clostridial diseases (including

diseases caused by Cl. haemolyticum and Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .



• Contains STIMUGEN, a patented, water-soluble adjuvant that enhances the immune response with minimal risk of injection-site reactions .


• Subcutaneous (SC) dose is 2 mL followed by a second 2-mL dose of ULTRACHOICE 8 four to six weeks later .

• For Cl. haemolyticum, repeat the dose every six months in animals subject to re-exposure .

CLOSTRIDIAL VACCINES

11Clostridial Vaccines

ULTRABAC® 7 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D Bacterin-Toxoid

USES:Aids in the prevention of diseases caused by the clostridial agents indicated above .

SUPPLIED:10-, 50- and 200-dose vials .

KEY FACTS:• Helps prevent seven clostridial

diseases (including diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .

• Helps provide comprehensive clostridial protection in one vaccine .

• Subcutaneous (SC) dose is 5 mL followed by a second dose given four to six weeks later . Annual revaccination with a single dose is recommended .

ULTRABAC® 8 Clostridium Chauvoei-Septicum-Haemolyticum- Novyi-Sordellii-Perfringens Types C & D Bacterin-Toxoid



KEY FACTS:• Helps prevent eight clostridial

diseases (including diseases caused by Cl. haemolyticum and Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .

• Helps provide comprehensive clostridial protection in one vaccine .


• For Cl. haemolyticum, repeat the dose every five to six months in animals subject to re-exposure .

ULTRABAC® 7/SOMUBAC® Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D-Haemophilus Somnus Bacterin-Toxoid

USES:Aids in the prevention of diseases caused by the clostridial agents indicated above and Histophilus somni (Haemophilus somnus) .


KEY FACTS:• Helps prevent seven clostridial

diseases (including diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .

• Helps protect calves and adult cattle against H. somni, a contributor to respiratory disease and the cause of thrombotic meningoencephalitis (TEME) and reproductive tract infection .


ULTRABAC® CD Clostridium Perfringens Types C & D Bacterin-Toxoid

USES:Aids in the prevention of enterotoxemia and enteritis caused by Clostridium perfringens Types B, C and D .


KEY FACTS:• Helps prevent clostridial diseases,

which continues to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .

• Helps prevent enterotoxemia and enteritis caused by Cl. perfringens Types B, C and D .


12 Clostridial Vaccines

ULTRACHOICE® CD Clostridium Perfringens Types C & D Bacterin-Toxoid

USES:Aids in the prevention of enterotoxemia and enteritis caused by Clostridium perfringens Types B, C and D .


KEY FACTS:• Helps provide protection in a

tissue-friendly 2-mL dose against enterotoxemia and enteritis caused by Cl. perfringens Types B, C and D .



ULTRACHOICE® 8 Clostridium Chauvoei-Septicum-Haemolyticum- Novyi-Sordellii-Perfringens Types C & D- Bacterin-Toxoid




tissue-friendly 2-mL dose against eight major clostridial diseases (including diseases caused by Cl. haemolyticum and Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .




ULTRACHOICE® 7 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D-Bacterin-Toxoid




tissue-friendly 2-mL dose against seven clostridial diseases (including diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .



13Clostridial Vaccines

HOOF-TECTM COPPER-SHOT TOPICAL SPRAYUSES:HOOF-TEC™ Copper-Shot Topical Spray provides a footbath in a bottle . This product is perfect for your heifers and dry cows or if you don’t have a footbath system . Spray undiluted when you need better management or dilute 1:1 with water to help maintain hoof health .

SUPPLIED:1-gal . and 5-gal . jugs, 15-gal . and 55-gal . drums, and a 250-gal . tote .

HOOF-TECTM COPPER-CUTTER DRY MIX USES:HOOF-TEC™ Copper-Cutter Dry Mix is a better alternative to traditional copper sulfate . It dissolves easily in water and is more cost-effective than copper sulfate . It can be used with HOOF-TEC 1000 Footbath Concentrate .

SUPPLIED:50-lb . bags .

FOOTBATH

14 Footbath

HOOF-TECTM ORGANIC FOOTBATH CONCENTRATE USES:HOOF-TEC™ Organic Footbath Concentrate is OMRI Listed® for use in organic production or processing and handling and offers organic dairy producers the same benefits and management options as HOOF-TEC 1000 Footbath Concentrate .

SUPPLIED:15-gal . and 55-gal . drums .

HOOF-TECTM ORGANIC TOPICAL SPRAY USES:HOOF-TEC™ Organic Topical Spray is OMRI Listed for use in organic production or processing and handling and offers organic dairy producers the same benefits and management options as HOOF-TEC Copper-Shot Topical Spray .

SUPPLIED:1-gal . and 5-gal . jugs and 15-gal . drum .

HOOF-TEC COMPLETE® USES:HOOF-TEC Complete® is an all-in-one footbath solution that is a combination of low pH copper sulfate and hoof-conditioning salts and minerals . Just mix HOOF-TEC Complete with water . No need for additional copper sulfate . And it can be integrated with your existing automated footbath system .

SUPPLIED:55-gal . drum and a 250-gal . tote .

HOOF-TECTM COPPER-FREE DRY MIX USES:HOOF-TEC™ Copper-Free Dry Mix allows you to completely replace copper sulfate in your footbath and dissolves easily in water with additional hoof conditioners . It can be used with HOOF-TEC 1000 Footbath Concentrate .


HOOF-TECTM 1000 FOOTBATH CONCENTRATE USES:HOOF-TEC™ 1000 Footbath Concentrate helps ionize copper ⎯ making it more available ⎯ so you can use up to 40% less .* Works with your current footbath procedure and may allow up to 200 more cows through each 50-gallon footbath .

SUPPLIED:5-gal . jug, 15-gal . and 55-gal . drums, and a 250-gal . tote .

*Based on traditional copper sulfate dosage rate of 5% of footbath volume . Copper sulfate dosage with HOOF-TEC 1000 Footbath Concentrate is reduced to a rate of 3% of footbath volume . The change in deposit results in a 40% reduction of copper sulfate use .

CLARIFIDE®/ CLARIFIDE® ULTRA

A nearly 28,000 (28K called CLARIFIDE)- or 62,000 (62K called CLARIFIDE Ultra)-marker DNA panel that provides genomic evaluation for dairy animals.

USES:For obtaining genomic predictions for over 50 production, health and type traits, composite indexes, parentage and inbreeding information, genetic conditions and milk protein components . Five (5) Holstein, two (2) Jersey, and two (2) Brown Swiss haplotypes associated with fertility are also reported . Results provide insight into an animal’s future genetic potential and help dairy producers make better decisions regarding which animals to raise as replacements and informs breeding and reproductive strategies .

SAMPLES:Submit tissue-sampling units (TSUs), blood cards (one blood card, not oversaturated) or whole blood (3 mL in purple-top tubes, refrigerated) on animals of any age . For animals older than 4 months, submit TSUs or hair (one hair collector with at least 20-30 intact hair bulbs) . Hair or TSU samples should be used for testing twins .

KEY FACTS:• CLARIFIDE® is available for Holstein, Jersey and Brown

Swiss, while CLARIFIDE® Ultra is only available for Jersey and Brown Swiss .

• Assists dairy producers with breeding, selection and other management decisions and helps speed up the long-term genetic progress of a herd .

• Genetic values are expressed as genomic predicted transmitting abilities (GPTAs) and may be used to evaluate dairy animals shortly after birth .

• Results are reported electronically in an Excel® spreadsheet that contains multiple summary reports of the information for simplified review and ease of data analysis .

• Holstein producers can also order tests and view results in ENLIGHT® at www.enlightdairy.com; an online, comprehensive management tool designed to help Holstein producers more efficiently manage herd genetics .

GENETICS

15Genetics

®ultra

CLARIFIDE® PLUS/ CLARIFIDE® ULTRA PLUS

A low-density (28K called CLARIFIDE Plus) and higher density (62K called CLARIFIDE Ultra Plus) DNA panel that provides genomic evaluations for Holsteins including wellness traits.

USES:CLARIFIDE® Plus (and the higher density CLARIFIDE® Ultra Plus) is the first commercially available U .S .-based genomic test that gives dairy producers the ability to directly predict disease risk in Holstein cattle . CLARIFIDE Plus includes genomic predictions for wellness traits that provide direct indication of genetic risk factors for six of the most common and costly animal health challenges on dairies .

For obtaining predictions for over 55 wellness, production, health and type traits, composite indexes, parentage and inbreeding information, halotypes or genetic conditions and milk protein components . Results provide insight into an animal’s future genetic potential and help dairy producers make better decisions regarding which animals to raise as replacements and breeding and reproductive strategies .

SAMPLES:Submit tissue-sampling units (TSUs), blood cards (one blood card, not oversaturated) or whole blood (3 mL in purple-top tubes, refrigerated) on animals of any age . For animals older than 4 months, submit TSUs or hair (one hair collector with at least 20-30 intact hair bulbs) . Hair or TSU samples should be used for testing twins .

KEY FACTS:• For Holstein cattle only .• Builds upon the same genetic offering as CLARIFIDE or

CLARIFIDE Ultra, plus the inclusion of wellness traits . Please see CLARIFIDE for further information .

• CLARIFIDE Plus also includes an exclusive index called the Dairy Wellness Profit Index™ (DWP$™) that incorporates all economically important traits including production, health, type and the new wellness traits and the polled trait to make more comprehensive and profitable genetic selection decisions due to greater genetic variation for profitability .

• Includes the Wellness Trait Index™ (WT$™), a multitrait index that focuses solely on wellness traits (mastitis, lameness, metritis, retained placenta, displaced abomasum, ketosis plus the economic value of the polled gene) to directly estimate differences in expected profitability related to differences in genetic risk for disease .

http://www.enlightdairy.com

16 Genetics

i50K® The beef industry’s newest, most cost-effective genomic solution with effectively the same accuracy as HD 50K.

USES:i50K® is a reliable, cost-effective genomic test that enables GE-EPDs to help seedstock breeders make more informed selection, mating and marketing decisions .

SAMPLES:Submit blood cards (one FTA card, not oversaturated) and completed order forms for animals of any age for testing according to the key facts provided above for different breeds of seedstock offering HD 50K . Twins should have hair or tissue samples used .

KEY FACTS:• i50K provides Angus, Red Angus, Brangus, Beefmaster and Limousin breeders with more accurate and complete GE-EPDs

for economically relevant traits leveraging cost-effective genotyping platforms .• i50K uses a process called imputation to infer 50K genotypes from lower-density genotypes with a high degree of

concordance, built upon the extensive foundation of reference genotypes from HD 50K .• i50K predictions utilize the same calibration or single step processes (depending on breed) as HD 50K, and the resulting

GE-EPD accuracies are unchanged .

HD 50K The beef industry’s most trusted genomic solution that includes genomic predictions for 19 traits plus parentage verification.

USES:Helps registered seedstock producers confidently select, mate and market bulls and females for better production potential and profitability . Greatly increases accuracy of predictions for young bulls and females with limited or no progeny, and allows producers to make earlier, more accurate decisions that accelerate genetic progress .

SAMPLES:Submit blood cards (one FTA card, not oversaturated) for animals of any age for testing .

KEY FACTS:• For Black Angus breeders, samples should be submitted

to Angus Genetics, Inc . (AGI), a wholly owned subsidiary of the American Angus Association in St . Joseph, Missouri .

• For Red Angus breeders, samples should be sumbitted to the Red Angus Association of America, and for Limousin and Lim-Flex breeders, samples should be submitted to the North American Limousin Foundation .

• For Brangus and Beefmaster breeders, co-branded order forms and samples should be submitted to Zoetis Genetics Laboratory in Kalamazoo, Michigan .

• Results reported as genomic-enhanced expected progeny differences (GE-EPDs) .

• The resulted GE-EPD accuracy is generally equivalent to tested bulls having an initial progeny proof of roughly a dozen or more calves/carcasses/daughters with performance data contributing to their EPD . Includes parentage verification and progeny Sire Match for GeneMax® tested commercial Angus females .

Genetic Condition Testing - beef cattle Testing for genetic conditions, including color, polled arthrogryposis multiplex (AM), contractural arachnodactyly (CA), developmental duplication (DD), neuropathic hydrocephalus (NH), osteopetrosis (OS), tibial hemimelia (TH), pulmonary hypoplasia with anasarca (PHA) and idiopathic epilepsy (IE)

USES:For DNA diagnostic testing of genetic defects in suspect animals, or those known to be carriers of recessive genes, to determine whether the individual is a carrier .

SAMPLES:Submit whole blood (in purple-top tubes), blood cards, semen samples or hair follicles (at least 25 follicles with bulb intact) for testing . Customers are advised to check with their respective breed association for specific ordering and sample submission instructions .

KEY FACTS:• Test results may be used to confirm carriers or recessive-

free animals, advance breeding decisions, eliminate the expression of the recessive conditions and facilitate marketing decisions .

• Once carrier females are identified, producers can: – Eliminate carriers from the herd – Breed carriers to recessive-free animals – Use carriers as embryo transfer recipients

GeneMax® Advantage

A genomic test created from a collaboration between Angus Genetics, Inc. (AGI), Certified Angus Beef and Zoetis for commercial replacement females (75% Angus or greater).

USES:Allows producers to select, mate and market commercial Angus heifers with ease and confidence by reliably identifying females with more desirable genetic merit for maternal, feedlot and carcass traits . Provides predictions for ten individual traits, three economic index scores, Smarter Outlier Reporting and Sire Match powered by HD 50K and i50K® tested bull batteries .

SAMPLES:Submit blood cards (one card, not oversaturated) or Allflex® tissue samples and completed order forms to AGI for animals of any age for testing .

KEY FACTS:• Three economic index scores for easier, more

dependable decision-making:− Cow Advantage: Predicts differences in profitability from heifer development, pregnancy and calving to the sale of weaned progeny .− Feeder Advantage: Predicts differences in the net return of feeder calf progeny due to growth, feed efficiency and CAB carcass merit .− Total Advantage: Predicts differences in profitability from genetic merit across all economically relevant traits captured in the Cow and Feeder Advantage index scores .

• Smart Outlier Reporting may be customized for specific customer needs to identify animals that likely possess extreme unfavorable genetics for cow cost from size and milk, docility and tenderness .

• Sire Match matches tested females to registered and transferred HD 50K and i50K tested sires to empower better mating and management of inbreeding .

GeneMax® Focus

A genomic test created from a collaboration between Angus Genetics, Inc. (AGI), Certified Angus Beef and Zoetis for predicting feedlot gain and marbling, as well as Sire Match (75% Angus or greater).

USES:This test predicts genetic merit for weaning weight, post-weaning gain, carcass weight, grade (marbling) and Sire Match information to make informed feeder/fed cattle marketing and/or replacement heifer decisions .

SAMPLES:Submit blood cards (one card, not oversaturated) or Allflex tissue samples and completed order forms to AGI for animals of any age for testing .

KEY FACTS:• On the ranch, GeneMax® Focus can assist with:

− Making keep/cull decisions− Identifying the highest value replacement females− Making better breeding decisions, informing feeder cattle growth, carcass performance and associated value

• In the feedlot, GeneMax Focus helps:− Manage risk by feeding more predictable gain and grade potential− Earn more predictable premiums by grid marketing cattle with known marbling ability− Buy the right cattle with confidence

17Genetics

SireTRACE® A DNA test to identify parentage and track progeny performance

USES:For tested animals and candidate parents, SireTRACE qualifies or excludes the sire and/or dam of record (typically for seedstock producers), or identifies the qualifying sire from multi-sire breeding programs (typically for commercial producers) . SireTRACE authenticated pedigree information contributes to more accurate genetic evaluation for seedstock animals, enables better management of mating decisions for avoidance of inbreeding, and may be used to facilitate evaluation of sires through SireTRACE enables progeny performance .

SAMPLES:Submit blood (3 mL in purple-top tubes) or blood cards (one card, not oversaturated) for animals of any age for testing . Hair (with at least 20 to 30 visible hair bulbs each) collected after the animal has reached 4 months of age, and semen (one straw) may also be submitted .

KEY FACTS:• Progeny performance data, sorted by sires or groups

of sires, can determine which bulls produce calves with superior and/or inferior performance across evaluated traits .

• Sire evaluations can continue throughout a bull’s productive lifetime, based on annual performance data from his progeny .

• Bulls can be managed within the bull battery for more successful breeding according to their differences in apparent serving capacity, dominance, and documented genetic merit across evaluated traits .

• Knowing the lineage of both sire and dam of retained replacement heifers can lend greater precision to future breeding decisions and accelerate genetic progress .

18 Genetics

PredicGEN™ The genomic test for crossbred British/Continental animals, focusing on carcass traits to help producers make selection or marketing decisions and improve carcass value.

USES:PredicGEN™ provides valuable insight into key carcass attributes associated with carcass premiums and enables better genetic management of antagonisms between marbling and yield grade in crossbred animals . This insight empowers producers to make informed selection, mating, management and marketing decisions to help ensure improved carcass merit .

SAMPLES:Submit blood cards (one FTA card, not oversaturated) or AllFlex tissue samples for animals of any age for testing . Twins should have hair or tissue samples used .

KEY FACTS:• PredicGEN provides accurate predictions of genetic

merit for key carcass traits — marbling score, USDA yield grade and tenderness, as well as an index that predicts carcass grid value .

• PredicGEN has been validated for use in a broad range of British and Continental breeds and their crosses .

• PredicGEN can be used to prioritize selection of replacements, as well as to differentiate the value of feeder calves on the basis of key outcomes defining carcass value .

• PredicGEN can be used in bull batteries owned by commercial cow/calf producers to document comparable across-breed carcass/consumer trait genetic merit, and enable sire assignment for progeny tested with PredicGEN .

• PredicGEN can add $60 – $80 or more in progeny value attributed to informed decisions .*

*Assuming typical herd variation in genetic merit for marbling and yield grade where half of replacement heifer candidates are selected based on grid merit with PredicGEN, the increase in average genetic merit in selected heifers would result in $10 – $11 additional carcass value per progeny. This is incremental and complementary to any increase in genetic merit associated with sire selection strategies. Over a typical commercial female’s lifetime, this represents an additional $60 – $80 or more in progeny value attributed to selection with PredicGEN. Assumes typical grid parameters with an $8 Choice-Select spread.

GROWTH IMPLANTS

SYNOVEX® H 200 mg testosterone propionate/20 mg estradiol benzoate

USES:For increased rate of weight gain and improved feed efficiency in heifers 400 pounds or more .

SUPPLIED:One pouch contains 10 10-dose cartridges (100 implants) .

KEY FACTS:• A growth-promoting implant containing 200 mg of

testosterone propionate and 20 mg of estradiol benzoate .

• One implant (eight pellets) is administered to each heifer by subcutaneous implantation in the middle one-third of the ear .

• The 10-dose cartridge is designed for use exclusively with the fixed-needle SYNOVEX Revolver or with the SX10 applicator with its unique retractable needle, which properly delivers the implant without crushing, bunching or dropping pellets .

SYNOVEX® C 100 mg progesterone/10 mg estradiol benzoate

USES:For increased rate of weight gain in suckling beef calves more than 45 days of age and up to 400 pounds of body weight . For improvement in rate of weight gain in steers weighing greater than 400 pounds and fed in confinement for slaughter when used as part of a re-implant program in which an initial SYNOVEX® C implant is followed at approximately 70 days by Synovex S .



progesterone and 10 mg of estradiol benzoate .

• One implant (four pellets) is administered to each calf by subcutaneous implantation in the middle one-third of the ear .

• May be used in suckling heifer and steer calves 45 days of age or older .

• The 10-dose cartridge is designed for use exclusively with the fixed-needle SYNOVEX Revolver or with the SX10 precision applicator with its unique retractable needle, which properly delivers the implant without crushing, bunching or dropping pellets .

SYNOVEX® S 200 mg progesterone/20 mg estradiol benzoate

USES:For increased rate of weight gain and improved feed efficiency in steers 400 pounds or more .



progesterone and 20 mg of estradiol benzoate . • One implant (eight pellets) is administered to each steer by

subcutaneous implantation in the middle one-third of the ear .


19Growth Implants

Do not use SYNOVEX products in veal calves . Refer to labels for complete directions for use, precautions, and warnings .

SYNOVEX CHOICE® 100 mg trenbolone acetate/14 mg estradiol benzoate

USES:For increased rate of weight gain in steers fed in confinement for slaughter, and for increased rate of weight gain and improved feed efficiency in heifers fed in confinement for slaughter .



trenbolone acetate and 14 mg of estradiol benzoate .

• One implant (four pellets) is administered to each steer or heifer by subcutaneous implantation in the middle one-third of the ear .


SYNOVEX® ONE FEEDLOT 200 mg trenbolone acetate/28 mg estradiol benzoate

USES:For increased rate of weight gain and improved feed efficiency for up to 200 days in steers and heifers fed in confinement for slaughter .


KEY FACTS:• The patented pore-forming barrier coating steadily

releases the trenbolone acetate and estradiol benzoate for 200 days of growth enhancement .

• One implant (eight pellets) is administered to each steer or heifer by subcutaneous implantation in the middle one-third of the ear .

• The 10-dose cartridge is designed for use exclusively with the SX10 precision applicator with its unique retractable needle, which properly delivers the implant without crushing, bunching or dropping pellets .

20 Growth Implants

Do not use SYNOVEX products in veal calves . Refer to labels for complete directions for use, precautions, and warnings .

SYNOVEX PLUS® 200 mg trenbolone acetate/28 mg estradiol benzoate

USES:For increased rate of weight gain and improved feed efficiency in steers and for increased rate of weight gain in heifers fed in confinement for slaughter .



trenbolone acetate and 28 mg of estradiol benzoate .

• One implant (eight pellets) is administered to each steer or heifer by subcutaneous implantation in the middle one-third of the ear .


SYNOVEX® ONE GRASS 150 mg trenbolone acetate/21 mg estradiol benzoate

USES:For increased rate of weight gain for up to 200 days in pasture steers and heifers (stocker, feeder and slaughter)


KEY FACTS:• The patented pore-forming barrier coating steadily

releases the trenbolone acetate and estradiol benzoate for 200 days of weight gain enhancement .

• One implant (six pellets) is administered to each steer or heifer by subcutaneous implantation in the middle one-third of the ear .

• The 10-dose cartridge is designed for use exclusively with the SX10 precision applicator with its unique retractable needle, which properly delivers the implant without crushing, bunching or dropping pellets .

ALBADRY PLUS® Suspension (penicillin/novobiocin sodium)

USES:Indicated for the treatment of subclinical mastitis caused by susceptible strains of Staphylococcus aureus and Streptococcus agalactiae in dry cows .

SUPPLIED:Packs of 12 and 144 10-mL disposable syringes (400 mg novobiocin and 200,000 IU procaine penicillin G per syringe) with individually wrapped isopropyl alcohol pads .

KEY FACTS:• Provides synergistic antibiotic combination of penicillin

and novobiocin .

• Bactericidal activity against major Staphylococcus and Streptococcus mastitis pathogens .

• Ideal duration of activity during the involution phase of the dry cow period (two to three weeks after milking stops), when the keratin plug has not formed and the cow is susceptible to infection .

• Contents of one syringe are infused into each quarter at dry off .

Do not use ALBADRY PLUS® 30 days prior to calving . Milk from treated cows must not be used for food during the first 72 hours after calving . Treated animals must not be slaughtered for food for 30 days following udder infusion .

ORBESEAL® (bismuth subnitrate)

USES:Indicated for prevention of new mastitis infections throughout the dry period .

SUPPLIED:Pails of 144 disposable syringes with individually wrapped isopropyl alcohol pads .

KEY FACTS:• Inert, nonantibiotic internal teat sealant for

intramammary infusion of nonlactating cows .

• Mimics the cow’s natural firstline of intramammary defense, the keratin plug .

• Provides a safe, physical barrier between the teat canal and the environment .

• Contains bismuth subnitrate, a safe, inert sealant .

• Contents of one syringe are infused into each teat cistern after administering a dry cow antibiotic therapy at dry off . Follow labeled dry period instructions specific to the antibiotic .

• If used alone, ORBESEAL® has zero milk withhold and zero pre-slaughter withdrawal .

• Refer to the ORBESEAL label for complete instructions on proper administration at dry off and removal at freshening .

ENVIRACOR® J-5

USES:Aids in the control of clinical signs associated with E. coli mastitis .


KEY FACTS:• Subcutaneous (SC) 5-mL dose given at dry off, 30 days later and within two

weeks of freshening .

• Patented adjuvant system for optimum immune response .

• Particularly valuable in recently freshened, low-SCC and high-production cows, which may be more susceptible to infection by E. coli .

• Three-dose vaccination program helps deliver protection and safety .

• Millions of doses given with demonstrated safety and efficacy .

MASTITIS PREVENTION AND TREATMENTDry Cow

21Mastitis Prevention and Treatment

SPECTRAMAST® DC Sterile Suspension (ceftiofur hydrochloride)

USES:Indicated for the treatment of subclinical mastitis in dairy cattle at the time of dry off associated with Staphylococcus aureus, Streptococcus dysgalactiae and Streptococcus uberis .

SUPPLIED:Packs of 12 and 144 10-mL disposable syringes (500 mg ceftiofur hydrochloride per syringe) with individually wrapped isopropyl alcohol pads .

KEY FACTS:• Extended-action oil base ensures long-lasting

effectiveness .

• Contents of one syringe are infused into each infected quarter at dry off .

• Milk taken from cows completing a 30-day dry cow period may be used for food with no milk discard due to ceftiofur residues .

IMPORTANT SAFETY INFORMATION:People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to SPECTRAMAST® DC . Product requires a 30-day dry cow period, and has a 16-day pre-slaughter withdrawal period following last treatment . Use of this product in a manner other than indicated on the label, or failure to adhere to the proper milk discard period, will result in violative residues . See full Prescribing Information, attached .

Following label use, no pre-slaughter withdrawal period is required for neonatal calves born from treated dams regardless of colostrum consumption .

22 Mastitis Prevention and Treatment

PIRSUE® Sterile Solution (pirlimycin hydrochloride)

USES:Indicated for the treatment of clinical and subclinical mastitis in lactating dairy cattle associated with Staphylococcus species such as Staphylococcus aureus, and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis .

SUPPLIED:Packs of 12 and 144 10-mL disposable syringes (50 mg pirlimycin hydrochloride per syringe) with individually wrapped isopropyl alcohol pads .

KEY FACTS:• For antibiotic treatment of clinical and subclinical

mastitis in lactating dairy cattle .

• Unique flexible therapy label (two to eight days) .

• Pirlimycin is unique in the way it is absorbed into the blood, which provides a long lasting effect and allows for once-per-day dosing .

• Once-per-day dosing allows you to optimize your hospital crew .

IMPORTANT SAFETY INFORMATION:PIRSUE has a nine-day pre-slaughter withdrawal period and an extended therapy withdrawal period of 21 days following last treatment . Discard milk during treatment and for 36 hours after last treatment regardless of treatment duration . Repeated infusion during extended duration therapy regimens can result in elevated somatic cell counts and clinical mastitis, which can result in animal death . If acute mastitis or other clinical signs of illness develop, discontinue therapy immediately and contact your veterinarian . See full Prescribing Information, attached .

SPECTRAMAST® LC Sterile Suspension (ceftiofur hydrochloride)

USES:Indicated for use in lactating dairy cattle for (1) the treatment of clinical mastitis associated with coagulase-negative staphylococci, Streptococcus dysgalactiae and Escherichia coli and (2) the treatment of diagnosed subclinical mastitis associated with coagulase-negative staphylococci and Streptococcus dysgalactiae .

SUPPLIED:Packs of 12 and 144 10-mL disposable syringes (125 mg ceftiofur hydrochloride per syringe) with individually wrapped isopropyl alcohol pads .

KEY FACTS:• For antibiotic treatment of clinical and subclinical

mastitis in lactating dairy cattle .

• Effective when used for the treatment of environmental staph and strep as well as E. coli infections .

• Once-a-day administration .

• Unique flexible therapy label (maximum of 8 days of treatment) .

IMPORTANT DIAGNOSTIC INFORMATION:SPECTRAMAST® LC is intended for use in lactating dairy cattle only with the specified, labeled pathogens . To assure responsible antimicrobial drug use, it is expected that subclinical mastitis will be diagnosed using a positive culture, or other pathogen-specific test, in addition to any other, appropriate veterinary medical evaluation prior to treatment .

IMPORTANT SAFETY INFORMATION:People with known hypersensitivity to penicillin or cephalosporins should avoid exposure to SPECTRAMAST LC . Product requires a 72-hour milk discard period and a 2-day pre-slaughter withdrawal period following last treatment . Use of this product in a manner other than indicated on the label, or failure to adhere to the proper milk discard period, will result in violative residues . See full Prescribing Information, attached .

Lactating Cow

23Mastitis Prevention and Treatment

ACTOGAINTM 45 (ractopamine hydrochloride Type A medicated article)

USES:Complete Feed: For increased rate of weight gain, improved feed efficiency and increased carcass leanness in cattle fed in confinement for slaughter during the last 28 to 42 days on feed .

Top-dress Feed: For increased rate of weight gain and improved feed efficiency in cattle fed in confinement for slaughter during the last 28 to 42 days on feed .

SUPPLIED:25-lb . plastic bag .

KEY FACTS:• Feeding ACTOGAINTM 45 during the last 28 to 42 days of

the finishing period redirects energy to make more lean muscle and less fat .

• ACTOGAIN contains ractopamine hydrochloride, the same beta agonist you’ve trusted for more than a decade .

• In recent studies, ACTOGAIN delivered +17 lb . in live weight, +11 lb . in carcass weight, +15% improvement in feed efficiency .1

Do not use ACTOGAIN in animals intended for breeding . Refer to label for complete directions for use, precautions, and warnings .

MEDICATED FEED ADDITIVES

AUREO S 700® (chlortetracycline, sulfamethazine Type A medicated article)

USES:As an aid in the maintenance of weight gain in the presence of respiratory disease such as shipping fever when fed in a 28-day program .

SUPPLIED:50-lb . multiwall paper bag with protective barrier ply .

KEY FACTS:• Established product with more

than 40 years of safe and effective use .

• Granular formulation gives uniform distribution in feed and minimizes carryover potential .

• Potent combination of two antibacterials .• Cost-effective .• Readily absorbed delivering high blood and lung tissue

concentrations .• A widely used feed medication in beef cattle starter diets .

Withdraw AUREO® S 700 seven (7) days prior to slaughter . Do not use in calves to be processed for veal .

Caution: Federal law restricts medicated feed containing this veterinary feed directive (VFD) drug to use by or on the order of a licensed veterinarian.

24 Medicated Feed Additives

1 Data on file, Study Report No . A131R-US-13-204, Zoetis Inc .

BOVATEC® (lasalocid Type A medicated article)

USES:For improved feed efficiency and increased rate of weight gain when used in medicated feeds for cattle fed in confinement for slaughter .For increased rate of weight gain when used in medicated feeds for pasture cattle (slaughter, stocker, feeder cattle, and dairy and beef replacement heifers) . Control of coccidiosis caused by Eimeria bovis and E. zuernii in cattle up to 800 pounds .

SUPPLIED:50-lb ., multiwall paper bag with protective barrier ply (BOVATEC® 91, 150 FP), or 50-lb . (7-gal .) plastic pails (BOVATEC Liquid 20)

KEY FACTS:• Increased rate of weight gain and feed efficiency .

• Effectively controls coccidiosis .

• Consistent gain improvement in cattle grazing pasture or provided high-roughage diets .

• Nutritional intake is not compromised and cattle adapt easily (no step-up period) .

• Wide range of free choice approvals (blocks, minerals, liquids, range cubes and tubs) .

• Approved for use in combination with AUREOMYCIN,® providing broad-spectrum health and performance benefits .

• Approved for use in combination with MGA® + Tylan® or MGA alone for feedlot heifers .

• BOVATEC Liquid 20 is the only liquid ionophore premix available .

Do not use BOVATEC in calves to be processed for veal . Do not allow horses or other equines access to feeds containing lasalocid, as ingestion may be fatal . Feeding undiluted or mixing errors resulting in excessive concentrations of lasalocid could be fatal to cattle and sheep .

AUREOMYCIN® (chlortetracycline Type A medicated article)

USES:Treatment and control of bacterial pneumonia caused by Pasteurella spp . Treatment of bacterial enteritis caused by Escherichia coli . Control of active infection of anaplasmosis caused by Anaplasma marginale . Reduction of liver condemnations due to liver abscesses .

SUPPLIED:50-lb . multiwall paper bag with protective barrier ply .

KEY FACTS:• Guaranteed potency and quality .

• Broad spectrum, effective against a wide range of respiratory and enteric diseases .

• Readily absorbed, delivering high blood and lung tissue concentrations .

• Approved for use in combination with BOVATEC,® DECCOX,® and CATTLYST® .

• Versatile product with applications in all phases of beef production, excluding veal .

• Convenient treatment option when individual animal handling is not practical .

• Available in both granular and meal form .• Reduces incidence of liver abscesses .• Zero-day slaughter withdrawal .• High margin of safety .

Do not use AUREOMYCIN® in calves to be processed for veal .


25Medicated Feed Additives

CHLORMAX® 50 (chlortetracycline Type A medicated article)

USES:Treatment and control of bacterial pneumonia caused by Pasteurella spp . Treatment of bacterial enteritis caused by Escherichia coli . Control of active infection of anaplasmosis caused by Anaplasma marginale . Reduction of liver condemnations due to liver abscesses .

SUPPLIED:50-lb multiwall paper bag with protective barrier ply .

KEY FACTS:• Broad spectrum, effective against a range of respiratory

and enteric diseases

• Readily absorbed, delivering high blood and lung tissue concentrations

• Versatile product with applications in all phases of beef production, excluding veal calves .

• High-quality meal formulation• Reduces incidence of liver abscesses• Refer to product label for withdrawal times

Do not feed CHLORMAX® 50 to calves to be processed for veal . Pre-slaughter withdrawal periods vary by indication . Consult product label for complete use directions and safety information including appropriate withdrawal period .


BOVATEC® 2.2 (lasalocid Type C medicated feed)

USES:For increased rate of weight gain in pasture cattle (slaughter, stocker, feeder cattle, as well as dairy and beef replacement heifers) .

SUPPLIED:44-lb . block, contains 2 .2 g lasalocid sodium per pound .

KEY FACTS:• Convenient delivery of BOVATEC®; reduced labor and

equipment cost .

• Has shown consistent gain improvement regardless of pasture type .

• Highest margin of safety among anticoccidial medication options .

• Complements most nonmedicated supplement programs .• No withdrawal period prior to slaughter is required .

Do not use BOVATEC in calves to be processed for veal . Do not allow horses or other equines access to feeds containing lasalocid, as ingestion may be fatal . Feeding undiluted or mixing errors resulting in excessive concentrations of lasalocid could be fatal to cattle and sheep . Contains copper . Do not feed to sheep .


MGA® 200 (melengestrol acetate Type A medicated article)

USES:For increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) in heifers fed in confinement for slaughter . For suppression of estrus in heifers intended for breeding .


KEY FACTS:• MGA® 200 is used in dry feed .

• Contains the progestin hormone melengestrol acetate (MGA) for increased rate of weight gain, improved feed efficiency and suppression of estrus .

• MGA may be fed in combination with BOVATEC® in a single dry supplement with or without Tylan® . MGA may be fed with Zilmax®, ACTOGAIN™ or Optaflexx®, and Rumensin® in a single dry supplement with or without Tylan . MGA is also approved for use in combination with oxytetracycline .

• MGA has no pre-slaughter withdrawal .

• Should be thoroughly mixed in the supplement of feedlot heifers to provide 0 .25-0 .50 mg of MGA per head per day . Consistent daily intake provides optimum improvements in rate of gain and feed utilization and a high degree of estrus suppression . Suppression of estrus is maximized at the 0 .50-mg feeding level .

DECCOX® (decoquinate Type A medicated article) DECCOX®-L (decoquinate Type B medicated feed) DECCOX®-M (decoquinate powder)

USES:For the prevention of coccidiosis in ruminating and non-ruminating calves (including veal calves) and cattle caused by Eimeria bovis and Eimeria zuernii . SUPPLIED:50-lb . multiwall paper bag with protective barrier ply . DECCOX®-L available in 50-lb . bags . DECCOX-M available in 5- and 50-lb . bags .

KEY FACTS:• Developed specifically for prevention of coccidiosis

• A nonantibiotic anticoccidial• Effective in preventing coccidiosis by stopping the

development of coccidia early in the life cycle• Reduces treatment costs and performance losses

associated with clinical outbreaks• The only anticoccidial feed medication approved for use

in veal calves• Versatile applications in dairy (milk replacer, whole milk,

complete feeds) and beef operations (top dress and complete feeds)

• Approved for use in combination with AUREOMYCIN,® providing respiratory treatment and coccidiosis prevention

Do not use DECCOX in cows producing milk for human consumption .

27Medicated Feed Additives

MGA® 500 (melengestrol acetate Type A medicated article)

USES:Type A medicated article for mixing with non-medicated feed for increased rate of weight gain, improved feed efficiency and suppression of estrus (heat) .

SUPPLIED:40-lb . containers (4 .627 gallons) .

KEY FACTS:• MGA® 500 is a liquid formulation .

• Contains the progestin hormone melengestrol acetate (MGA) for increased rate of weight gain, improved feed efficiency and suppression of estrus in heifers fed for slaughter .

• MGA 500 Premix may be fed in combination with BOVATEC®, in combination with ACTOGAINTM and Rumensin®, with Zilmax® or Optaflexx®, and Rumensin® in a single liquid supplement with or without Tylan® . MGA is also approved for use in combination with oxytetracycline .

• MGA has no pre-slaughter withdrawal .

• Should be thoroughly mixed in liquid Type C medicated feed, which must be fed at 0 .5-2 .0 lb . per head daily to provide 0 .25-0 .50 mg of MGA per head per day . Consistent daily intake provides optimum improvements in rate of gain and feed utilization and a high degree of estrus suppression . Suppression of estrus is maximized at the 0 .50-mg feeding level .


PARASITICIDES

DECTOMAX® Injectable (doramectin)

USES:Broad-spectrum treatment and control of internal and external parasites of cattle .

SUPPLIED:100-mL, 200-mL and 500-mL multidose vials .

KEY FACTS:• For treatment and control of various

species of gastrointestinal roundworms, lungworms, eyeworms, grubs, lice and mange mites .

• No other single product controls a broader spectrum of internal and external parasites ⎯ including 36 stages of adult parasites, L4 larvae and inhibited larvae .

• Has extended activity against Ostertagia ostertagi (21 days), Cooperia punctata (28 days) and C. oncophora (14 days) .

• Safe for use in beef cattle, including pregnant cows, newborn calves and bulls and dairy replacement heifers up to 20 months of age .

• Tissue-friendly injectable solution permits precise dosing .

• Dosage is 1 mL (10 mg doramectin) per 110 lb . body weight by either subcutaneous (SC) or intramuscular (IM) injection .

DECTOMAX® Injectable has a 35-day pre-slaughter withdrawal period . Do not use in female dairy cattle 20 months of age or older . Do not use in calves to be processed for veal . DECTOMAX has been developed specifically for cattle and swine . Use in dogs may result in fatalities .

DECTOMAX® Pour-On (doramectin)

USES:Proven to effectively control infections and to protect cattle from reinfection with Cooperia oncophora and Ostertagia ostertagi for 28 days and Cooperia punctata for 35 days after treatment .

SUPPLIED:1-liter multidose bottles, and 2 .5-L and 5-L multidose backpack containers .

KEY FACTS:• For treatment and control of various species of

gastrointestinal roundworms, lungworms, eyeworms, grubs, lice, horn flies and mange mites .

• Controls 33 stages of internal and external parasites with a single, convenient application .

• Provides seven-day persistent activity against horn flies .

• Weatherproof formulation won’t wash off .

• Safe for use on any age or class of beef cattle, including pregnant cows, calves and bulls and dairy replacement heifers up to 20 months of age .

• Dosage is 1 mL (5 mg doramectin) per 22 lb . body weight applied topically .

DECTOMAX Pour-On has a 45-day pre-slaughter withdrawal period . Do not use in female dairy cattle 20 months of age or older . Do not use in calves to be processed for veal . DECTOMAX has been developed specifically for cattle and swine . Use in dogs may result in fatalities .

29Parasiticides

VALBAZEN® Suspension (albendazole)

USES:Removal and control of stomach worms (including fourth-stage inhibited larvae of Ostertagia ostertagi), intestinal worms, lungworms, tapeworms and mature liver flukes .

SUPPLIED:500-mL, 1-L and 5-L bottles .

KEY FACTS:• One product controls four major

groups of parasitic worms ⎯ tapeworms, stomach worms, lungworms and liver flukes .

• Kills inhibited fourth stage Ostertagia (brown stomach worm) larvae, the most important internal parasite of cattle .

• Special drench gun makes administration fast and easy .

• Dosage is 4 mL/100 lb . body weight .

Cattle must not be slaughtered within 27 days after the last treatment with VALBAZEN® . Do not use in female dairy cattle of breeding age . Do not administer to female cattle during the first 45 days of pregnancy or for 45 days after removal of bulls .

30 Parasiticides

REPRODUCTIVE MANAGEMENT

EAZI-BREEDTM CIDR® Cattle Insert (progesterone intravaginal insert)

USES:Synchronization and advancement of estrus .

SUPPLIED:Each insert is impregnated with 1 .38 g of progesterone in elastic silicone molded over a nylon spine . Inserts are packaged in a plastic pouch with 10 inserts to a pouch . A special EAZI-BREEDTM CIDR® Applicator is available separately .

KEY FACTS:• More cows and heifers become pregnant earlier,

resulting in higher pregnancy rates .

• Easier and more accurate heat detection .

• More focused heat detection and easier artificial insemination (AI) breeding within a narrower window of time .

• Heifers freshening at a younger and more consistent age .

• Accurate breeding and calving dates .

• Improved efficiencies in labor management .

Avoid contact with skin by wearing protective gloves when handling EAZI-BREED CIDR inserts . Do not use in heifers of insufficient size or age for breeding or in cattle with abnormal, immature, or infected genital tracts . Do not use inserts more than once .

FACTREL® Injection (gonadorelin injection)

USES:FACTREL® Injection is approved for use with LUTALYSE® Injection (dinoprost tromethamine injection) or LUTALYSE® HighCon Injection (dinoprost tromethamine injection) to synchronize estrous cycles to allow for fixed-time artificial insemination (FTAI) in lactating dairy cows .

FACTREL is also indicated for treatment of ovarian follicular cysts in cattle . When used in cattle with ovarian follicular cysts, treatment effect is to reduce the number of days to next estrus .

SUPPLIED:20-mL vials (50 mcg/mL), 50-mL vials (50 mcg/mL) .

KEY FACTS:• This gonadotropin-releasing hormone (GnRH) is a

key component of a Food and Drug Administration-approved FTAI protocol when used in conjunction with LUTALYSE Injection in lactating dairy cattle .

• Backed by data with more than 12,000 combined cows studied in competitive trials which prove that FTAI with FACTREL and LUTALYSE provide an effective method of synchronizing estrus .1,2,3

• Flexible dosage treatment regimens to meet needs of individual operations and animals .

• Improves breeding efficiency in a FTAI protocol .

IMPORTANT SAFETY INFORMATION:FACTREL is for use in cattle only . See full Prescribing Information, attached .

1 Data on File, Study Report No . 13PETREPRO01-08D, Zoetis Inc .2 Poock S, Lucy M . Conception rate for postpartum dairy cows

treated with different gonadorelin (GnRH) products for first or resynchronized timed AI . Presented at 2015 Midwest ADSA/ASAS Meeting, Des Moines, IA, March 16-18, 2015 .

3 Caldwell V, Tison N, Martineau R, Dubuc J, Des Côteaux L . Non-inferiority randomized field clinical trial of two GnRH commercial products used in a systematic double-ovsynch protocol at first breeding in dairy cows, in Proceedings . Proc Am Assoc Bov Pract Conf 2014 .

31Reproductive Management

LUTALYSE® Injection (dinoprost tromethamine injection)

USES:Used to control the timing of estrous and ovulation in estrus cattle that have a corpus luteum, treatment of pyometra .

For use with FACTREL® Injection (gonadorelin injection) to synchronize estrous cycles to allow fixed-time artificial inseminiation in lactating dairy cows .

For use with EAZI-BREEDTM CIDR® Cattle Insert for synchronization of estrus in lactating dairy cows .

For use with EAZI-BREED CIDR Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows and advancement of first pubertal estrus in beef heifers .


KEY FACTS:• Stimulate luteolysis, which naturally regresses the

corpus luteum .

• Effective in treatment of pyometra (chronic endometritis) in cattle .

• Treatment of unobserved (silent) estrus in lactating dairy cattle .

• An entirely natural prostaglandin .

• A synchronized breeding program with LUTALYSE and FACTREL can:

• Improve pregnancy rates• Reduce time necessary for heat detection• Make more efficient use of labor• Reduce cull rates

IMPORTANT SAFETY INFORMATION FOR LUTALYSE/LUTALYSE HIGHCON:Women of childbearing age and persons with respiratory problems should exercise extreme caution when handling LUTALYSE/LUTALYSE HighCon . LUTALYSE/LUTALYSE HighCon are readily absorbed through the skin and may cause abortion and/or bronchiospasms, therefore spillage on the skin should be washed off immediately with soap and water . Aseptic techniques should be used to reduce the possibility of post-injection clostridial infections . Do not administer LUTALYSE/ LUTALYSE HighCon in pregnant cattle unless cessation of pregnancy is desired . See full Prescribing Information for LUTALYSE, attached . See full Prescribing Information for LUTALYSE HighCon, attached .

32 Reproductive Management

LUTALYSE® HighCon Injection (dinoprost tromethamine injection)

USES:LUTALYSE® HighCon Injection is a high-concentration formula of LUTALYSE® Injection (dinoprost tromethamine injection) and gives you the same results as the LUTALYSE Injection you know and trust, in smaller, more convenient to administer 2-mL doses . LUTALYSE HighCon is the first and only prostaglandin approved for subcutaneous administration .

LUTALYSE HighCon is approved for use with FACTREL Injection (gonadorelin injection) to synchronize estrous cycles to allow for fixed-time artificial insemination (FTAI) in lactating dairy cows . It also is approved for use with EAZI-BREED™ CIDR® Cattle Inserts in heifers and cows to improve breeding efficiency and pregnancy success . It’s important to note that LUTALYSE HighCon is approved for use in cattle only, not equine or swine like LUTALYSE.

SUPPLIED:20-mL vial contains 10 doses,100-mL vial contains 50 doses,250-mL vial contains 125 doses .

KEY FACTS:• Approved for a convenient 2-mL dose .

• The first and only prostaglandin with an Food and Drug Administration-approved subcutaneous claim in addition to intramuscular administration .

• Now producers and veterinarians have flexible options to choose a subcutaneous route of administration consistent with strict Beef Quality Assurance standards and Dairy Animal Care and Quality Assurance .

• Available in three bottle sizes, allowing choices that best fit management needs for handling and administration .

• An entirely natural prostaglandin .

• Useful therapeutically for controlled breeding .

• A synchronized breeding program with LUTALYSE HighCon and FACTREL can:

• Improve pregnancy rates• Reduce time necessary for heat detection• Make more efficient use of labor• Reduce cull rates

RESPIRATORY-REPRODUCTIVE VACCINES

BOVI-SHIELD GOLD® BVD Bovine Virus Diarrhea Vaccine (Modified-Live Virus)

USES:Aids in preventing respiratory disease caused by bovine viral diarrhea (BVD) virus Types 1 and 2, and when administered subcutaneously, prevents viremia caused by BVD Types 1 and 2 viruses .


KEY FACTS:• Prevents BVD Types 1 and 2 viremia when administered

subcutaneously .

• Aids in the prevention of respiratory disease caused by BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously .

• Shown to be safe when given to pregnant cows or calves nursing pregnant cows .*

• Single 2-mL intramuscular or subcutaneous dose . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .

BOVI-SHIELD GOLD® IBR-BVD Bovine Rhinotracheitis-Virus Diarrhea Vaccine (Modified-Live Virus)

USES:Prevents respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus, viremia caused by bovine viral diarrhea (BVD) virus Types 1 and 2, and aids in preventing respiratory disease caused by BVD Types 1 and 2 viruses when administered by the subcutaneous route of administration . When administered intramuscularly, BOVI-SHIELD GOLD® IBR-BVD aids in preventing respiratory disease caused by IBR virus and BVD Types 1 and 2 viruses .



subcutaneously .

• Prevents respiratory disease caused by IBR virus for at least 279 days when administered subcutaneously .



• Single 2-mL subcutaneous or intramuscular dose . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .

* Do not use in pregnant cattle (abortions can result) unless they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP® vaccine pre-breeding initially and within 12 months thereafter . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above . To help ensure safety in pregnant cattle, heifers must receive at least 2 doses of any BOVI-SHIELD GOLD FP or PREGGUARD GOLD FP vaccine with the second dose administered approximately 30 days prebreeding.

33Respiratory-Reproductive Vaccines

BOVI-SHIELD GOLD® 4 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3 Vaccine (Modified-Live Virus)

USES:Prevents respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus, viremia caused by bovine viral diarrhea (BVD) virus Types 1 and 2, and aids in preventing respiratory disease caused by BVD virus Types 1 and 2, and respiratory disease caused by parainfluenza 3 (PI3) virus when administered by the subcutaneous route of administration . When administered intramuscularly, BOVI-SHIELD GOLD® 4 aids in preventing respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses and PI3 virus .



subcutaneously .• Prevents respiratory disease caused by IBR virus for at

least 279 days when administered subcutaneously .• Aids in the prevention of respiratory disease caused by

BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously .

• Aids in the prevention of respiratory disease caused by PI3 virus when administered either intramuscularly or subcutaneously .



BOVI-SHIELD GOLD® 5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)

USES:Prevents respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus, viremia caused by bovine viral diarrhea (BVD) virus Types 1 and 2, and aids in preventing respiratory disease caused by BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV) when administered by the subcutaneous route of administration . When administered intramuscularly, BOVI-SHIELD GOLD® 5 aids in preventing respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, PI3 virus and BRSV .



subcutaneously .• Prevents respiratory disease caused by IBR virus for at

least 279 days when administered subcutaneously .• Aids in the prevention of respiratory disease caused by

BVD Types 1 and 2 viruses for at least 279 days when administered subcutaneously .

• Aids in the prevention of respiratory disease caused by BRSV and PI3 virus when administered either intramuscularly or subcutaneously .




Respiratory-Reproductive Vaccines34

BOVI-SHIELD GOLD FP® 5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2 and respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus; aids in preventing abortion caused by IBR virus and respiratory disease caused by BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV) and BVD Type 2 testicular infection when administered subcutaneously . When administered intramuscularly, BOVI-SHIELD GOLD FP® 5 prevents persistently infected calves caused by BVD virus Types 1 and 2 and aids in preventing abortion caused by IBR virus; respiratory disease caused by IBR, BVD Types 1 and 2 viruses, PI3 virus and BRSV; and BVD Type 2 testicular infection .


KEY FACTS:• Helps prevent BVD Types 1 and 2 persistent infection for

at least 365 days .• Aids in the prevention of IBR abortions for at least 365

days .• Prevents respiratory disease caused by IBR virus for at

least 279 days .†• Aids in the prevention of respiratory disease caused by

BVD Types 1 and 2 viruses for at least 279 days .†• Aids in the prevention of respiratory disease caused by

BRSV and PI3 virus .


• Single 2-mL subcutaneous or intramuscular dose .

BOVI-SHIELD GOLD FP® 5 L5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)- Leptospira Canicola-Grippotyphosa-Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2; aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV); BVD Type 2 testicular infection; and leptospirosis caused by the five Leptospira serovars indicated above .


KEY FACTS:• Shown to be safe when given to pregnant cows or calves

nursing pregnant cows .*• Helps prevents BVD Types 1 and 2 persistent infection for at

least 365 days .• Aids in the prevention of IBR abortions for at least

365 days .• Aids in the prevention of respiratory disease caused by

IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3 virus .• Aids in the prevention of leptospirosis caused by the five

serovars indicated above .• Single 2-mL intramuscular dose .

† Prevents IBR respiratory disease and IBR and BVD Types 1 and 2 respiratory DOI claims only apply to SC route of administration .



BOVI-SHIELD GOLD FP® 5 VL5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)-Campylobacter Fetus-Leptospira Canicola-Grippotyphosa- Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2; aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV); BVD Type 2 testicular infection; campylobacteriosis (vibrosis) caused by Campylobacter fetus and leptospirosis caused by the five Leptospira serovars indicated above .


KEY FACTS:• Helps prevent BVD Types 1 and 2 persistent infection for at

least 365 days .

• Aids in the prevention of IBR abortions for at least 365 days .

• Aids in the prevention of respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3

virus .

• Aids in the prevention of campylobacteriosis caused by C. fetus and leptospirosis caused by the five serovars indicated above .


• Single 2-mL intramuscular dose followed by a single dose of VIBRIN/LEPTOFERM-5® three to four weeks later .



BOVI-SHIELD GOLD FP® 5 L5 HB Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)-Leptospira Canicola-Grippotyphosa-Hardjo- Icterohaemorrhagiae-Pomona Bacterin

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2; aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV); and BVD Type 2 testicular infection . Prevents infection and urinary shedding caused by Leptospira borgpetersenii serovar Hardjo type hardjo-bovis (LHB) and aids in the prevention of diseases caused by L. pomona, L. grippotyphosa, L. canicola and L. icterohaemorrhagiae .


KEY FACTS:• Helps prevent BVD Types 1 and 2 persistent infection for

at least 365 days .

• Prevents LHB kidney colonization and urinary shedding for at least 365 days .

• Prevents LHB genital tract colonization .

• Aids in the prevention of LHB fetal infections .


• Aids in the prevention of IBR abortion for at least 365 days .


• Aids in the prevention of respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, BRSV and PI3 virus when administered intramuscularly .


• Single 2-mL intramuscular or subcutaneous dose followed by a single dose of SPIROVAC® four to six weeks later . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .

BOVI-SHIELD GOLD ONE SHOT® Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus), Mannheimia Haemolytica Toxoid

USES:Prevents respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus; prevents viremia caused by bovine viral diarrhea (BVD) Types 1 and 2 viruses; aids in prevention of respiratory disease caused by BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus, and bovine respiratory syncytial virus (BRSV); aids in prevention of bovine pneumonia caused by Mannheimia haemolytica Type A1 .


KEY FACTS:• Convenient one dose administration .

• The only combination vaccine that prevents three important bovine respiratory disease conditions while also providing the strongest available protection against Mannheimia haemolytica .

• Helps prevent bovine respiratory disease .

• Prevents respiratory disease caused by IBR virus .

• Prevents viremia caused by BVD Types 1 and 2 viruses .

• Aids in prevention of respiratory disease caused by BVD Types 1 and 2 viruses, PI

3 virus and BRSV .

• Aid in prevention of bovine pneumonia caused by Mannheimia haemolytica Type A1 .

• Single 2-mL subcutaneous administration in the neck region .



BOVI-SHIELD® IBR Bovine Rhinotracheitis Vaccine (Modified-Live Virus)

USES:Prevents respiratory disease caused by infectious bovine rhinotracheitis (IBR) virus when administered by the subcutaneous route of administration . Aids in the prevention of IBR when administered by the intramuscular route .

SUPPLIED:50-dose vial .

KEY FACTS:• Prevents respiratory disease caused by IBR virus for at

least 279 days when administered by the subcutaneous route .

• Not for use in pregnant cows (abortions can result) .

• Single 2-mL subcutaneous dose or intramuscular . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .

BOVI-SHIELD GOLD FP® 5 VL5 HB Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)-Campylobacter Fetus-Leptospira Canicola-Grippotyphosa- Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2; aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV); and BVD Type 2 testicular infection . Prevents infection and urinary shedding caused by Leptospira borgpetersenii serovar Hardjo type hardjo-bovis (LHB) and aids in the prevention of campylobacteriosis (vibriosis) caused by Campylobacter fetus and diseases caused by L. pomona, L grippotyphosa, L. canicola and L. icterohaemorrhagiae .


KEY FACTS:• Helps prevent BVD Types 1 and 2 persistent infection for at

least 365 days .

• Prevents LHB kidney colonization and urinary shedding for at least 365 days .

• Prevents LHB genital tract colonization .

• Aids in the prevention of LHB fetal infections .


• Aids in the prevention of IBR abortion for at least 365 days .


• Aids in the prevention of respiratory disease caused by BVD Types 1 and 2 viruses, BRSV, PI3 virus and IBR virus when administered intramuscularly .


• Single 5 mL intramuscular or subcutaneous dose followed by a single dose of SPIROVAC® VL5 four to six weeks later . Calves vaccinated before 6 months of age should be revaccinated after 6 months of age .



CATTLEMASTER GOLD FP® 5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza3-Respiratory Syncytial Virus Vaccine (Modified-Live and Killed Virus)

USES:Aids in the prevention of abortion caused by infectious bovine rhinotracheitis (IBR), persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2, and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV) .


KEY FACTS:• Helps provide demonstrated protection from the four

most common viral respiratory diseases .

• Killed BVD Type 2 virus helps deliver exceptional respiratory protection even against a lethal challenge .1

• The only killed BVD vaccine line with the power to help deliver protection from BVD persistent infection and IBR abortion .*

• Demonstrated safe modified-live IBR virus, PI3 virus and BRSV protection .

• Adjuvant system stimulates the immune system for exceptional IBR and BVD protective levels .

• Safe and convenient, vaccinate any calf, any cow, anytime .

• Beef-friendly subcutaneous injection .

1 Data on file, Study Report No . 3131R-60-02-251, Zoetis Inc . *Fetal Protection from BVD persistent infection when administered prior to breeding .

CATTLEMASTER GOLD FP® 5 L5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza3-Respiratory Syncytial Virus Vaccine (Modified-Live and Killed Virus)- Leptospira Canicola-Grippotyphosa-Hardjo- Icterohaemorrhagiae-Pomona Bacterin

USES:Aids in the prevention of abortion caused by infectious bovine rhinotracheitis (IBR) virus, persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2, respiratory disease caused by IBR virus, BVD Types 1 and 2 virus, parainfluenza 3 (PI3) virus and bovine respiratory syncytial virus (BRSV) and leptospirosis caused by the five Leptospira serovars indicated above .


KEY FACTS:• Helps provide demonstrated protection from the four

most common viral respiratory diseases, plus five-way leptospirosis protection .

• Killed BVD Type 2 virus helps deliver exceptional respiratory protection even against a lethal challenge .1

• The only killed BVD vaccine line with the power to help deliver protection from BVD persistent infection and IBR abortion .*

• Demonstrated safe modified-live IBR virus, PI3 virus and BRSV protection .

• Adjuvant system stimulates the immune system for exceptional IBR and BVD protective levels .

• Safe and convenient, vaccinate any calf, any cow, anytime .

• Beef-friendly subcutaneous injection .

1 Data on file, Study Report No . 3131R-60-02-251, Zoetis Inc . *Fetal Protection from BVD persistent infection when administered prior to breeding .


CATTLEMASTER® 4+VL5 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live and Killed Virus)- Campylobacter Fetus-Leptospira Canicola-Grippotyphosa-Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES:Aids in the prevention of diseases caused by infectious bovine rhinotracheitis (IBR) virus, bovine viral diarrhea (BVD) Type 1 virus, parainfluenza 3 (PI3) virus, bovine respiratory syncytial virus (BRSV), campylobacteriosis (vibrosis) caused by Campylobacter fetus and the leptospirosis caused by the five Leptospira serovars indicated above .


KEY FACTS:• Helps provide protection against four major viral

respiratory diseases of cattle, plus protection against campylobacteriosis (vibriosis) and five common causes of leptospirosis .

• Contains chemically altered, temperature-sensitive IBR and PI3 strains that do not grow outside the upper respiratory tract and are incapable of systemic replication or fetal infection .

• The nonshedding, nonimmunosuppressive and nonabortigenic viral agents used in CATTLEMASTER® vaccines are safe for use in any cow, any calf, anytime .

• Intramuscular dose is 5-mL followed by a second dose given two to four weeks later .

• Annual revaccination with a single dose is recommended .

• Occasional hypersensitivity reactions may occur up to 18 hours post-vaccination . Owners should be advised to observe animals during this period . While this event appears to be rare overall, dairy cattle may be affected more frequently than other cattle .

INFORCETM 3 Bovine Rhinotracheitis-Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)

USES:Prevents respiratory disease caused by bovine respiratory syncytial virus (BRSV), and aids in the prevention of infectious bovine rhinotracheitis (IBR) and parainfluenza 3 (PI3) .

SUPPLIED:1-, 10-, 25- and 50-dose vials .

KEY FACTS:• First and only respiratory vaccine with the highest level

of disease prevention currently available against BRSV .

• Developed for single nostril administration .

• Provides at least six months of protection against IBR respiratory disease and at least 57 days of protection against BRSV respiratory disease after single nostril administration .

• Contains proprietary, temperature-sensitive IBR and PI3 strains, and a naturally temperature-sensitive BRSV strain that replicate effectively in the nasal passages .

• Helps prime the immune system for a memory response to subsequent disease challenges .

• Stimulates interferon release for protection .

• Safe and effective for use in all classes and types of cattle in all management situations .

• Provides at least six months duration of immunity against IBR respiratory disease .


LEPTOFERM-5® Leptospira Canicola-Grippotyphosa-Hardjo-Icterohaemorrhagiae-Pomona Bacterin

USES:Aids in the prevention of leptospirosis caused by the five serovars indicated above .


KEY FACTS:• Helps provide protection against a

contagious disease .

• Single intramuscular dose is 2-mL, with annual revaccination .

ONE SHOT® BVD Bovine Virus Diarrhea Vaccine (modified-live virus) Mannheimia Haemolytica Toxoid

USES:Aids in the protection of Mannheimia haemolytica and bovine viral diarrhea (BVD) Types 1 and 2 viruses, two of the major respiratory viruses that cause bovine respiratory disease (BRD) . Use ONE SHOT® BVD and INFORCE 3 concurrently for comprehensive respiratory protection .


KEY FACTS:• Helps young calves build the immunity they need prior

to commingling of dairy calves and at turnout for beef calves .

• Helps provide a convenient and effective way to combat BRD .

WARNING:Do not use in pregnant cows (abortions can result) unless they were vaccinated, according to label directions, with any BOVI-SHIELD GOLD FP® or PREGGUARD GOLD FP vaccine within the past 12 months . Do not use in calves nursing pregnant cows unless their dams were vaccinated within the past 12 months as described above .

ONE SHOT® Mannheimia Haemolytica Bacterin-Toxoid

USES:Aids in the prevention of bovine pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 .


KEY FACTS:• Helps protect against the primary cause of respiratory

death in cattle, shipping fever and pneumonia caused by Mannheimia (Pasteurella) haemolytica Type A1 .

• Contains killed bacterial culture plus a toxoid .


• Single subcutaneous dose is 2 mL .


ONE SHOT ULTRA® 7 Clostridium Chauvoei-Septicum-Novyi-Sordellii- Perfringens Types C & D-Mannheimia Haemolytica Bacterin-Toxoid



KEY FACTS:• Helps prevent seven clostridial diseases (including

diseases caused by Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .



• Contains STIMUGEN®, a patented, water-soluble adjuvant that enhances the immune response with minimal risk of injection-site reactions .


• Subcutaneous dose is 2-mL followed by a second 2 mL dose of ULTRACHOICE® 7 four to six weeks later .

ONE SHOT ULTRA® 8 Clostridium Chauvoei-Septicum-Haemolyticum- Novyi-Sordellii-Perfringens Types C & D-Mannheimia Haemolytica Bacterin-Toxoid



KEY FACTS:• Helps prevent eight clostridial diseases (including

diseases caused by Cl. haemolyticum and Cl. perfringens Types B, C and D), which continue to be of economic importance in cattle . Clostridium bacteria are universally present and produce potent toxins that can result in rapid death of otherwise healthy animals .



• Contains STIMUGEN, a patented, water-soluble adjuvant that enhances the immune response with minimal risk of injection-site reactions .


• Subcutaneous dose is 2 mL followed by a second 2-mL dose of ULTRACHOICE® 8 four to six weeks later .



PREGGUARD GOLD FP® 10 Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3 Vaccine (Modified-Live Virus)- Campylobacter Fetus-Leptospira Canicola- Grippotyphosa-Hardjo-Icterohaemorrhagiae- Pomona Bacterin

USES:Prevents persistently infected calves caused by bovine viral diarrhea (BVD) virus Types 1 and 2 and aids in preventing abortion caused by infectious bovine rhinotracheitis (IBR) virus and respiratory disease caused by IBR virus, BVD Types 1 and 2 viruses, and parainfluenza 3 (PI3) virus; BVD Type 2 testicular infection; campylobacteriosis (vibriosis) caused by Campylobacter fetus and leptospirosis caused by the five Leptospira serovars indicated above . A 12-month duration of immunity has been demonstrated against IBR induced abortion and persistently infected calves caused by BVD Types 1 and 2 viruses .


KEY FACTS:• Helps prevent BVD Types 1 and 2 persistent infection

for at least 365 days .

• Aids in the prevention of IBR abortions for at least 365 days .

• Aids in the prevention of respiratory disease caused by IBR virus, BVD virus Types 1 and 2, and PI3 virus .

• Aids in the prevention of campylobacteriosis caused by C. fetus and leptospirosis caused by the five serovars indicated above .


• Intramuscular dose is 2 mL, given to breeding cows and heifers approximately one month prior to breeding or being added to the herd, followed by a single dose of VIBRIN/LEPTOFERM-5® two to four weeks later to help provide primary C. fetus and Leptospira immunization .

RESVAC® 4/SOMUBAC® Bovine Rhinotracheitis-Virus Diarrhea- Parainfluenza 3-Respiratory Syncytial Virus Vaccine (Modified-Live Virus)-Haemophilus Somnus Bacterin

USES:Aids in the prevention of diseases caused by infectious bovine rhinotracheitis virus, bovine viral diarrhea Type 1 virus, parainfluenza 3 virus, bovine respiratory syncytial virus and Histophilus somni (Haemophilus somnus) .


KEY FACTS:• Helps provide protection against four of the most

common bovine viral respiratory diseases plus H. somni .

• Intramuscular dose is 2-mL . Administer two doses two to four weeks apart .


SOMUBAC® Haemophilus Somnus Bacterin

USES:Aids in the prevention of disease caused by Histophilus somni (Haemophilus somnus) .


KEY FACTS:• Helps protect calves and adult

cattle against H. somni, a contributor to respiratory disease and the cause of thrombotic meningoencephalitis (TEME) and reproductive tract infection .

• Contains three inactivated H. somni isolates ⎯ from respiratory, reproductive and nervous tissue .

• Subcutaneous dose is 2 mL followed by a second dose two to four weeks later .




SPIROVAC® Leptospira Hardjo Bacterin

USES:Prevention of infection caused by Leptospira borgpetersenii serovar Hardjo type hardjo-bovis, including genital and renal tract colonization, and urinary shedding for up to 12 months .


KEY FACTS:• Provides 12-month duration of immunity, resulting in

less time and labor required for vaccination .

• Safe for use in pregnant cows, enabling whole-herd vaccination .

• Subcutaneous dose is 2 mL followed by a second dose given four to six weeks later .


SPIROVAC® L5 Leptospira Canicola-Grippotyphosa-Hardjo- Icterohaemorrhagiae-Pomona Bacterin

USES:Prevention of infection caused by Leptospira borgpetersenii serovar hardjo type hardjo-bovis, including genital and renal tract colonization and urinary shedding for up to 12 months . Aids in the prevention of diseases caused by L. pomona, L. grippotyphosa, L. canicola and L. icterohaemorrhagiae .


KEY FACTS:• Provides 12 month duration of immunity against

Leptospira borgpetersenii serovar Hardjo type hardjo-bovis, resulting in less time and labor required for vaccination .


• Subcutaneous or intramuscular dose is 2 mL followed by a second dose given four to six weeks later .


SPIROVAC® VL5 Campylobacter Fetus-Leptospira Canicola- Grippotyphosa-Hardjo-Icterohaemorrhagiae- Pomona Bacterin

USES:Prevention of infection caused by Leptospira borgpetersenii serovar Hardjo type hardjo-bovis, including genital and renal tract colonization and urinary shedding for up to 12 months . Aids in the prevention of diseases caused by L. pomona, L. grippotyphosa, L. canicola, L. icterohaemorrhagiae and Campylobacter fetus .


KEY FACTS:• Provides 12 month duration of immunity against

Leptospira borgpetersenii serovar Hardjo type hardjo-bovis, resulting in less time and labor required for vaccination .


• Subcutaneous or intramuscular dose is 5 mL followed by a second dose given four to six weeks later .



STAYBRED® VL5 Campylobacter Fetus-Leptospira-Canicola- Grippotyphosa-Hardjo-Icterohaemorrhagiae- Pomona Bacterin

USES:Aids in the prevention of diseases caused by Campylobacter fetus and the five Leptospira serovars indicated above .


KEY FACTS:• Vaccination is the most cost-effective method of

controlling two of the most important bovine reproductive diseases ⎯ campylobacteriosis (vibriosis) and leptospirosis ⎯ that can be difficult to detect, particularly in adult cattle .

• Intramuscular dose is 2 mL followed by a second dose two to four weeks later given to all breeding-age cows and heifers 30 to 60 days before exposure or being added to the breeding herd .


• Occasional hypersensitivity reactions may occur up to 18 hours post-vaccination . Owners should be advised to observe animals during this period . While this event appears to be rare overall, dairy cattle may be affected more frequently than other cattle .

VIBRIN® Campylobacter Fetus Bacterin

USES:Aids in the prevention of campylobacteriosis (vibriosis) caused by Campylobacter fetus .


KEY FACTS:• Helps protect against campylobacteriosis,

a common but difficult-to-detect reproductive disease of cattle .

• A single dose is effective .

• May be given as early as seven months before breeding, making it ideal for use at fall pregnancy check .

• Single subcutaneous dose is 2 mL given to all breeding cows and heifers between 30 days and seven months before breeding .

TSV-2® Bovine Rhinotracheitis-Parainfluenza3 Vaccine (Modified-Live Virus)

USES:Aids in the prevention of diseases caused by infectious bovine rhinotracheitis (IBR) virus and parainfluenza 3 virus .

SUPPLIED:1-, 10-, 25- and 50-dose vials .

KEY FACTS:• Intranasal (IN) administration results in rapid local

immunity at the site of natural infection .

• Stimulates local and systemic immunity .

• Rapid protection makes TSV-2® a tool to use in the face of a potential IBR outbreak in young cattle or when receiving long-haul, high-risk calves .

• Safe for use in pregnant cows .

• Single IN dose is 2 mL, with annual revaccination .


OTHER HEALTH MANAGEMENT

Other Health Management46

THERABLOAT® (poloxalene)

USES:To treat legume (alfalfa, clover) bloat in cattle .

SUPPLIED:2-fl . oz . (59 .1-mL) vial containing 25 g of poloxalene per fl . oz .

KEY FACTS:• Relieves legume bloat within minutes .• Contains the surfactant poloxalene, an antifoaming agent

that works by collapsing gas bubbles that cause bloat .• May be used in lactating animals .• Provided in concentrated form for easy storage and

handling .• For animals up to 500 lb ., 1 fl . oz . added to 1 pint of

water is given in a drenching bottle . For animals over 500 lb ., 2 fl . oz . are used .

• Do not use in humans .

OTHER VACCINE SOLUTIONS

SolidBac® Pinkeye IR/PR® Moraxella Bovis Bacterin

USES:Aids in the prevention and control of pinkeye (infectious bovine keratoconjunctivitis) caused by Moraxella bovis .

SUPPLIED:Five 10-dose clips (50 doses) .

KEY FACTS:• Implant system delivers both initial and booster doses at

the same time for season-long pinkeye protection .

• Immediate release (IR) pellet helps provide protection while programmed release (PR) pellet provides a slow-release booster .

• No more mixing, spillage or waste .

• Flexible, tissue-friendly injection site locations .

ESCHERICHIA COLI BACTERIAL EXTRACT VACCINE with SRP® technology E. Coli O157 vaccine with SRP (Siderophore Receptors and Porins)

USES:Helps reduce the amount of Escherichia coli (E. coli) 0157 in the intestines of cattle and helps decrease the amount shed in the feces to minimize E.ncoli 0157 exposure and infection of herdmates .

SUPPLIED:100-mL vial (50 doses) .

KEY FACTS:• The first and only vaccine conditionally licensed to

reduce the amount of E. coli 0157 in cattle .

• Has been shown to help reduce the number of cattle testing positive for the bacteria by 85% .1

• Those animals still testing positive demonstrated a 98% reduction in concentrations of E. coli .1

* This product license is conditional . Efficacy and potency test studies are in progress .

1 Thomson DU, Loneragan GH, Thornton AB, et al . Use of a siderophore receptor and porin proteins-based vaccine to control the burden of Escherichia coli 0157:H7 in feedlot cattle . Foodborne Pathog Dis . 2009;6:871-877 .

SRP® SALMONELLA Salmonella Newport Vaccine with SRP (Siderophore Receptors and Porins)

USES:Aids in the control of disease and fecal shedding caused by infection with Salmonella Newport .

SUPPLIED:100-mL vial (50 doses) .

KEY FACTS:• Helps control infection and fecal

shedding of Salmonella Newport, resulting in reduced disease incidence and improved herd performance .1

• The SRP antibodies generated by vaccination with SRP® SALMONELLA vaccine have been shown to recognize the SRPs of several common Salmonella serotypes .2

• Administer 2 mL (1 dose) subcutaneously ahead of the shoulder . Revaccinate in two or four weeks . Dry cows and bred heifers should be vaccinated twice before calving; whole-herd vaccination may be done at any stage of lactation as an aid to control salmonellosis . Revaccinate annually .

1 Hermesch DR, Thomson DU, Loneragan GH, Renter DR, White BJ . Effects of a commercially available vaccine against Salmonella enterica serotype Newport on milk production, somatic cell count and shedding of Salmonella organisms in female dairy cattle with no clinical signs of salmonellosis . Am J Vet Res . 2008;69:1229-1234 .

2 Data on file, Epitopix Study Report No . N-0005-136-142, Zoetis Inc .

47Other Vaccine Solutions

SERVICES

PEOPLEFIRSTTM Human Capital Solutions

The industry’s first comprehensive human capital and business management solutions service Since 2009, PeopleFirst™ Human Capital Solutions provides owners, managers, supervisors and employees of agricultural operations, veterinary clinics and ranch and farm retail with comprehensive and strategic services to address leadership development, employee training and business objectives and strategies .

BUSINESS SERVICES:

• Profit Solver® — The ultimate financial diagnostic tool for your veterinary practice . Profit Solver can increase clinic profitability by a scientific method of determining fair service pricing . Practice-specific recommendations are made using your own labor, equipment and inventory costs . Guaranteed to double your investment the first year, or your money back* .

• Strategic Planning — Custom and standard consulting help create a strategic plan for your business by identifying your three-year objectives, aligning your team around your strategic intent and creating an action plan to accomplish your goals .

• Succession Planning — We will work with you to develop a plan to transfer your assets . We are experts at facilitating those difficult conversations, with family members or business partners, to satisfy your goals . We’ll work with your own lawyer and accountant to put the plan in place .

• Marketing Planning — We’ll work with your staff to develop plans to help your business grow .

• Customized services — An array of consultative services can be customized to meet your business needs, client surveys, scenario planning and action planning .

EMPLOYEE SERVICES:

• Leadership Certificate Program — This course, delivered in English and Spanish, develops leadership skills for managers and supervisors to help improve how they run their operation, agribusiness or veterinary practice .

• Learning Management Portal — Online technology automates and centralizes employee orientation to ensure everyone develops the right skills to achieve organizational objectives . The portal gives your organization the ability to provide continuous training, track/score completion and customize and formalize learning plans .

• Focused Leadership Principles — The next step in advancing leadership skills for managers in the agricultural industry . Designed for leaders who have an understanding of leadership fundamentals and best practices and want to further develop their leadership skills .

• Customized services — An array of consultative services can be customized to meet your needs, including full organizational evaluations, engagement and 360-degree feedback, leadership training, change management and executive coaching .

Please contact your local Zoetis representative to find out more about PeopleFirst .

*Zoetis guarantees that if you implement, follow and adhere to the recommendations agreed upon during the Profit Solver implementation, for the opportunities identified (e .g ., the customer must be willing to raise fees or reduce costs for services as agreed upon during the implementation) for one full year, then you will increase the profit from your business in an amount equivalent to at least twice the first year’s fees paid for Profit Solver . The guarantee does not apply if your goal is to maintain the existing profit level of the business rather than increase it .

Services48

PRESCRIBINGINFORMATION

50

Sterile Injectable SolutionAntimicrobial180 mg of danofloxacin as the mesylate salt/mLFor subcutaneous use in beef cattle.Not for use in cattle intended for dairy production or in calves to be processed for veal.CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Federal law prohibits the extra-label use of this drug in food-producing animals.DESCRIPTION: ADVOCIN is a sterile injectable solution containing danofloxacin mesylate, a synthetic fluoroquinolone antimicrobial agent. Danofloxacin mesylate is the non-proprietary designation for (1S)-1cyclopropyl-6-fluoro-1,4-dihydro-7-(5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl)-4-oxo-3-quinolone carboxylic acid monomethanesulfonate. The empirical formula is C19H20FN3O3 • CH3SO3H and the molecular weight is 453.49. Figure 1. The chemical structure of danofloxacin mesylate.

Each mL contains 180 mg of danofloxacin as the mesylate salt, 200 mg 2-pyrrolidone, 50 mg polyvinyl pyrrolidone, 20.3 mg heavy magnesium oxide, 2.5 mg phenol, 5 mg monothioglycerol, hydrochloric acid or sodium hydroxide as needed to adjust pH, nitrogen headspace and water for injection, q.s. INDICATIONS: For the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica and Pasteurella multocida in beef cattle and for the control of BRD in beef cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida.DOSAGE AND ADMINISTRATION: Care should be taken to dose accurately. Administered dose volume should not exceed 15 mL per injection site. Single-Dose Therapy (BRD Treatment and Control in Cattle at High Risk): Administer subcutaneously at 8 mg/kg of body weight (2 mL/100 lb) as a one-time injection.Multi-Day Therapy (BRD Treatment): Administer subcutaneously at 6 mg/kg of body weight (1.5 mL/100 lb) with this treatment repeated once approximately 48 hours following the first injection.

ADVOCIN Dosage and Treatment Schedule Dose Volume (mL) Cattle Weight 6 mg/kg, given twice, 8 mg/kg given once (lb) 48 hours apart (treatment and control (treatment) in cattle at high risk)

50 0.75 1 100 1.5 2 150 2.25 3 200 3 4 250 3.75 5 300 4.5 6 400 6 8 500 7.5 10 600 9 12 700 10.5 14 800 12 16* 900 13.5 18* 1000 15 20** Administered dose volume should not exceed 15 mL per injection site.Clinical field studies indicate that ADVOCIN (danofloxacin injection) Sterile Injectable Solution is effective for the control of respiratory disease in beef cattle at high risk of developing BRD. Cattle at high risk of developing BRD typically experience one or more of the following risk factors:

• Commingling from multiple sale barns/sources• Extended transport times and shrink• Exposure to wet or cold weather conditions or wide temperature

swings• Stressful arrival processing procedures (such as castration, dehorning,

or branding)• Recent weaning or poor vaccination history

RESIDUE WARNINGS: Animals intended for human consumption must not be slaughtered within 4 days from the last treatment. Do not use in cattle intended for dairy production. A withdrawal period has not been established for this product in preruminating calves. Do not use in calves to be processed for veal.

HUMAN WARNINGS: For use in animals only. Keep out of reach of children. Avoid contact with eyes. In case of contact, immediately flush eyes with copious amounts of water for 15 minutes. In case of dermal contact, wash skin with soap and water. Consult a physician if irritation persists following ocular or dermal exposures. Individuals with a history of hypersensitivity to quinolones should avoid this product. In humans, there is a risk of user photosensitization within a few hours after excessive exposure to quinolones. If excessive accidental exposure occurs, avoid direct sunlight.

To report adverse reactions or to obtain a copy of the Material Safety Data Sheet (MSDS), call 1-888-963-8471.PRECAUTIONS: The effects of danofloxacin 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.Quinolone-class drugs should be used with caution in animals with known or suspected central nervous system (CNS) disorders. In such animals, quinolones have, in rare instances, been associated with CNS stimulation, which may lead to convulsive seizures.Quinolone-class drugs have been shown to produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature, rapidly growing animals of various species. Refer to Animal Safety for information specific to danofloxacin.ADVERSE REACTIONS: A hypersensitivity reaction was noted in 2 healthy calves treated with ADVOCIN in a laboratory study. In one location of a multi-site field trial, one out of the 41 calves treated with 6 mg/kg q 48 hours showed lameness on Day 6 only. In this same field trial location one of 38 calves treated with 8 mg/kg once became lame 4 days after treatment and remained lame on the last day of the study (Day 10). Another calf in the same treatment group developed lameness on the last day of the study.CLINICAL PHARMACOLOGY: (a) Pharmacokinetics: Danofloxacin distributes extensively throughout the body, as evidenced by a steady state volume of distribution (VDss) in cattle exceeding 1 L/kg. Danofloxacin concentrations in the lung homogenates markedly exceed those observed in plasma, further suggesting extensive distribution to the indicated site of infection. Danofloxacin is rapidly eliminated from the body (apparent terminal elimination T½ ranging from 3–6 hours), and negligible accumulation was observed when animals were dosed twice, 48 hours apart.

Danofloxacin is rapidly absorbed and is highly bioavailable when administered as a subcutaneous injection in the neck. Linear pharmacokinetics has been demonstrated when danofloxacin is administered to cattle by subcutaneous injection at doses between 1.25 to 10 mg/kg. No statistically significant gender difference was observed in peak or total systemic exposure following a single subcutaneous administration of danofloxacin to heifers and steers at a dose of 6 mg/kg body weight (Table 1).

Table 1. Danofloxacin pharmacokinetic values in male and female cattle (n=6/group) after a single subcutaneous injection into the lateral neck region at a dose of 6 mg danofloxacin/kg body weight Steers Heifers Mean %CVe Mean %CV a AUC0-24 µg x hr/mL 9.4 10 8.8 9 b F% 92 5 87 3 a Cmax µg/mL 1.25 16 1.27 13 a,c Tmax hr 3.2 42 1.7 31 d CL L/hr 0.54 12 0.62 9 d VDss L/kg 2.7 7 2.6 4 a T½ hr 4.8 18 4.2 7a AUC0-24 = area under the plasma concentration versus time curve from hr zero to hr 24 postdose. Cmax = maximum observed concentration. Tmax = time to Cmax.b Bioavailability (F%) = extent of drug absorption following subcutaneous administration. Within subject F values were determined as the ratio of AUC0-inf values estimated following a 6 mg/kg dose administered by either a subcutaneous or intravenous injection.c Statistically significant differences in Tmax were detected between genders. Given the similarity in Cmax values, these differences are not expected to have any clinical relevance.d Clearance (CL) and Volume of distribution at steady state (VDss) were determined from data obtained after intravenous administration of a 6 mg/kg dose.e Coefficient of variation %

(b) Microbiology: Danofloxacin exerts its activity by inhibiting the bacterial DNA gyrase enzyme, thereby blocking DNA replication. Inhibition of DNA gyrase is lethal to bacteria and danofloxacin has been shown to be rapidly bactericidal. Danofloxacin is active against gram-negative and gram-positive bacteria.The Minimum Inhibitory Concentrations (MIC) of danofloxacin for pathogens isolated in natural infections from various clinical studies in North America, 1996–1997, were determined using the standardized microdilution technique (Sensititre/Alamar, Accumed International), and are shown in Table 2.Table 2. Danofloxacin minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from 1996-1997 pivotal BRD treatment field studies in the U.S.

Indicated Pathogen

Number of Isolates

MIC50**

(µg/mL)MIC90

** (µg/mL)

MIC Range (µg/mL)

Mannheimia haemolytica

106 0.06 0.06 ≤0.015 to 0.12

Pasteurella multocida

94 ≤0.015 0.06 ≤0.015 to 0.12

* 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.

Table 3. Danofloxacin minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from 2013 pivotal field studies in the U.S. and Canada for the control of BRD in cattle at high risk of developing BRD.

Indicated Pathogen

Number of Isolates

MIC50**

(µg/mL)MIC90

** (µg/mL)

MIC Range (µg/mL)


507 0.03 0.06 ≤0.008 to >8


324 ≤0.008 0.12 ≤0.008 to 1.0

* 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: The effectiveness of 8 mg/kg administered once and the 6 mg/kg BW alternate day regimen was confirmed in 4 well-controlled studies of naturally acquired bacterial respiratory infections in feedlot age cattle. These studies were conducted under commercial conditions at 4 locations in North America. Bacterial pathogens isolated in the clinical field trial are provided in the Microbiology section.The effectiveness of ADVOCIN for the control of BRD in cattle at high risk of developing BRD associated with Mannheimia haemolytica and Pasteurella multocida was demonstrated in a multi-site study conducted in North America. The study enrolled a total of 1,480 commercial, crossbred-beef, Holstein and Holstein-cross steer calves at high risk of developing BRD associated with M. haemolytica and P. multocida. At enrollment, calves were randomly administered a one-time subcutaneous injection of either ADVOCIN at a dosage rate of 8 mg/kg of body weight or an equivalent volume of sterile saline. Cattle were observed daily for clinical signs of BRD and were evaluated for clinical success on Day 10 post-treatment. The treatment success rate of ADVOCIN-treated calves (86.0%) was statistically significantly (p=0.0068) greater than that of saline-treated calves (76.3%) (based on back-transformed least squares means). No adverse events associated with ADVOCIN administration were reported in the study.ANIMAL SAFETY: Safety studies were conducted in feeder calves using single doses of 10, 20, or 30 mg/kg for 6 consecutive days and 18, 24, or 60 mg/kg for 3 consecutive days. No clinical signs of toxicity were observed at doses of 10 and 20 mg/kg when administered for 6 days, nor at doses of 18 and 24 mg/kg when administered for 3 days. Articular cartilage lesions, consistent with fluoroquinolone chondropathy, were observed after examination of joints from animals as follows: one of 5 animals administered 18 mg/kg for 3 days; one of 6 animals administered 20 mg/kg for 6 days; 5 of 6 animals administered 30 mg/kg for 6 days; and in all 4 animals administered 60 mg/kg for 3 days. Clinical signs of inappetence, transient lameness (2/6), ataxia (2/6), tremors (2/6), nystagmus (1/6), exophthalmos (1/6), and recumbency (2/6) were observed when a dose of 30 mg/kg was administered for 6 consecutive days. Recumbency and depression were seen in one out of 4 animals administered 60 mg/kg for 3 days. Swelling at the injection site was noted at each dose level.Safety was also evaluated in 21-day-old calves. In one group, these immature animals were given injections of 6 mg/kg on study days 0, 2, 3, 5, 6, and 8. A second group of animals received injections of 18 mg/kg for a total of 2 injections 48 hours apart. The only treatment-related sign was erythema of the nasal pad in 3 of 6 calves that received 18 mg/kg. One calf in the 6 mg/kg group had pre-treatment scleral erythema, and developed nasal erythema after treatment that may or may not have been treatment-related. No changes in clinical pathology parameters were observed. No articular cartilage lesions were observed in the joints at any dosage.An injection site study conducted in feeder calves demonstrated that the product can induce a transient local reaction in the subcutaneous tissue and underlying tissue.TOXICOLOGY: Ninety-day oral toxicity studies in dogs and rats established a no observable effect level (NOEL) of 2.5 mg/kg bw/day and 2.4 mg/kg bw/day, respectively. Higher doses in juvenile dogs produced arthropathy, a typical quinolone-associated side effect. In chronic rodent bioassays, no evidence of carcinogenicity was associated with long-term danofloxacin administration in rats and mice. No teratogenic effects were observed in rodents at doses up to 50 mg/kg bw/day (mice) or 100 mg/kg bw/day (rats) or in rabbits at the highest dose tested of 15 mg/kg bw/day. A three-generation rat reproductive toxicity study established a NOEL of 6.25 mg/kg bw/day. Microbial safety analyses indicate that danofloxacin residues present in edible tissues of treated animals under the current use conditions would most likely not cause adverse effects on the human intestinal micro flora of the consumer.STORAGE INFORMATION: Store at or below 30°C (86°F). Protect from light. Protect from freezing. The color is yellow to amber and does not affect potency.HOW SUPPLIED: ADVOCIN (180 mg danofloxacin/mL) is supplied in 100- and 250-mL, amber-glass, sterile, multi-dose vials.NADA #141-207, Approved by FDA

Distributed by:Zoetis Inc.Kalamazoo, MI 49007

Use Only as DirectedCONTACT INFORMATION: To report suspected adverse effects and/or obtain a copy of the MSDS or for technical assistance, call Zoetis Inc. at 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.

Revised: May 2014 Made in France

8713843A&P

51

Antibiotic100 mg of tulathromycin/mLFor 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.DESCRIPTIONDRAXXIN 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-hexopyrano-syl]-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-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.INDICATIONSBeef and Non-Lactating Dairy CattleBRD – 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 CalvesBRD - DRAXXIN Injectable Solution is indicated for the treatment of BRD associated with M. haemolytica, P. multocida, H. somni, and M. bovis.SwineDRAXXIN 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 ADMINISTRATIONCattleInject 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.

®

(tulathromycin) Injectable Solution

Table 1. DRAXXIN Cattle Dosing Guide Animal Weight Dose Volume (Pounds) (mL) 100 1.1 200 2.3 300 3.4 400 4.5 500 5.7 600 6.8 700 8.0 800 9.1 900 10.2 1000 11.4

SwineInject 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 Swine Dosing Guide Animal Weight Dose Volume (Pounds) (mL) 15 0.2 30 0.3 50 0.6 70 0.8 90 1.0 110 1.3 130 1.5 150 1.7 170 1.9 190 2.2 210 2.4 230 2.6 250 2.8 270 3.1 290 3.3

CONTRAINDICATIONSThe use of DRAXXIN Injectable Solution is contraindicated in animals previously found to be hypersensitive to the drug.WARNINGSFOR USE IN ANIMALS ONLY.NOT FOR HUMAN USE.KEEP OUT OF REACH OF CHILDREN.NOT FOR USE IN CHICKENS OR TURKEYS.

RESIDUE WARNINGSCattleCattle 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.SwineSwine intended for human consumption must not be slaughtered within 5 days from the last treatment.

PRECAUTIONSCattleThe 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.SwineThe 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 REACTIONSCattleIn 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.SwineIn 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 PHARMACOLOGYAt 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. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Pathogens. Clin. Infect. Dis., 27:28-32.2 Nightingale, C.J. 1997. Pharmacokinetics and Pharma-codynamics of Newer Macrolides. Pediatr. Infect. Dis. J., 16:438-443.CattleFollowing 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 rumi-nating 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.SwineFollowing intramuscular administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is completely and rapidly absorbed (Tmax ~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 (CLsystemic = 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.MICROBIOLOGYCattleTulathromycin 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.

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 < 0.0001) for DRAXXIN-treated pigs than for saline-treated pigs in both studies (8.52% vs. 23.62% and 11.31% vs. 26.42%).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 SAFETYCattleSafety 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.SwineSafety 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 restless-ness 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 CONDITIONSStore at or below 25°C (77°F)HOW SUPPLIEDDRAXXIN Injectable Solution is available in the following package sizes:50 mL vial100 mL vial250 mL vial500 mL vialNADA 141-244, Approved by FDA

To report a suspected adverse reaction or to request a safety data sheet 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.For additional DRAXXIN product information call: 1-888-DRAXXINor go to www.DRAXXIN.com

032908ZOA&PMade in Brazil Revised: February 2014

Distributed by:Zoetis Inc. Kalamazoo, MI 49007

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 1999. 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 saline- treated 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 2004. 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 2007. 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 MIC50 ** MIC90** MIC range pathogen isolated isolates (μg/mL) (μg/mL) (μg/mL) Mannheimia haemolytica 1999 642 2 2 0.5 to 64

Pasteurella multocida 1999 221 0.5 1 0.25 to 64

Histophilus somni 1999 36 4 4 1 to 4

Mycoplasma ≤ 0.063 bovis 1999 43 0.125 1 to > 64 Moraxella bovis 2004 55 0.5 0.5 0.25 to 1 Fusobacterium ≤ 0.25 necrophorum 2007 116 2 64 to > 128 Porphyromonas ≤ 0.25 levii 2007 103 8 128 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.

SwineIn 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 CO2-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 MIC50 ** MIC90** MIC range pathogen isolated isolates (μg/mL) (μg/mL) (μg/mL) Actinobacillus 2000-2002 135 16 32 16 to 32 pleuropneumoniae 2007-2008 88 16 16 4 to 32 Haemophilus 0.25 parasuis 2000-2002 31 1 2 to > 64 Pasteurella 2000-2002 55 1 2 0.5 to > 64 multocida 2007-2008 40 1 2 ≤ 0.03 to 2 Bordetella bronchiseptica 2000-2002 42 4 8 2 to 8


EFFECTIVENESSCattleBRD – 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 saline- treated 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 = 0.0001 and 15.0% vs. 30.7%, P < 0.0001).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 < 0.0001) 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. Cattle 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. Cattle 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 < 0.0001 and 83.3% vs. 50%, P = 0.0088).SwineIn 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,

52

53

(tulathromycin injection)Injectable Solution

Antibiotic25 mg of tulathromycin/mLFor use in suckling calves, dairy calves, veal calves, and swine. Not for use in ruminating cattle.

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

DESCRIPTIONDRAXXIN 25 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 25 contains 25 mg of tulathromycin as the free base in a 50% propylene glycol vehicle, monothioglycerol (5 mg/mL), citric acid (4.8 mg/mL) with hydrochloric acid and sodium hydroxide added to adjust pH. DRAXXIN 25 consists of an equilibrated mixture of two isomeric forms of tulathromycin in a 9:1 ratio.

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-ribohexopyrano-syl]oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexam-ethyl-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-ri-bohexopyrano-syl]oxy]-2-[(1R,2R)-1,2-dihydroxy-1-methylbutyl]-8-hydroxy-3,6,8,10,12-pentamethyl-9-[[3,4,6-tri-deoxy-3-(dimethylamino)-β-D-xylohexopyranosyl]oxy]-1-oxa-4-azacyclotridecan-13-one, respectively.

INDICATIONSSwineDRAXXIN 25 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.

Suckling Calves, Dairy Calves, and Veal CalvesBRD - DRAXXIN 25 Injectable Solution is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis.

DOSAGE AND ADMINISTRATIONSwineInject intramuscularly as a single dose in the neck at a dosage of 2.5 mg/kg (1 mL/22 lb) Body Weight (BW). Do not inject more than 4 mL per injection site.

Table 1. DRAXXIN 25 Swine Dosing Guide (25 mg/mL)

Animal Weight Dose Volume (Pounds) (mL) 4 0.2 10 0.5 15 0.7 20 0.9 22 1.0 25 1.1 30 1.4 50 2.3 70 3.2 90 4.0

CalvesInject subcutaneously as a single dose in the neck at a dosage of 2.5 mg/kg (1 mL/22 lb) body weight (BW). Do not inject more than 11.5 mL per injection site.

Table 2. DRAXXIN 25 Calf Dosing Guide (25 mg/mL)

Animal Weight Dose Volume (Pounds) (mL) 50 2.3 75 3.4 100 4.5 150 7.0 200 9.0 250 11.5

CONTRAINDICATIONSThe use of DRAXXIN 25 Injectable Solution is contraindicated in animals previously found to be hypersensitive to the drug.

WARNINGSFOR USE IN ANIMALS ONLY.NOT FOR HUMAN USE.KEEP OUT OF REACH OF CHILDREN.NOT FOR USE IN CHICKENS OR TURKEYS.

RESIDUE WARNINGSSwineSwine intended for human consumption must not be slaughtered within 5 days from the last treatment.CalvesCalves intended for human consumption must not be slaughtered within 22 days from the last treatment with DRAXXIN 25 Injectable Solution. This drug is not for use in ruminating cattle.

PRECAUTIONSSwineThe effects of Draxxin 25 Injectable Solution 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.CattleThe effects of Draxxin 25 Injectable Solution 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.

ADVERSE REACTIONSSwineIn one field study, one out of 40 pigs treated with DRAXXIN Injectable Solution (100 mg/mL) at 2.5 mg/kg BW exhibited mild salivation that resolved in less than four hours.CalvesIn one BRD field study, two calves treated with DRAXXIN Injectable Solution (100 mg/mL) at 2.5 mg/kg BW exhibited transient hypersalivation. One of these calves also exhibited transient dyspnea, which may have been related to pneumonia.

Post Approval Experience The following adverse events are based on post approval adverse drug experience reporting for DRAXXIN Injectable Solution (100 mg/mL). Not all adverse events are reported to the FDA CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data. The following adverse events are listed in decreasing order of reporting frequency in cattle: Injection site reactions and anaphylaxis/anaphylactoid reactions. For a complete listing of adverse reactions for DRAXXIN Injectable Solution or DRAXXIN 25 Injectable Solution reported to the CVM see: http://www.fda.gov/AnimalVeterinary.

CLINICAL PHARMACOLOGYAt physiological pH, tulathromycin (a weak base) is approximately 50 times more soluble in hydrophilic than lipophilic 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 lung parenchyma as compared to the plasma, and these elevated concentrations can remain in lung tissue for several days beyond that which can be measured in the plasma. However the clinical relevance of these elevated lung concentrations is undetermined.

As a class, macrolides tend to be primarily bacteriostatic, but may be bactericidal against some pathogens.2 When acting as a cidal compound, they 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.3 Tulathromycin is eliminated from the body primarily unchanged via biliary excretion.1 Carbon, C. 1998. Pharmacodynamics of Macrolides, Azalides, and Streptogramins: Effect on Extracellular Patho-

gens. Clin. Infect. Dis., 27:28-32.2 Nightingale, C.J. 1997. Pharmacokinetics and Pharmacodynamics of Newer Macrolides. Pediatr. Infect. Dis. J.,

16:438-443.3 Andes D, Anon J, Jacobs MR, Craig WA. (2004). Application of pharmacokinetics and pharmacodynamics to

antimicrobial therapy of respiratory tract infections. Clin Lab Med., 24:477-502.

SwineFollowing intramuscular (IM) administration to feeder pigs at a dosage of 2.5 mg/kg BW, tulathromycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution exceeds 15 L/kg, which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half- life (60 to 90 hours) despite a rapid systemic free drug clearance (187 mL/kg/hr). There are no gender differences in swine tulathromycin pharmacokinetics.

Comparative Bioavailability SummaryDespite slightly lower peak concentrations with DRAXXIN 25 Injectable Solution, a single IM dose of 2.5 mg tulathromycin/kg BW of either DRAXXIN Injectable Solution (100 mg/mL) or DRAXXIN 25 Injectable Solution (25 mg/mL) resulted in comparable tulathromycin total systemic exposure. Therefore, DRAXXIN 25 Injectable Solution is considered to be therapeutically equivalent to DRAXXIN Injectable Solution when administered to swine by IM injection at a dose of 2.5 mg tulathromycin/kg BW.

CalvesFollowing subcutaneous (SC) administration into the neck of feeder calves at a dosage of 2.5 mg/kg BW, tulath-romycin is nearly completely absorbed, with peak plasma concentrations achieved within ~0.25 hr. The volume of distribution exceeds 11 L/kg4, which is consistent with extensive tissue binding. This large distribution volume results in a long terminal elimination half- life of more than 100 hours, despite a rapid systemic free drug clearance (170 mL/kg/hr). No pharmacokinetic differences are observed in castrated male versus female calves.

Comparative Bioavailability SummaryDespite lower peak concentrations with DRAXXIN 25 Injectable Solution, a single SC dose of 2.5 mg tulathromycin/kg BW of either DRAXXIN Injectable Solution (100 mg/mL) or DRAXXIN 25 Injectable Solution (25 mg/mL) resulted in comparable total systemic tulathromycin exposure. Therefore, DRAXXIN 25 Injectable Solution is considered to be therapeutically equivalent to DRAXXIN Injectable Solution when administered to calves by SC injection at a dose of 2.5 mg tulathromycin/kg BW.4 Clearance and volume estimates are based on intersubject comparisons of 2.5 mg/kg BW administered by either

subcutaneous or intravenous injection.

MICROBIOLOGYSwineTulathromycin has demonstrated in vitro activity against A. pleuropneumoniae, P. multocida, B. bronchiseptica, H. parasuis, and M. hyopneumoniae. The MICs of tulathromycin against indicated pathogens collected from field studies were determined using methods recommended by the Clinical and Laboratory Standards Institute (CLSI, M31-A and M31-A3). MICs for H. parasuis were determined using Veterinary Fastidious Medium and were incu-bated up to 48 hours at 35 to 37°C in a CO2-enriched atmosphere. These values are represented in Table 3, below.

Table 3. 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 MIC50** MIC90** MIC pathogen isolated isolates (μg/mL) (μg/mL) range (μg/mL)

Actinobacillus 2000-2002 135 16 32 16 to 32 pleuropneumoniae 2007-2008 88 16 16 4 to 32 Haemophilus 2000-2002 31 1 2 0.25 to > 64 parasuis Pasteurella 2000-2002 55 1 2 0.5 to> 64 multocida 2007-2008 40 1 2 ≤ 0.03 to 2 Bordetella 2000-2002 42 4 8 2 to 8 bronchiseptica

*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.

CalvesTulathromycin has demonstrated in vitro activity against M. haemolytica, P. multocida, H. somni, and M. bovis, four pathogens associated with BRD. The MICs of tulathromycin against indicated pathogens collected from field studies using DRAXXIN Injectable Solution (100 mg/mL) were determined using methods recommended by the CLSI (M31-A2). These values are represented in Table 4, below.

54

Table 4. Tulathromycin minimum inhibitory concentration (MIC) values* for indicated pathogens isolated from field studies evaluating BRD in the U.S.

Indicated Date No. of MIC50** MIC90** MIC pathogen isolated isolates (μg/mL) (μg/mL) range (μg/mL) Mannheimia 1999 642 2 2 0.5 to 64 haemolytica Pasteurella 1999 221 0.5 1 0.25 to 64 multocida Histophilus 1999 36 4 4 1 to 4 somni Mycoplasma 1999 43 0.125 1 ≤ 0.063 to bovis > 64


EFFECTIVENESSSwinePlasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution (100 mg/mL) support the effectiveness for DRAXXIN 25 Injectable Solution.

In a multi-location field study to evaluate the treatment of naturally occurring SRD, 266 pigs were treated with DRAXXIN Injectable Solution (100 mg/mL). 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 Injectable Solution (100 mg/mL) 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 < 0.0001) for DRAXXIN-treated pigs than for saline-treated pigs in both studies (8.52% vs. 23.62% and 11.31% vs. 26.42%).

The effectiveness of DRAXXIN Injectable Solution (100 mg/mL) 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%).

CalvesPlasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution (100 mg/mL) support the effectiveness for DRAXXIN 25 Injectable Solution.

BRD - In a multi-location field study, 314 calves with naturally occurring BRD were treated with DRAXXIN Injectable Solution (100 mg/mL). 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 Injectable Solution (100 mg/mL)-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 saline-treated 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 Injectable Solution (100 mg/mL) 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 Injectable Solution (100 mg/mL) 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 Injectable Solution (100 mg/mL) was 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.

Two induced infection model studies were conducted to confirm the effectiveness of DRAXXIN Injectable Solution (100 mg/mL) 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 per-centages were statistically significantly lower in the DRAXXIN-treated calves compared with saline-treated calves (11.3% vs. 28.9%, P = 0.0001 and 15.0% vs. 30.7%, P < 0.0001).

ANIMAL SAFETYSwinePlasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore systemic target animal safety studies conducted with DRAXXIN Injectable Solution support the systemic safety for DRAXXIN 25 Injectable Solution.

Safety studies were conducted in pigs receiving a single intramuscular dose of 25 mg/kg BW, or 3 weekly intramus-cular doses of 2.5, 7.5, or 12.5 mg/kg BW (both studies utilized DRAXXIN Injectable Solution (100 mg/mL)). 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.

Sixteen growing pigs were injected with either saline or DRAXXIN 25 Injectable Solution as a single injection of 4 mL. Injection site observations included two instances of erythema in the DRAXXIN 25-treated group on Day 1 post-injection. No heat, sensitivity, firmness, necrosis, drainage, or swelling was observed at any injection sites in either treatment group. The gross and microscopic findings in the DRAXXIN 25-treated group were consistent with inflammatory changes induced by injections and were considered to be mild or moderate with progression to macroscopic resolution by Day 28 post-injection and microscopic resolution by Day 42 post-injection.

CalvesPlasma concentrations of tulathromycin administered as DRAXXIN Injectable Solution (100 mg/mL) or as DRAXXIN 25 Injectable Solution were demonstrated to be therapeutically equivalent (see CLINICAL PHARMACOLOGY, Comparative Bioavailability Summary). Therefore effectiveness studies conducted with DRAXXIN Injectable Solution support the effectiveness for DRAXXIN 25 Injectable Solution.

A safety study was conducted in feeder calves receiving DRAXXIN Injectable Solution (100 mg/mL) as 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 DRAXXIN Injectable Solution (100 mg/mL) as 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 DRAXXIN Injectable Solution (100 mg/mL) at 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 micro-scopically.

Sixteen growing cattle were injected with either saline (eight animals) as a single injection of 11.5 mL or DRAXXIN 25 Injectable Solution (eight animals) as a single injection of either 2.5 mg/kg BW or a dose volume of 11.5 mL (whichever volume was higher). One calf in the DRAXXIN 25-treated group was observed to have firmness at the injection site for a single day. Two DRAXXIN 25-treated calves exhibited injection site swelling. In one calf, the swelling resolved within 48 hours. In the other calf, the swelling was observed over a three-day period, after which the calf underwent a scheduled necropsy, preventing further injection site observations. No injection site swelling was observed in saline-treated animals. At necropsy, three of the saline-treated calves and five of the DRAXXIN 25-treated calves had altered tissue present at the injection site. The gross and microscopic findings in the DRAXXIN 25-treated group were consistent with inflammatory changes induced by injections, were considered to be mild to marked, and progressed to macroscopic resolution and microscopic resolution by Day 42 post-injection.

STORAGE CONDITIONS:Store at or below 25°C (77°F). Use within 90 days of first vial puncture.

HOW SUPPLIEDDRAXXIN 25 Injectable Solution is available in the following package sizes:50 mL vial100 mL vial250 mL vial

NADA 141-349, Approved by FDA


To report a suspected adverse reaction or to request a safety data sheet 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.For additional DRAXXIN 25 product information call: 1‑888‑DRAXXIN or go to www.DRAXXIN.com

060005AAA&PMade in Brazil Revised: September 2014

55

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.

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 Gram-negative 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:

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, non-lactating 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.

DOSAGETreatment 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 non-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). 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.• Cattle 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.

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.

Weight Dose Volume (lb) (mL) 1100 16.5 1200 18.0 1300 19.5 1400 21.0 1500 22.5 1600 24.0 1700 25.5 1800 27.0 1900 28.5 2000 30.0

Weight Dose Volume (lb) (mL) 100 1.5 200 3.0 300 4.5 400 6.0 500 7.5 600 9.0 700 10.5 800 12.0 900 13.5 1000 15.0

(Ceftiofur Crystalline Free Acid)Sterile Suspension

Figure 2. Subcutaneous administration of EXCEDE Sterile Suspension in the middle third of the posterior aspect of the ear.

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).

locations forinjections

main ear arteries (avoid) large vein

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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.

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.

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 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.

CONTRAINDICATIONS As with all drugs, the use of EXCEDE Sterile Suspension is contraindicated in animals pre viously found to be hypersensitive to the drug.

WARNINGSFOR 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 1-888-963-8471. 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.

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 (MIC90) 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 Cattle) and base of the ear (BOE Cattle) in beef cattle as well into the base of the ear (BOE Lactating) in lactating dairy cattle.

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 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.

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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).

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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

Cmax (μg CE/mL) 6.90 ± 2.68 6.39 ± 1.79 4.44 ± 1.65 tmax (h) 12.0 ± 6.2 19.8 ± 5.81 19.00 ± 8.02 AUC 0-LOQ (μg•h/mL) 376 ± 66.1 412 ± 67.3 313 ± 85.5 t>0.2, model (h) 183 ± 40.8 NE NE t>0.2, nca (h) 246 ± 48.5 218 ± 45.5 205 ± 35.7 t1/2 (h) 62.3 ± 13.5 40.7 ± 11.2 43.92 ± 9.84

Cmax (μg CE/mL) = maximum plasma concentration (in μg CE/mL).tmax (h) = the time after injection when Cmax 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.t1/2 (h) = terminal phase biological half life (in hours)NE = Not estimated

56

The effectiveness of EXCEDE Sterile Suspension for the treatment of bovine foot rot was evaluated in a six-location field effectiveness study. Cattle diagnosed with bovine foot rot were enrolled and treated with EXCEDE Sterile Suspension, administered by subcutaneous injection in the base of the ear as a single dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW or an equivalent volume of a vehicle control. Cattle were clinically evaluated 7 days post-treatment for treatment success, which was based on defined decreases in lesion, swelling and lameness scores. A total of 169 beef and dairy cattle were included in the analysis. There was a statistically significant difference (p = 0.0054) in treatment success for EXCEDE-treated cattle (58.4%) compared to vehicle-treated control cattle (13.2%). The effectiveness of EXCEDE Sterile Suspension for the treatment of acute metritis was evaluated in a 15-location field effectiveness study. A total of 1023 cows with a fetid vaginal discharge and a rectal temperature of ≥ 103 °F were enrolled in the study and treated with either a two-dose regimen of EXCEDE (6.6 mg CE/BW) or an equivalent volume of vehicle control, administered approximately 72 hours apart at the base of opposite ears. At 14 days post-treatment, each cow remaining in the study was examined and rectal temperature and vaginal discharge score were recorded. Cows with a non-fetid discharge, and a rectal temperature < 103 °F, and that did not require alternate (“escape”) therapy during the 14_day observation period were classified as a cure. The cure rate was significantly higher (p < 0.0001) in EXCEDE-treated cows (362/493, 74.3%) than in vehicle-treated cows (271/489, 55.3%). One cow died 15 to 20 minutes after the second administration of EXCEDE. Necropsy findings determined the probable cause of death to be intra-arterial injection.

ANIMAL SAFETYSystemic Safety Studies After parenteral administration, ceftiofur crystalline free acid (as EXCEDE Sterile Suspension), ceftiofur sodium and ceftiofur hydrochloride are rapidly metabolized to desfuroylceftiofur. Therefore, studies conducted with ceftiofur sodium are adequate to evaluate the systemic safety of EXCEDE Sterile Suspension. Results from a five-day tolerance study conducted with ceftiofur sodium in normal feeder calves indicated that ceftiofur was well tolerated at 25 mg CE/lb/day for five consecutive days, approx-imately 8 times the approved dose of EXCEDE Sterile Suspension 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur administered parenterally had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were admin is tered ceftiofur sodium intramuscularly at 0 (vehicle control), 1, 3, 5 or 10 mg CE/lb/day thus, evaluating up to 3.3 times the approved dose of EXCEDE Sterile Suspension of 3.0 mg CE/lb/day (6.6 mg CE/kg) BW. There were no adverse systemic effects, indicating that ceftiofur has a wide margin of safety when injected intramuscularly into feeder calves. Local tissue tolerance to subcutaneous injection of EXCEDE Sterile Suspension in the posterior ear of cattle was evaluated in a separate study. The systemic safety of ceftiofur concentrations resulting from product administration at the base of the ear was established via a pharmacokinetic comparison of the two routes of administration (base of the ear versus middle third of the ear). Based upon the results of this relative bioavailability study, it was determined that the two routes of administration are therapeutically equivalent. To support systemic target animal safety for the 2-dose metritis regimen, five projected daily doses of NAXCEL Sterile Powder (ceftiofur sodium) at 2.2 mg/kg BW were compared pharmacokinetically with EXCEDE administered 2 times at a 72 hour interval at 6.6 mg/kg BW. The peak concentration (Cmax) and the extent of exposure (AUC) after two doses of EXCEDE were statistically no higher than the exposure following five daily doses of NAXCEL Sterile Powder in beef cattle.Investigation of Intra-Arterial and Intravenous Injection In approximately 6000 animals enrolled in the BRD clinical studies, nine animals died following injection of EXCEDE Sterile Suspension. All deaths were within 30 minutes of the time of injection. The exact cause was confirmed in three animals. These deaths resulted from inadvertent intra-arterial injection of this oil-based suspension into one of the two major auricular (ear) arteries. Intra-arterial injection at this location resulted in direct administration of the oil-based formula tion into the arterial blood supply of the brain resulting in embolism and death. Since intra-arterial injection was confirmed in three animals that died following injection of EXCEDE Sterile Suspension, the consequences of purposeful intra-arterial injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Two heifers (body weight approximately 225 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE Sterile Suspension in the middle auricular artery. Both heifers collapsed immediately and died within approximately eight minutes of injection. Intra-arterial injection of EXCEDE Sterile Suspension in the ear will result in death and must be avoided. Since subcutaneous injection in the ear may potentially result in inadvertent intravenous administration of an injectable product, the consequences of purposeful intravenous injection of EXCEDE Sterile Suspension were investigated in feeder cattle. Three heifers and three steers (body weight range 197-223 kg) were given a single 3.0 mg CE/lb (6.6 mg CE/kg) BW bolus dose of EXCEDE Sterile Suspension in the jugular vein and were monitored for adverse effects following injection. One steer and one heifer had transient (2 to 5 minutes) increases in heart rate without any other untoward signs in these or the other cattle. Intravenous injection of EXCEDE Sterile Suspension is an unacceptable route of administration.Safety Studies in Beef Cattle Middle of the ear injection: A study was designed and conducted to specifically address tissue tolerance in cattle when EXCEDE Sterile Suspension was administered as a single subcutaneous injection into the posterior aspect of the ear of cattle at the recommended dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Results from this study indicate that the subcutaneous injection of EXCEDE Sterile Suspension into the middle third of the posterior aspect of the ear of cattle is well tolerated and characterized by a biphasic thickening of the ear. The initial increase in thickness is attributed to the space required for the volume of injected material. Additional increases in thickness were observed through Day 14 after injection. After Day 14, post injection ear thickness decreased in all animals. One animal carried an injected ear in a drooping position for 7 days post injection. At necropsy, subcutaneous areas of discoloration and some foci of hemorrhage were observed in ears of injected cattle. The discoloration was markedly reduced in size by the end of the study. Ears are inedible tissues in the US (9 CFR 301.2). No signs of irritation were observed on the edible portions of the carcass around the base of the ear. The local tolerance of the ear of cattle to a single subcutaneous injection of EXCEDE Sterile Suspension was also evaluated in a large multi-location effectiveness study. None of the 1927 animals treated with EXCEDE Sterile Suspension were removed from this trial due to ear irritation although swelling was noted at some injection sites. Leak back and/or bleeding from the injection site was observed in a small fraction of the treated animals immediately after administration. It was concluded that administration of EXCEDE Sterile Suspension in the posterior aspect of the ear was well tolerated and was acceptable under feedlot conditions. A study evaluated the 56-day feedlot performance of beef steers administered EXCEDE Sterile Suspension alone, EXCEDE Sterile Suspension with a growth promoting implant, growth promoting implant alone, or neither product, in a total of 207 Angus and Angus cross-bred steers. The administration of EXCEDE Sterile Suspension in the posterior aspect of the ear with or without growth promoting implants was well tolerated by cattle and did not adversely affect feedlot cattle performance. Based upon the results of this study, the location of implants administered after EXCEDE Sterile Suspension may need to be adjusted slightly within the boundaries of the middle third of the ear in some animals.

Figure 9. LS-Mean DCA Plasma Concentration Time Profile Following Two Subcutaneous Injections of EXCEDE 72 hours apart at a Dose of 3.0 mg CE/lb (6.6 mg CE/kg) BW in 12 lactating cows.

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Table 3. Average (n = 12) Pharmacokinetic Parameters Following Two Subcutaneous Injections of EXCEDE Sterile Suspension at a Dose 3.0 mg CE/lb (6.6 mg CE/kg) BW at a 72 Hour Interval.

PK Parameter Mean ± Standard Deviation AUC0-LOQ (μg•h/mL) 651 ± 119 t½ (h) 55.7 ± 4.84 t>0.2 (h) 341 ± 34.0 Tmax (h) 77.1 ± 33.4 Cmax (μg/mL) 5.98 ± 2.51

MICROBIOLOGY Ceftiofur has demonstrated in vitro activity against Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, three major pathogens associated with BRD, and against Fusobacterium necrophorum and Porphyromonas levii associated with bovine foot rot. A summary of the susceptibility of BRD and foot rot pathogens is presented in Table 4. BRD isolates were obtained from cattle enrolled in a field study conducted in the United States that were diagnosed with BRD. Foot rot isolates were obtained from cattle enrolled in a field study conducted in the United States and Canada that were diagnosed with foot rot. Susceptibility testing was conducted according to the Clinical and Laboratory Standards Institute (CLSI) M7-A3 and M11-A6 standards for BRD and foot rot isolates, respectively.

Table 4. Ceftiofur minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from cattle with naturally occurring BRD or foot rot.

Indicated Year of Number of MIC50** MIC90** MIC range pathogen isolation isolates (μg/mL) (μg/mL) (μg/mL) Mannheimia haemolytica 1996 to 1997 75 0.008 0.015 0.001 to 0.015 Pasteurella multocida 1996 to 1997 43 0.004 0.004 0.001 to 0.015 Histophilus somni 1996 to 1997 11 0.004 0.004 0.002 to 0.015 Fusobacterium necrophorum 2006 to 2007 148 ≤ 0.25 0.5 ≤ 0.25 to >128 Porphyromonas levii 2006 to 2007 141 ≤ 0.25 2.0 ≤ 0.25 to 16* 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.

Based on pharmacokinetic and clinical effectiveness studies of ceftiofur in cattle after a single administration of 3.0 mg CE/lb (6.6 mg CE/kg) BW and the MIC and susceptibility data, the following breakpoints are recommended for BRD pathogens by CLSI.

Table 5. CLSI-accepted interpretive criteria* for ceftiofur against cattle respiratory pathogens.

Pathogen Disk Zone diameter MIC breakpoint potency (mm) (μg/mL)

S I R S I R

Mannheimia haemolytica Pasteurella multocida 30 μg ≥ 21 18 to 20 ≤ 17 ≤ 2.0 4.0 ≥ 8.0 Histophilus somni

S – Susceptible I – Intermediate R – Resistant

* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to determine antimicrobial susceptibility. Interpretive criteria for bovine foot rot pathogens have not been established.

EFFECTIVENESS A field dose confirmation study for the treatment of BRD evaluated the effectiveness of single doses of 2.0 and 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) BW for the treatment of the bacterial component of BRD under field conditions. All treatments were administered subcutaneously in the middle third of the posterior aspect of the ear. Cattle were clinically evaluated on Days 2 to 4, 14 and 28 and were observed on all other study days. The 3.0 mg CE/lb (6.6 mg CE/kg) BW EXCEDE Sterile Suspension dose significantly (p ≤0.05) increased Day 14 treatment success rate, defined as animals that did not require any ancillary treatment and had a rectal temperature of <104°F, normal respiration index, and had no or mild depression on that day. The effectiveness of a single dose of EXCEDE Sterile Suspension for the control of BRD in feedlot cattle was evaluated in a nine-location field effectiveness study. In addition to standard processing on arrival at feedlots, cattle (n=3911) considered to be at high risk for BRD were assigned to one of four arrival treatments, including EXCEDE Sterile Suspension at 2.0 or 3.0 mg CE/lb (4.4 or 6.6 mg CE/kg) BW or negative control. Effectiveness evaluation was based on the incidence of clinical BRD within 28 days following arrival processing. Administration of a single dose of EXCEDE Sterile Suspension administered subcutaneously in the middle third of the poste rior aspect of the ear at arrival processing significantly reduced the incidence of BRD in high-risk feedlot cattle in the 28-day period after arrival processing compared to negative controls. Base of the ear administration (beef and non-lactating dairy cattle) and middle third of the ear administration (lactating dairy cattle) were compared to the middle third of the ear pharmacoki netic data for beef and non-lactating dairy cattle and were found to be therapeutically equivalent.

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Base of the ear injection: The local tolerance of the ear to a single subcutaneous injection at the base of the ear of EXCEDE Sterile Suspension was evaluated in a multi-location field study in 2926 beef cattle. Normal restraint was adequate for adminis tration of EXCEDE Sterile Suspension for 99.8% of cattle. No post injection problems (exces sive bleeding or leak back) were observed in 99.8% of cattle. On Days 28 and 56 post-injec tion, 97.8% and 98.9% of the cattle had “normal” (no observed swelling) ears. In a residue study, 72 beef cattle were injected in the base of the ear with EXCEDE Sterile Suspension at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Injection sites were observed daily from treatment to necropsy (4, 7, 10, or 13 days post-injection) for swelling and drooping, and evaluated grossly at necropsy, using skinning and trimming procedures similar to slaughterhouse practices. All animals had injection site swelling during the study; swelling resolved prior to euthanasia in 23 of 72 animals. None of the animals showed ear drooping. At necropsy, signs of inflammation (hemorrhage, conges tion, and firmness of tissue) and presence of drug material were seen in the area around the injection site and on the carcass. At 13 days post-injection, gross lesions were found in the inedible portions of the base of the ear in all 18 animals, and in the exposed carcass tissue in 11 of 18 animals. The ventral base of the ear injection technique was evaluated in a conditions of use study in 200 beef cattle. Each animal received a single injection of EXCEDE Sterile Suspension at a dose of 6.6 mg CE/kg BW at the base of the ear using the ventral injection technique. Normal restraint was adequate for 95.5% of animals in the study. Injection site scores were normal for 65.3% and 92.5% of cattle on Days 14 and 28, respectively. One animal had an unusually large swelling on Day 7 which reduced to a size comparable to other study animals by Day 14.Safety Studies in Lactating Dairy Cattle The local tolerance of the ear to a single subcutaneous injec tion at the base of the ear of EXCEDE Sterile Suspension was evaluated in a multi-location field study in 114 adult dairy cattle. Successful injection in the base of the ear was achieved in 97.4% of cattle using nor mal facilities and restraint equipment. No leak back or excessive bleeding was observed fol lowing injection for 99.1% of cattle, with injection volumes ranging from 15 to 30 mL. On Days 28 and 56 following injection of EXCEDE Sterile Suspension in the base of the ear, 95.6% and 100% of ears, respectively, were observed as normal with no injection site swelling. In a residue study, six dairy cows were injected in the base of the ear at a dose rate of 3.0 mg CE/lb (6.6 mg CE/kg) BW of EXCEDE Sterile Suspension. No animals exhibited drooping ears at any time after treatment but all animals had signs of swelling at the injection site at all observation times after treatment. Cows were slaughtered 10 days after injection. At necropsy, all six cows showed evidence of injection site inflammation (discoloration of fat tissue/fascia) and four of six cows had discoloration of tissue dor sal and posterior to the ear canal on the carcass. In addition to discoloration, tan nodules and a milky white fluid exudate were also present at the sectioned surface. Injection site safety for base of the ear administration was evaluated in the metritis effectiveness study described above. Normal restraint was adequate for ≥ 97.8% of injections administered. Injection site scores were normal in 50.3%, 73.2%, and 96.4% at 2 or 3, 11, and 54±3 days after the second injection, respectively. The ventral and rostral base of the ear injection techniques were compared with the toward the opposite eye technique in a conditions of use study in 197 lactating dairy cattle. Normal restraint was adequate for 89.8% (ventral), 98% (rostral), and 100% (opposite eye) of animals in the study. Injection site scores were normal for 32% (rostral), 46.9% (ventral), and 47.9% (opposite eye) of cattle on Day 14, and 73% (rostral), 87.8% (ventral), and 64.6% (opposite eye) of cattle on Day 28, respectively.

TISSUE AND MILK RESIDUE DEPLETION 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 dairy cattle. In this study, cows received a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in tissues such as the kidney, liver and muscle by 13 days after dosing. These data collectively support a 13-day pre-slaughter withdrawal period. A pivotal milk residue decline study was conducted in lactating dairy cattle. In this study, cows received a single injection of 3.0 mg CE/lb (6.6 mg CE/kg) BW. Ceftiofur residues in milk were less than tolerances at all time points after treatment. These data collectively support that no milk discard period is required for this product.Two-Dose Residue Decline Studies A pivotal tissue residue decline study was conducted in dairy cattle. In this study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval between injections. Ceftiofur residues in tissues were less than the tolerances for ceftiofur residues in the kidney by 13 days after the second dose. These data collectively continue to support a 13-day pre-slaughter withdrawal period after the last dose. A pivotal milk residue decline study was conducted in lactating dairy cattle. In this study, cows received two injections of 3.0 mg CE/lb (6.6 mg CE/kg) BW with a 72 hour interval between injections. Milk residue decline data from this study supports that no milk discard period is required for this product.

STORAGE CONDITIONS Store at controlled room temperature 20° to 25°C (68° to 77°F). Shake well before using. Contents should be used within 12 weeks after the first dose is removed.

HOW SUPPLIED EXCEDE Sterile Suspension is available in the following package sizes: 100 mL vial 250 mL vial

NADA #141-209, Approved by FDA

Distributed by:Zoetis Inc. Kalamazoo, MI 49007

www.EXCEDE.com or call 1-888-963-8471

Revised: August 2013

10423902A&P58

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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.

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 poly oxyethylene 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-furanyl car bon yl)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 Mann heimia haemolytica, Pasteurella multocida and Histophilus somni.

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

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

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.

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) 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 intra mammary, 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.

Comparative Bioavailability Summary

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.

Table 1: Comparative treatment values (arithmetic mean ± SD) for the plasma PK estimates of total ceftiofur (parent compound plus desfuroylceftiofur metabolites) in swine following an IM administration of 2.27 mg CE/lb (5.0 mg CE/kg) BW, as either EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile Suspension (test article).

PK Parameter EXCENEL RTU EXCENEL RTU EZ

Cmax (μg/mL) 18.2 ± 4.09 19.7 ± 3.39

AUC0-LOQ (μg*h/mL) 257 ± 57.1 263 ± 54.8

tmax (h) 1.5 ± 0.49 1.5 ± 0.73

t1/2 (h) 20.0 ± 1.56 20.0 ± 1.82

t>0.2 (h) 83.1 ± 10.3 82.5 ± 10.5

Cmax - maximum plasma concentration AUC0-LOQ - the area under the plasma concentration vs. time curve from time of injection to the limit of quantification of the assaytmax - the time after initial injection to when Cmax occurst1/2 - the plasma half life of the drugt>0.2 - the time plasma concentrations remain above 0.2 µg/mL.

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 (5.0 mg CE/kg) BW (Table 2).

Table 2: Back-transformed least squares (LS) means and 90% confidence interval (CI) for the two pivotal pharmacokinetic parameters, Cmax and AUC0-LOQ in swine following an IM administration of 2.27 mg CE/lb (5.0 mg CE/kg) BW, as either EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile Suspension (test article).

PK ParameterLS Mean

Difference90% CI BE†

Cmax 1.10 1.03 to 1.18 Yes

AUC0-LOQ 1.03 0.99 to 1.06 Yes

† If the 90% CI of the LS mean difference is within the limits of 0.80 to 1.25, then the results support bioequivalence of treatment groups

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 5.0 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 meta bolites 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

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 Suspen sion at a dose of 1.0 mg CE/lb (2.2 mg CE/kg) BW is provided in Table 3.

Table 3: Comparative treatment values (arithmetic mean ± SD) for the plasma PK estimates of total ceftiofur (parent compound plus desfuroylceftiofur metabolites) in cattle following an IM or SC administration of 1.0 mg CE/lb (2.2 mg CE/kg) BW, as either EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile Suspension (test article).

PK Parameter

IM SC

EXCENEL RTU

EXCENEL RTU EZ

EXCENEL RTU

EXCENEL RTU EZ

Cmax (μg/mL)

8.58 ± 1.50 9.25 ± 1.73 8.40 ± 1.42 9.19 ± 1.65

AUC0-LOQ (μg*h/mL)

89.4 ± 13.8 88.5 ±17.0 86.7 ± 20.3 91.0 ± 20.2

tmax (h)1.71 ± 0.706 1.73 ± 0.489

2.08 ± 0.670

2.25 ± 0.872

t1/2 (h) 32.0 ± 8.48 29.3 ± 7.35 34.0 ± 8.52 32.9 ± 6.91

t>0.2 (h): 42.2 ± 6.20 41.2 ± 6.11 40.5 ± 5.28 41.5 ± 7.32

Cmax - maximum plasma concentrationAUC0-LOQ - the area under the plasma concentration vs. time curve from time of injection to the limit of quantification of the assay tmax - the time after initial injection to when Cmax occurst1/2 - the plasma half life of the drugt>0.2 - the time plasma concentrations remain above 0.2 µg/mL

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 1.0 mg CE/lb (2.2 mg CE/kg) BW (Table 4).

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Table 4: Back-transformed least squares (LS) means and 90% confidence intervals (CI) for the two pivotal pharmacokinetic parameters, Cmax and AUC0-LOQ in cattle following an IM and SC administration of 1.0 mg CE/lb (2.2 mg CE/kg) BW, as either EXCENEL RTU (reference article) or as EXCENEL RTU EZ Sterile Suspension (test article).

PK Parameter

IM SC

LS Mean Difference

90% CILS Mean

Difference90% CI

Cmax 1.08 1.00 to 1.16 1.09 1.02 to 1.18

AUC0-LOQ 0.984 0.94 to 1.03 1.06 0.99 to 1.13

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.

Table 5: CLSI-accepted interpretive criteria for ceftiofur against swine and cattle respiratory pathogens.*

Pathogen Diskpotency

Zone diameterinterpretive standards

(mm)

MIC breakpoint(μg/mL)

S I R S I R

Actinobacillus pleuropneumoniae


Salmonella Choleraesuis

30 μg ≥ 2118 to 20

≤ 17 ≤ 2.0 4.0 ≥ 8.0



Histophilus somni

S – SusceptibleI – IntermediateR – Resistant

* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to determine antimicrobial susceptibility.

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 AUC0-LOQ and Cmax. 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 AUC0-LOQ and Cmax. 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 AUC0-LOQ and Cmax 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 article-related 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.


Revised: March 2013


61


Factrel® Injection(gonadorelin injection)50 mcg gonadorelin per mL (as gonadorelin hydrochloride) Solution for Intramuscular Injection.

For use in cattle only

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

DESCRIPTIONFACTREL Injection is a sterile solution containing 50 micrograms of synthetic gonadorelin (as hy dro chloride) per mL in aqueous formulation containing 0.6% sodium chloride and 2% benzyl alcohol (as a preservative).Gonadorelin is the gonad otro pin releasing hormone (GnRH) which is produced by the hypothalamus and causes the release of the gonado tro pin luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary.FACTREL Injection has the identical amino acid sequence as endo genous gonadorelin; 5-oxo Pro-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 with identical phys iological activities. The molecular weight of gonadorelin is 1182 with a molecular formula of C55H75N17O13. The corresponding values for gonado relin hydrochloride are 1219 (1 HCI) expressed as C55H75N17O13HCI, or 1255 (2 HCI) expressed as C55H75N17O13 2HCI.

INDICATIONS FOR USEFor the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and replacement dairy and beef heifers. The treatment effect of FACTREL Injection when used in lactating dairy cows, beef cows, and replacement dairy and beef heifers is a reduction in the number of days to first estrus.For use with LUTALYSE® (dinoprost tromethamine injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows.

DOSAGEFor the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and replacement dairy and beef heifers: Administer 2 mL of FACTREL Injection as a single intramuscular injection.For use with LUTALYSE (dinoprost tromethamine injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework:

• Administer the first dose of FACTREL Injection (2-4 mL) at Day 0• Administer LUTALYSE (25 mg dinoprost, as dinoprost tromethamine

injection) Injection by intramuscular injection 6-8 days after the first dose of FACTREL Injection.

• Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE injection.

• Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected estrus using standard herd practices.

Below are three examples of treatment regimens for FTAI that fit within the dosage regimen framework described immediately above:

Example 1 Example 2 Example 3

Day 0 (Monday) 1st FACTREL 1st FACTREL 1st FACTREL

Day 7 (the following Monday)

LUTALYSE LUTALYSE LUTALYSE

Day 9 (Wednesday)

2nd FACTREL + FTAI at 48 hours after LUTALYSE

2nd FACTREL 48 hours after LUTALYSE

2nd FACTREL 56 hours after LUTALYSE

Day 10 (Thursday)

FTAI 24 hours after 2nd

FACTREL

FTAI18 hours after 2nd

FACTREL

MECHANISM OF ACTIONFollicular cysts are enlarged non-ovulatory follicles resulting from a malfunction of the neuroendocrine mechanism controlling follicular maturation and ovulation. Exogenous administration of agents possessing luteinizing hormone (LH) activity, such as pituitary extracts or human chorionic gonadotropin, often causes ovulation or regression of follicular cysts. FACTREL Injection induces release of endogenous luteinizing hormone (LH) to produce this same effect. Gonadorelin, through release of LH has been demonstrated to induce ovulation of dominant ovarian follicles present on the bovine ovary during the estrous cycle. Administration of FACTREL Injection has the same effect.

WARNINGS AND PRECAUTIONSFor use in animals only. Not for human use. Keep out of reach of children.

RESIDUE WARNINGSNo withdrawal period or milk discard time is required when used according to labeling.

EFFECTIVENESSFor the treatment of ovarian follicular cysts in lactating dairy cows, beef cows, and replacement dairy and beef heifers:The treatment effect of FACTREL Injection when used in lactating dairy cows, beef cows, and replacement dairy and beef heifers is a reduction in the number of days to first estrus. There were no significant differences in days from treatment to conception, frequency of cows conceiving at first or subsequent heats, or conception rates among treated or non-treated control animals, when FACTREL Injection was used alone for treatment of cystic ovaries.For use with LUTALYSE (dinoprost tromethamine injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows:A field study was conducted to compare control (0 mL FACTREL Injection) to two doses of 2, 3 or 4 mL FACTREL Injection (100-200 mcg gonadorelin) for use with LUTALYSE Injection to synchronize estrous cycles to allow FTAI in lactating dairy cows under field conditions. Cows were examined prior to study start and only clinically normal cows were enrolled. A total of 1142 cows were enrolled at 6 commercial dairies. Cows were assigned randomly in blocks of 4 cows to each of 4 treatment groups consisting of:

Day 0: 2, 3 or 4 mL dose of FACTREL Injection or no injection (Control)Day 7: 5 mL LUTALYSE Injection (all treatment groups)Day 9: 2, 3 or 4 mL dose of FACTREL Injection or no injection (Control)Day 10: Fixed-time artificial insemination

On Day 9 the second dose of FACTREL Injection (cows received the same dose as for first treatment) was given either 48 or 56 hours after the dose of LUTALYSE Injection and FTAI was conducted 24 or 17 hours later, respectively. For control cows FTAI was performed 72 hours after the LUTALYSE Injection dose was administered. All treatment groups had significantly greater pregnancy rates to FTAI than cows administered LUTALYSE Injection alone, and were 17.1, 27.3, 29.1 and 32.2% for cows receiving 0 (Control), 2, 3 or 4 mL FACTREL Injection, respectively.

SAFETY AND TOXICITYIn cows the intramuscular administration of up to 12.5 times maximum recommended dosage (2,500 mcg/day) of FACTREL Injection for 3 days did not affect any physiological or clinical parameter. Likewise, single intramuscular doses of 500 mcg did not interfere with pregnancy. No evidence of irritation at injection site was found in any animal.A total of 1142 cows were enrolled in the previously noted field study that evaluated the effectiveness of two doses of 2, 3 or 4 mL of FACTREL Injection for use with LUTALYSE Injection to synchronize estrous cycles to allow FTAI in lactating dairy cows. Cows were observed daily for abnormal clinical signs. Over the course of the study there were 148 adverse health events documented in 118 cows. These adverse health events were common conditions in dairy cows (mastitis, lameness and pneumonia) and are not considered related to treatment.

ADVERSE REACTIONSTo report suspected adverse events, for technical assistance or to obtain a copy of the Material Safety Data Sheet (MSDS) contact Zoetis Inc. at 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.

HOW SUPPLIEDFACTREL Injection (gonadorelin injection), 50 mcg/mL is available in 20 mL and 50 mL multi-dose vials (box of one).

STORAGE CONDITIONSStore at refrigerator temperature 2° to 8°C (36° to 46°F). Use contents within 1 month of first vial puncture.



Revised: May 2015 40004714A&P

62

Lutalyse® Injection(dinoprost tromethamine injection)5 mg dinoprost/mL as dinoprost tromethamineCaution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTIONLUTALYSE® Injection (5 mg dinoprost/mL) is a sterile solution containing the naturally occurring prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each mL contains dinoprost tromethamine equivalent to 5 mg dinoprost: also, benzyl alcohol, 16.5 mg added as preservative and water for injection.When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost tromethamine is a white or slightly off-white crystalline powder that is readily soluble in water at room temperature in concentrations to at least 200 mg/mL.

INDICATIONS FOR USE

Cattle: LUTALYSE Injection is indicated as a luteolytic agent. LUTALYSE Injection is effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days prior to treatment.Future reproductive performance of animals that are not cycling will be unaffected by injection of LUTALYSE Injection.• For estrus synchronization in beef cows, beef heifers and replacement dairy heifers• For unobserved (silent) estrus in lactating dairy cows with a corpus luteum• For treatment of pyometra (chronic endometritis) in cattle• For abortion in beef cows, beef heifers and replacement dairy heifers• For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial

insemination (FTAI) in lactating dairy cows• For use with EAZI-BREEDTM CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in

lactating dairy cows• For use with EAZI-BREEDTM CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus

in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers

Swine:• For parturition induction in swine

Mares:• For controlling the timing of estrus in estrous cycling mares• For difficult-to-breed mares (clinically anestrous mares that have a corpus luteum)

MANAGEMENT CONSIDERATIONS Many factors contribute to success and failure of reproduction management, and these factors are important also when time of breeding is to be regulated with LUTALYSE Injection. Some of these factors are:

a. Cattle must be ready to breed—they must have a corpus luteum and be healthy; b. Nutritional status must be adequate as this has a direct effect on conception and the initiation of estrus in

heifers or return of estrous cycles in cows following calving; c. Physical facilities must be adequate to allow cattle handling without being detrimental to the animal;d. Estrus must be detected accurately if timed Al is not employed;e. Semen of high fertility must be used;f. Semen must be inseminated properly.

A successful breeding program can employ LUTALYSE Injection effectively, but a poorly managed breeding program will continue to be poor when LUTALYSE Injection is employed unless other management deficiencies are remedied first. Cattle expressing estrus following LUTALYSE Injection are receptive to breeding by a bull. Using bulls to breed large numbers of cattle in heat following LUTALYSE Injection will require proper management of bulls and cattle.

DOSAGE AND ADMINISTRATIONAs with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once.No vial stopper should be entered more than 20 times. For this reason, the 100 mL bottle should only be used for cattle. The 30 mL bottle may be used for cattle, swine, or mares.

Cattle: 1. For Estrus Synchronization in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a

corpus luteum. Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly either once or twice at a 10 to 12 day interval. With the single injection, cattle should be bred at the usual time relative to estrus. With the two injections cattle can be bred after the second injection either at the usual time relative to detected estrus or at about 80 hours after the second injection of LUTALYSE Injection. Estrus is expected to occur 1 to 5 days after injection if a corpus luteum was present. Cattle that do not become pregnant to breeding at estrus on days 1 to 5 after injection will be expected to return to estrus in about 18 to 24 days.

2. For Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly. Breed cows as they are detected in estrus. If estrus has not been observed by 80 hours after injection, breed at 80 hours. If the cow returns to estrus, breed at the usual time relative to estrus.

3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 5 mL LUTALYSE Injection (25 mg dinoprost) intramuscularly.

4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Inject a dose of 25 mg dinoprost (5 mL) intramuscularly.

Cattle that abort will abort within 35 days of injection.

5. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to 4 mL FACTREL Injection (100-200 mcggonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework:

• Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 • Administer LUTALYSE (25 mg dinoprost, as dinoprost tromethamine) Injection by intramuscular injection

6-8 days after the first dose of FACTREL Injection. • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE injection. • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows on detected

estrus using standard herd practices.

Below are three examples of treatment regimens for FTAI that fit within the dosage regimen framework described immediately above:

Example 1 Example 2 Example 3

Day 0 (Monday) 1st FACTREL 1st FACTREL 1st FACTRELDay 7 (the followingMonday)

LUTALYSE LUTALYSE LUTALYSE

Day 9(Wednesday)

2nd FACTREL+ FTAIat 48 hours afterLUTALYSE

2nd FACTRELat 48 hours afterLUTALYSE

2nd FACTREL56 hours afterLUTALYSE

Day 10(Thursday)

FTAI24 hours after2nd FACTREL

FTAI18 hours after2nd FACTREL

6. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for Synchronization of Estrus in Lactating Dairy Cows:

• Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example if administered on a Monday remove the following Monday).

• Administer 5 mL LUTALYSE Injection at the time of removal of the EAZI-BREED CIDR Cattle Insert. • Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and

inseminate animals found in estrus following normal herd practices.

7. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers:

• Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday).

• Inject 5 mL LUTALYSE Injection (equivalent to 5 mg/mL dinoprost) 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 day administration period.

• Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus.

Swine: For Parturition Induction in Swine: For intramuscular use for parturition induction in swine. LUTALYSE Injection is indicated for parturition induction in swine when injected within 3 days of normal

predicted farrowing. The response to treatment varies by individual animals with a mean interval from administration of 2 mL LUTALYSE Injection (10 mg dinoprost) to parturition of approximately 30 hours. This can be employed to control the time of farrowing in sows and gilts in late gestation.

Management Considerations: Several factors must be considered for the successful use of LUTALYSE Injection for parturition induction in swine. The product must be administered at a relatively specific time (treatment earlier than 3 days prior to normal predicted farrowing may result in increased piglet mortality). It is important that adequate records be maintained on (1) the average length of gestation period for the animals on a specific location, and (2) the breeding and projected farrowing dates for each animal. This information is essential to determine the appropriate time for administration of LUTALYSE Injection.

Mares: LUTALYSE Injection is indicated for its luteolytic effect in mares. Administer a single intramuscular injection of 1 mg per 100 lbs (45.5 kg) body weight which is usually 1 mL to 2 mL LUTALYSE Injection. This luteolytic effect can be utilized to control the timing of estrus in estrous cycling and clinically anestrous mares that have a corpus luteum in the following circumstances:

1. Controlling Time of Estrus of Estrous Cycling Mares: Mares treated with LUTALYSE Injection during diestrus (4 or more days after ovulation) will return to estrus within 2 to 4 days in most cases and ovulate 8 to 12 days after treatment. This procedure may be utilized as an aid to scheduling the use of stallions.

2. Difficult-to-Breed Mares: In extended diestrus there is failure to exhibit regular estrous cycles which is different from true anestrus. Many mares described as anestrus during the breeding season have serum progesterone levels consistent with the presence of a functional corpus luteum. A proportion of “barren”, maiden, and lactating mares do not exhibit regular estrous cycles and may be in extended diestrus. Following abortion, early fetal death and resorption, or as a result of “pseudopregnancy”, there may be serum progesterone levels consistent with a functional corpus luteum. Treatment of such mares with LUTALYSE Injection usually results in regression of the corpus luteum followed by estrus and/or ovulation. Treatment of “anestrous” mares which abort subsequent to 36 days of pregnancy may not result in return to estrus due to presence of functional endometrial cups.

WARNINGS AND PRECAUTIONS

User Safety: Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. In the early stages, women may be unaware of their pregnancies. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water.

To report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS) contact Zoetis Inc. at 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: No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. No preslaughter drug withdrawal period is required for labeled uses in swine. Use of this product in excess of the approved dose may result in drug residues. Do not use in horses intended for human consumption.

Animal Safety Warnings: Severe localized clostridial infections associated with injection of LUTALYSE Injection have been reported. In rare instances, such infections have resulted in death.Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions. Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestin would be expected to have a reduced response to LUTALYSE Injection. Do not administer to sows and/or gilts prior to 3 days of normal predicted farrowing as an increased number of stillbirths and postnatal mortality may result. In mares, LUTALYSE Injection is ineffective when administered prior to day-5 after ovulation.Mare pregnancy status should be determined prior to treatment since LUTALYSE Injection has been reported to induce abortion and parturition when sufficient doses were administered. Mares should not be treated if they suffer from either acute or subacute disorders of the vascular system, gastrointestinal tract, respiratory system, or reproductive tract.

ADVERSE REACTIONS

Cattle: Limited salivation has been reported in some instances.

Swine: The most frequently observed side effects were erythema and pruritus, slight incoordination, nesting behavior, itching, urination, defecation, abdominal muscle spasms, tail movements, hyperpnea or dyspnea, increased vocalization, salivation, and at the 100 mg (10x) dose only, possible vomiting. These side effects are transitory, lasting from 10 minutes to 3 hours, and were not detrimental to the health of the animal.

Mares: The most frequently observed side effects are sweating and decreased rectal temperature. However, these have been transient in all cases observed and have not been detrimental to the animal.Other reactions seen have been increase in heart rate, increase in respiration rate, some abdominal discomfort, locomotor incoordination, and lying down. These effects are usually seen within 15 minutes of injection and disappear within one hour. Mares usually continue to eat during the period of expression of side effects. One anaphylactic reaction of several hundred mares treated with LUTALYSE Injection was reported but was not confirmed.

Contact Information: To report adverse reactions call Zoetis Inc. at 1-888-963-8471.

CLINICAL PHARMACOLOGY

General Biologic Activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. Prostaglandins, especially PGF2α, have been shown to 1) increase in the uterus and blood to levels similar to levels achieved by exogenous administration which elicited luteolysis, 2) be capable of crossing from the uterine vein to the ovarian artery (sheep), 3) be related to IUD induced luteal regression (sheep), and 4) be capable of regressing the corpus luteum of most mammalian species studied to date. Prostaglandins have been reported to result in release of pituitary tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in the process of ovulation and gamete transport. Also PGF2α has been reported to cause increase in blood pressure, bronchoconstriction, and smooth muscle stimulation in certain species.

Metabolism: A number of metabolism studies have been done in laboratory animals. The metabolism of tritium labeled dinoprost (3H PGF2 alpha) in the rat and in the monkey was similar.Although quantitative differences were observed, qualitatively similar metabolites were produced.A study demonstrated that equimolar doses of 3H PGF2 alpha Tham and 3H PGF2 alpha free acid administered intravenously to rats demonstrated no significant differences in blood concentration of dinoprost. An interesting observation in the above study was that the radioactive dose of 3H PGF2 alpha rapidly distributed in tissues and dissipated in tissues with almost the same curve as it did in the serum. The half-life of dinoprost in bovine blood has been reported to be on the order of minutes. A complete study on the distribution of decline of 3H PGF2 alpha Tham in the tissue of rats was well correlated with the work done in the cow. Cattle serum collected during 24 hours after doses of 0 to 250 mg dinoprost have been assayed by RIA for dinoprost and the 15-keto metabolites. These data support previous reports that dinoprost has a half-life of minutes. Dinoprost is a natural prostaglandin. All systems associated with dinoprost metabolism exist in the body; therefore, no new metabolic, transport, excretory, binding or other systems need be established by the body to metabolize injected dinoprost.

TARGET ANIMAL SAFETY

Laboratory Animals: Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and 20.0 mg dinoprost/kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg dinoprost/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg dinoprost/kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg dinoprost/kg/day respectively. This was due to the expected luteolytic properties of the drug.A 14-day continuous intravenous infusion study in rats at 20 mg PGF2α per kg body weight indicated prostaglandins of the F series could induce bone deposition. However, such bone changes were not observed in monkeys similarly administered LUTALYSE Injection at 15 mg dinoprost per kg body weight for 14 days.

Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis, organ weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There was no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5˚ F through the 6th hour after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteolytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose required for abortion varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead to complications at abortion. However, induction of parturition or abortion with any exogenous compound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at latter stages of gestation.

Swine: In pigs, evaluation was made of clinical observations, food consumption, clinical pathologic determinations, body weight changes, urinalysis, organ weights, and gross and microscopic observations following treatment with single doses of 10, 30, 50 and 100 mg dinoprost administered intramuscularly. The results indicated no treatment related effects from dinoprost treatment that were deleterious to the health of the animals or to their offspring.

Mares: Dinoprost tromethamine was administered to adult mares (weighing 320 to 485 kg; 2 to 20 years old), at the rates of 0, 100, 200, 400, and 800 mg per mare per day for 8 days. Route of administration for each dose group was both intramuscularly (2 mares) and subcutaneously (2 mares). Changes were detected in all treated groups for clinical (reduced sensitivity to pain; locomotor incoordination; hypergastromotility; sweating; hyperthermia; labored respiration), blood chemistry (elevated cholesterol, total bilirubin, LDH, and glucose), and hematology (decreased eosinophils; increased hemoglobin, hematocrit, and erythrocytes) measurements. The effects in the 100 mg dose, and to a lesser extent, the 200 mg dose groups were transient in nature, lasting for a few minutes to several hours. Mares did not appear to sustain adverse effects following termination of the side effects.Mares treated with either 400 mg or 800 mg exhibited more profound symptoms. The excessive hyperstimulation of the gastrointestinal tract caused a protracted diarrhea, slight electrolyte imbalance (decreased sodium and potassium), dehydration, gastrointestinal irritation, and slight liver malfunction (elevated SGOT, SGPT at 800 mg only). Heart rate was increased but pH of the urine was decreased. Other measurements evaluated in the study remained within normal limits. No mortality occurred in any of the groups. No apparent differences were observed between the intramuscular and subcutaneous routes of administration. Luteolytic doses of dinoprost tromethamine are on the order of 5 to 10 mg administered on one day, therefore, LUTALYSE Injection was demonstrated to have a wide margin of safety. Thus, the 100 mg dose gave a safety margin of 10 to 20X for a single injection or 80 to 160X for the 8 daily injections.

Additional studies investigated the effects in the mare of single intramuscular doses of 0, 0.25, 1.0, 2.5, 3.0, 5.0, and 10.0 mg dinoprost tromethamine. Heart rate, respiration rate, rectal temperature, and sweating were measured at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hr. after injection. Neither heart rate nor respiration rates were significantly altered (P > 0.05) when compared to contemporary control values. Sweating was observed for 0 of 9, 2 of 9, 7 of 9, 9 of 9, and 8 of 9 mares injected with 0.25, 1.0, 2.5, 3.0, 5.0, or 10.0 mg dinoprost tromethamine, respectively. Sweating was temporary in all cases and was mild for doses of 3.0 mg or less but was extensive (beads of sweat over the entire body and dripping) for the 10 mg dose. Sweating after the 5.0 mg dose was intermediate between that seen for mares treated with 3.0 and 10.0 mg. Sweating began within 15 minutes after injection and ceased by 45 to 60 minutes after injection. Rectal temperature was decreased during the interval 0.5 until 1.0, 3 to 4, or 5 hours after injection for 0.25 and 1.0 mg, 2.5 and 3.0, or 5.0 and 10.0 mg dose groups, respectively. Average rectal temperature during the periods of decreased temperature was on the order of 97.5 to 99.6, with the greatest decreases observed in the 10 mg dose group.

EFFECTIVENESS

Cattle:

For Treatment of Pyometra (chronic endometritis) in Cattle: In studies conducted with LUTALYSE Injection, pyometra was defined as presence of a corpus luteum in the ovary and uterine horns containing fluid but not a conceptus based on palpation per rectum. Return to normal was defined as evacuation of fluid and return of the uterine horn size to 40mm or less based on palpation per rectum at 14 and 28 days. Most cattle that recovered in response to LUTALYSE Injection recovered within 14 days after injection. After 14 days, recovery rate of treated cattle was no different than that of non-treated cattle.

For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers: Commercial cattle were palpated per rectum for pregnancy in six feedlots. The percent of pregnant cattle in each feedlot less than 100 days of gestation ranged between 26 and 84; 80% or more of the pregnant cattle were less than 150 days of gestation. The abortion rates following injection of LUTALYSE Injection increased with increasing doses up to about 25 mg. As examples, the abortion rates, over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90% and 78% for cattle up to 100 days of gestation when injected IM with LUTALYSE Injection doses of 0,1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted relative abortion rate based on the dose titration data, was about 93% for the 5 mL (25 mg) LUTALYSE Injection dose for cattle injected up to 100 days of gestation.

For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: For a full description of the studies conducted for the use of FACTREL Injection and LUTALYSE Injection, please refer to the labeling for FACTREL Injection.

Mares:

For Difficult-to-Breed Mares: In one study with 122 Standardbred and Thoroughbred mares in clinical anestrus for an average of 58 days and treated during the breeding season, behavioral estrus was detected in 81 percent at an average time of 3.7 days after injection with 5 mg LUTALYSE Injection; ovulation occurred an average of 7.0 days after treatment. Of those mares bred, 59% were pregnant following an average of 1.4 services during that estrus.

HOW SUPPLIEDLUTALYSE Injection is available in 30 and 100 mL vials.

STORAGE, HANDLING, AND DISPOSALStore at controlled room temperature 20° to 25°C (68° to 77°F). Use contents within 12 weeks of first vial puncture. Protect from freezing.



Made in Spain

Revised: August 2015

P1208-678US/11-14A&P

63

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Lutalyse® HighCon Injection(dinoprost tromethamine injection)12.5 mg dinoprost/mL as dinoprost tromethamine For use in cattle only.Not for use in horses and swine.Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTIONLUTALYSE® HighCon Injection (12.5 mg dinoprost/mL) is a sterile solution containing the naturally occurring prostaglandin F2 alpha (dinoprost) as the tromethamine salt. Each mL contains dinoprost tromethamine equivalent to 12.5 mg dinoprost: also, benzyl alcohol, 16.5 mg added as preservative and water for injection. When necessary, pH was adjusted with sodium hydroxide and/or hydrochloric acid. Dinoprost tromethamine is a white or slightly off-white crystalline powder that is readily soluble in water at room temperature in concentrations to at least 200 mg/mL.

INDICATIONS FOR USELUTALYSE HighCon Injection is indicated as a luteolytic agent. LUTALYSE HighCon Injection is effective only in those cattle having a corpus luteum, i.e., those which ovulated at least five days prior to treatment. • For estrus synchronization in beef cows, beef heifers and replacement dairy heifers • For unobserved (silent) estrus in lactating dairy cows with a corpus luteum • For treatment of pyometra (chronic endometritis) in cattle • For abortion in beef cows, beef heifers and replacement dairy heifers • For use with FACTREL (gonadorelin injection) Injection to synchronize estrous cycles to allow

fixed-time artificial insemination (FTAI) in lactating dairy cows • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization

of estrus in lactating dairy cows • For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization

of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers

MANAGEMENT CONSIDERATIONSMany factors contribute to success and failure of reproduction management, and these factors are important also when time of breeding is to be regulated with LUTALYSE HighCon Injection. Some of these factors are: a. Cattle must be ready to breed—they must have a corpus luteum and be healthy; b. Nutritional status must be adequate as this has a direct effect on conception and the

initiation of estrus in heifers or return of estrous cycles in cows following calving; c. Physical facilities must be adequate to allow cattle handling without being detrimental to

the animal; d. Estrus must be detected accurately if timed Al is not employed; e. Semen of high fertility must be used; f. Semen must be inseminated properly. A successful breeding program can employ LUTALYSE HighCon Injection effectively, but a poorly managed breeding program will continue to be poor when LUTALYSE HighCon Injection is employed unless other management deficiencies are remedied first. Cattle expressing estrus following LUTALYSE HighCon Injection are receptive to breeding by a bull. Using bulls to breed large numbers of cattle in heat following LUTALYSE HighCon Injection will require proper management of bulls and cattle. Future reproductive performance of animals that are not cycling will be unaffected by injection of LUTALYSE HighCon Injection.

DOSAGE AND ADMINISTRATION As with any multi-dose vial, practice aseptic techniques in withdrawing each dose to decrease the possibility of post-injection bacterial infections. Adequately clean and disinfect the vial stopper prior to entry with a sterile needle and syringe. Use only sterile needles, and use each needle only once. No vial stopper should be entered more than 20 times. 1. For Estrus Synchronization in Beef Cows, Beef Heifers and Replacement Dairy Heifers.

LUTALYSE HighCon Injection is used to control the timing of estrus and ovulation in estrous cycling cattle that have a corpus luteum. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) intramuscularly or subcutaneously either once or twice at a 10 to 12 day interval. With the single injection, cattle should be bred at the usual time relative to estrus. With the two injections cattle can be bred after the second injection either at the usual time relative to detected estrus or at about 80 hours after the second injection of LUTALYSE HighCon Injection. Estrus is expected to occur 1 to 5 days after injection if a corpus luteum was present. Cattle that do not become pregnant to breeding at estrus on days 1 to 5 after injection will be expected to return to estrus in about 18 to 24 days.

2. For Unobserved (Silent) Estrus in Lactating Dairy Cows with a Corpus Luteum. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. Breed cows as they are detected in estrus. If estrus has not been observed by 80 hours after injection, breed at 80 hours. If the cow returns to estrus, breed at the usual time relative to estrus.

3. For Treatment of Pyometra (chronic endometritis) in Cattle. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection.

4. For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers. LUTALYSE HighCon Injection is indicated for its abortifacient effect in beef cows, beef heifers and replacement dairy heifers during the first 100 days of gestation. Inject a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection. Cattle that abort will abort within 35 days of injection.

5. For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: Administer 2 to 4 mL FACTREL Injection (100-200 mcg gonadorelin) per cow as an intramuscular injection in a treatment regimen with the following framework:

• Administer the first dose of FACTREL Injection (2-4 mL) at Day 0 • Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular

or subcutaneous injection 6-8 days after the first dose of FACTREL Injection. • Administer a second dose of FACTREL Injection (2-4 mL) 30 to 72 hours after the LUTALYSE

HighCon Injection. • Perform FTAI 0 to 24 hours after the second dose of FACTREL Injection, or inseminate cows

on detected estrus using standard herd practices. Below are three examples of treatment regimens for FTAI that fit within the dosage regimen

framework described immediately above:

Example 1 Example 2 Example 3Day 0 (Monday) 1st FACTREL 1st FACTREL 1st FACTRELDay 7 LUTALYSE LUTALYSE LUTALYSE(the following HighCon HighCon HighConMonday)Day 9 2nd FACTREL 2nd FACTREL 2nd FACTREL (Wednesday) + FTAI 48 hours 56 hours at 48 hours after after after LUTALYSE LUTALYSE LUTALYSE HighCon HighCon HighCon Day 10 FTAI FTAI(Thursday) 24 hours 18 hours after 2nd after 2nd FACTREL FACTREL

6. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for Synchronization of Estrus in Lactating Dairy Cows:

• Administer one EAZI-BREED CIDR Cattle Insert per animal and remove 7 days later (for example if administered on a Monday remove the following Monday).

• Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection at the time of removal of the EAZI-BREED CIDR Cattle Insert.

• Observe animals for signs of estrus on Days 2 to 5 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals found in estrus following normal herd practices.

7. For use with EAZI-BREED™ CIDR® (progesterone intravaginal insert) Cattle Insert for synchronization of estrus in suckled beef cows and replacement beef and dairy heifers, advancement of first postpartum estrus in suckled beef cows, and advancement of first pubertal estrus in beef heifers:

• Administer one EAZI-BREED CIDR Cattle Insert per animal for 7 days (for example, if administered on a Monday remove on the following Monday).

• Administer a dose of 2 mL LUTALYSE HighCon Injection (25 mg dinoprost) by intramuscular or subcutaneous injection 1 day prior to EAZI-BREED CIDR Cattle Insert removal, on Day 6 of the 7 day administration period.

• Observe animals for signs of estrus on Days 1 to 3 after removal of the EAZI-BREED CIDR Cattle Insert and inseminate animals about 12 hours after onset of estrus.

WARNINGS AND PRECAUTIONSUser Safety: Not for human use. Keep out of the reach of children. Women of childbearing age, asthmatics, and persons with bronchial and other respiratory problems should exercise extreme caution when handling this product. In the early stages, women may be unaware of their pregnancies. Dinoprost tromethamine is readily absorbed through the skin and can cause abortion and/or bronchiospasms. Accidental spillage on the skin should be washed off immediately with soap and water. Residue Warnings: No milk discard or preslaughter drug withdrawal period is required for labeled uses in cattle. Use of this product in excess of the approved dose may result in drug residues. Animal Safety Warnings: Severe localized clostridial infections associated with injection of LUTALYSE Injection have been reported. In rare instances, such infections have resulted in death. Aggressive antibiotic therapy should be employed at the first sign of infection at the injection site whether localized or diffuse. Do not administer intravenously (IV) as this route may potentiate adverse reactions. Non-steroidal anti-inflammatory drugs may inhibit prostaglandin synthesis; therefore this class of drugs should not be administered concurrently. Do not administer to pregnant cattle, unless abortion is desired. Cattle administered a progestin would be expected to have a reduced response to LUTALYSE Injection.

ADVERSE REACTIONSLimited salivation has been reported in some instances.Contact Information: To report suspected adverse events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS) contact Zoetis Inc. at 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.

CLINICAL PHARMACOLOGYGeneral Biologic Activity: Prostaglandins occur in nearly all mammalian tissues. Prostaglandins, especially PGE’s and PGF’s, have been shown, in certain species, to 1) increase at time of parturition in amniotic fluid, maternal placenta, myometrium, and blood, 2) stimulate myometrial activity, and 3) to induce either abortion or parturition. Prostaglandins, especially PGF2α, have been shown to 1) increase

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in the uterus and blood to levels similar to levels achieved by exogenous administration which elicited luteolysis, 2) be capable of crossing from the uterine vein to the ovarian artery (sheep), 3) be related to IUD induced luteal regression (sheep), and 4) be capable of regressing the corpus luteum of most mammalian species studied to date. Prostaglandins have been reported to result in release of pituitary tropic hormones. Data suggest prostaglandins, especially PGE’s and PGF’s, may be involved in the process of ovulation and gamete transport. Also PGF2α has been reported to cause increase in blood pressure, bronchoconstriction, and smooth muscle stimulation in certain species.Metabolism: A number of metabolism studies have been done in laboratory animals. The metabolism of tritium labeled dinoprost (3H PGF2 alpha) in the rat and in the monkey was similar. Although quantitative differences were observed, qualitatively similar metabolites were produced. A study demonstrated that equimolar doses of 3H PGF2 alpha Tham and 3H PGF2 alpha free acid administered intravenously to rats demonstrated no significant differences in blood concentration of dinoprost. An interesting observation in the above study was that the radioactive dose of 3H PGF2 alpha rapidly distributed in tissues and dissipated in tissues with almost the same curve as it did in the serum. The half-life of dinoprost in bovine blood has been reported to be on the order of minutes. A complete study on the distribution of decline of 3H PGF2 alpha Tham in the tissue of rats was well correlated with the work done in the cow. Cattle serum collected during 24 hours after doses of 0 to 250 mg dinoprost have been assayed by RIA for dinoprost and the 15-keto metabolites. These data support previous reports that dinoprost has a half-life of minutes. Dinoprost is a natural prostaglandin. All systems associated with dinoprost metabolism exist in the body; therefore, no new metabolic, transport, excretory, binding or other systems need be established by the body to metabolize injected dinoprost.Relative Bioavailability Study: The requirement for substantial evidence of effectiveness was fulfilled by a pharmacokinetic study comparing the relative bioavailability of the subcutaneous (SC) administration of 25 mg of LUTALYSE HighCon Injection (12.5 mg dinoprost/mL) to the approved intramuscular (IM) administration of 25 mg of LUTALYSE Injection (5 mg dinoprost/mL). The effectiveness data for LUTALYSE Injection at doses of 25 and 35 mg IM were used to support an adjusted Test/Reference (T/R) ratio of 1.4 and 90% Confidence Intervals of 80 - 164% for Cmax and AUC to demonstrate therapeutic equivalence. The pivotal relative bioavailability study was a randomized, non-replicated, three treatment, three period, six sequence crossover study in 24 cows (4 cows per sequence). Each cow received a single dose of 25 mg dinoprost administered as 5 mL of LUTALYSE Injection IM, 5 mL of LUTALYSE Injection SC, or 2 mL of LUTALYSE HighCon SC, with a washout period of 48 hours between doses. Plasma samples were collected at 60 and 10 minutes prior to dose administration, and at 5, 10, 15, 20, 30, 75 minutes, and at 2, 3, 4.5, 6, 7.5, and 12 hours after each dose. Samples were analyzed by UPLC-MS/MS for PGF2α (dinoprost) and PGFm (metabolite) concentrations. PGFm was chosen as the analyte of interest because its concentrations are reflective of exogenously administered dinoprost (after subtraction of endogenous concentrations), and it has a longer half-life and therefore less blood level fluctuations than PGF2α. The results of the relative bioavailability study are summarized in Table 1. The Cmax and AUClast of LUTALYSE HighCon were within the adjusted 90% Confidence Intervals. Therefore, the SC administration of 25 mg of LUTALYSE HighCon was considered to be equivalent to the IM administration of 25 mg of LUTALYSE Injection.

Table 1: Relative Bioavailability Results for LUTALYSE HighCon InjectionParameter Product/ LSMean Ratio Lower Upper

Route T/R† 90% CI 90% CILUTALYSEInjection 41.26(IM)*

Cmax LUTALYSE(ng/mL) Injection 50.80 1.23 110.99 136.60

(SC)LUTALYSEHighCon 55.12 1.34 120.42 148.20Injection(SC)LUTALYSEInjection 66.85(IM)*

AUClast LUTALYSE(hr*ng/mL) Injection 67.25 1.00 96.26 105.12

(SC)LUTALYSEHighCon 65.81 0.98 94.20 102.87Injection(SC)

Cmax - maximum plasma concentrationAUClast - the area under the plasma concentration vs. time curve from time of injection to the limit of

quantification of the assay* Reference product and route of administration† Geometric means

TARGET ANIMAL SAFETY Laboratory Animals: Dinoprost was non-teratogenic in rats when administered orally at 1.25, 3.2, 10.0 and 20.0 mg dinoprost/kg/day from day 6th-15th of gestation or when administered subcutaneously at 0.5 and 1.0 mg/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14. Dinoprost was non-teratogenic in the rabbit when administered either subcutaneously at doses of 0.5 and 1.0 mg dinoprost/kg/day on gestation days 6, 7 and 8 or 9, 10 and 11 or 12, 13 and 14 or 15, 16 and 17 or orally at doses of 0.01, 0.1 and 1.0 mg dinoprost/kg/day on days 6-18 or 5.0 mg/kg/day on days 8-18 of gestation. A slight and marked embryo lethal effect was observed in dams given 1.0 and 5.0 mg dinoprost/kg/day respectively. This was due to the expected luteolytic properties of the drug.A 14-day continuous intravenous infusion study in rats at 20 mg PGF2α per kg body weight indicated prostaglandins of the F series could induce bone deposition. However, such bone

changes were not observed in monkeys similarly administered 15 mg dinoprost per kg body weight for 14 days.Cattle: In cattle, evaluation was made of clinical observations, clinical chemistry, hematology, urinalysis, organ weights, and gross plus microscopic measurements following treatment with various doses up to 250 mg dinoprost administered twice intramuscularly at a 10 day interval or doses of 25 mg administered daily for 10 days. There was no unequivocal effect of dinoprost on the hematology or clinical chemistry parameters measured. Clinically, a slight transitory increase in heart rate was detected. Rectal temperature was elevated about 1.5˚ F through the 6th hour after injection with 250 mg dinoprost, but had returned to baseline at 24 hours after injection. No dinoprost associated gross lesions were detected. There was no evidence of toxicological effects. Thus, dinoprost had a safety factor of at least 10X on injection (25 mg luteolytic dose vs. 250 mg safe dose), based on studies conducted with cattle. At luteolytic doses, dinoprost had no effect on progeny. If given to a pregnant cow, it may cause abortion; the dose required for abortion varies considerably with the stage of gestation. Induction of abortion in feedlot cattle at stages of gestation up to 100 days of gestation did not result in dystocia, retained placenta or death of heifers in the field studies. The smallness of the fetus at this early stage of gestation should not lead to complications at abortion. However, induction of parturition or abortion with any exogenous compound may precipitate dystocia, fetal death, retained placenta and/or metritis, especially at latter stages of gestation. Injection Site Safety Summary: Eight non-lactating, non-pregnant dairy cows were injected with saline and eight animals were injected with LUTALYSE HighCon (12.5 mg dinoprost/mL @ 25 mg/animal) twice, at an interval of ten days. The first injection was administered in the left neck on Day 0 and the second injection was administered in the right neck on Day 10. Clinical observations were conducted on Days -14, -1, 0, 1, 2, 10, and 11, and injection site observations were conducted on all animals once on Days -14, -1, and once daily from Day 0 until Day 11. Animals were euthanized on Day 11. There were no abnormal clinical observations or general health observations related to drug administration during the conduct of the study. Injection site observations revealed no findings of erythema, heat, or sensitivity. No hardness was noted at the injection sites in any control animal post treatment administration. In the treated group, two animals had hardness noted on the right neck on Day 11. This hardness was probably a result of test article administration at that site on the previous day. No abnormal skin appearance was noted in any animal during this study. Swelling with a volume of 3.53 cm3 was observed on Day 11 in the right neck in one treated animal. At necropsy discoloration (variations of dark red, tan, gray, or yellow mottled) in the subcutaneous tissue was observed at all dinoprost injection sites. More discolored subcutaneous tissue was present at the Day 10 injection sites compared to the Day 0 injection sites. There was no discoloration observed in the deep muscle tissue. In summary, this study demonstrated that subcutaneous injection of LUTALYSE HighCon was well tolerated when injected subcutaneously into dairy cows at a dose of 25 mg dinoprost/cow twice at an interval of 10 days.

EFFECTIVENESSThe requirement for substantial evidence of effectiveness was fulfilled by a pharmacokinetic study comparing the relative bioavailability of the SC administration of 25 mg of LUTALYSE HighCon Injection (12.5 mg dinoprost/mL) to the approved IM administration of 25 mg of LUTALYSE Injection (5 mg dinoprost/mL) (see CLINICAL PHARMACOLOGY, Relative Bioavailability Study). This study demonstrated the equivalence of the SC administration of 25 mg of LUTALYSE HighCon to the IM administration of 25 mg of LUTALYSE Injection. Therefore, the effectiveness studies conducted with LUTALYSE Injection support the effectiveness of LUTALYSE HighCon Injection.For Treatment of Pyometra (chronic endometritis) in Cattle: In studies conducted with LUTALYSE Injection, pyometra was defined as presence of a corpus luteum in the ovary and uterine horns containing fluid but not a conceptus based on palpation per rectum. Return to normal was defined as evacuation of fluid and return of the uterine horn size to 40mm or less based on palpation per rectum at 14 and 28 days. Most cattle that recovered in response to LUTALYSE Injection recovered within 14 days after injection. After 14 days, recovery rate of treated cattle was no different than that of non-treated cattle.For Abortion in Beef Cows, Beef Heifers and Replacement Dairy Heifers: Commercial cattle were palpated per rectum for pregnancy in six feedlots. The percent of pregnant cattle in each feedlot less than 100 days of gestation ranged between 26 and 84; 80% or more of the pregnant cattle were less than 150 days of gestation. The abortion rates following injection of LUTALYSE Injection increased with increasing doses up to about 25 mg. As examples, the abortion rates, over 7 feedlots on the dose titration study, were 22%, 50%, 71%, 90% and 78% for cattle up to 100 days of gestation when injected IM with LUTALYSE Injection doses of 0, 1 (5 mg), 2 (10 mg), 4 (20 mg) and 8 (40 mg) mL, respectively. The statistical predicted relative abortion rate based on the dose titration data was about 93% for the 5 mL (25 mg) LUTALYSE Injection dose for cattle injected up to 100 days of gestation.For use with FACTREL® (gonadorelin injection) Injection to synchronize estrous cycles to allow fixed-time artificial insemination (FTAI) in lactating dairy cows: For a full description of the studies conducted for the use of FACTREL Injection and LUTALYSE Injection, please refer to the labeling for FACTREL Injection.

HOW SUPPLIEDLUTALYSE HighCon Injection is available in 20, 100 and 250 mL vials.

STORAGE, HANDLING AND DISPOSALStore below 25°C (77°F), with brief excursions between 0°C and 40°C (32°F and 104°F). Use contents within 12 weeks of first vial puncture. Stopper may be punctured a maximum of 20 times.NADA #141-442, Approved by FDA


Made in SpainRevised: August 2015

P1207-669US/06-15A&P

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Naxcel®

brand of ceftiofur sodium sterile powder

For intramuscular and subcutaneous injection in cattle only. For intramuscular injection in swine, sheep, goats, and horses. For subcutaneous injection only in dogs, day-old chickens and day-old turkey poults. This product may be used in lactating dairy cattle, sheep, and goats.

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, swine, chickens and turkeys for disease prevention purposes; at unapproved doses, frequencies, durations, or routes of administration; and in unapproved major food producing species/production classes.

DESCRIPTION NAXCEL Sterile Powder contains the sodium salt of ceftiofur which is a broad spectrum cephalosporin antibiotic active against gram-positive and gram-negative bacteria including β-lactamase-producing strains. Like other cephalosporins, ceftiofur is bactericidal in vitro, resulting from inhibition of cell wall synthesis. Each mL of the reconstituted drug contains ceftiofur sodium equivalent to 50 mg ceftiofur. The pH was adjusted with sodium hydroxide and mono basic potassium phosphate. Chemical Structure of Ceftiofur Sodium

Chemical Name of Ceftiofur Sodium5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-car boxylic acid, 7-[ [(2-amino-4-thiazolyl)(methoxy imino)-acetyl]amino]-3-[[(2-furanylcarbonyl)thio] methyl]-8-oxo-, monosodium salt, [6R-[6α,7β(Z)]]-

RECONSTITUTION OF THE STERILE POWDER NAXCEL Sterile Powder should be reconstituted as follows:

1 gram vial–Reconstitute with 20 mL Sterile Water for Injection. Each mL of the resulting solution contains ceftiofur sodium equivalent to 50 mg ceftiofur.4 gram vial–Reconstitute with 80 mL Sterile Water for Injection. Each mL of the resulting solution contains ceftiofur sodium equivalent to 50 mg ceftiofur. Shake thoroughly prior to use.

INDICATIONSCattle NAXCEL Sterile Powder is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. NAXCEL Sterile Powder is also indicated for treatment of acute bovine interdigital necrobacillosis (foot rot, pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus.Swine NAXCEL Sterile Powder is indicated for treatment/control of swine bacterial respiratory disease (swine bacterial pneumonia) associated with Actinobacillus (Haemophilus) pleuro pneu moniae, Pasteurella multocida, Salmonella choleraesuis and Streptococcus suis.Sheep NAXCEL Sterile Powder is indicated for treatment of sheep respiratory disease (sheep pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida.Goats NAXCEL Sterile Powder is indicated for treatment of caprine respiratory disease (goat pneumonia) associated with Mannheimia haemolytica and Pasteurella multocida.Horses NAXCEL Sterile Powder is indicated for treatment of respiratory infections in horses associated with Streptococcus zooepidemicus.Dogs NAXCEL Sterile Powder is indicated for the treatment of canine urinary tract infections associated with Escherichia coli and Proteus mirabilis.Day-Old Chicks NAXCEL Sterile Powder is indicated for the control of early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old chicks.Day-Old Turkey Poults NAXCEL Sterile Powder is indicated for the control of early mortality, associated with E. coli organisms susceptible to ceftiofur, in day-old turkey poults.

DOSAGE AND ADMINISTRATIONCattle Administer to cattle by intramuscular or subcutaneous injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24-hour intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recov ered) after the initial three treatments. Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner’s judgement of severity of disease (i.e., for respiratory disease, extent of elevated body temperature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite; and for foot rot, extent of swelling, lesion and severity of lameness).Swine Administer to swine by intramuscular injection at the dosage of 1.36 to 2.27 mg ceftiofur per pound (3.0 to 5.0 mg/kg) of body weight (1 mL of reconstituted sterile solution per 22 to 37 lbs body weight). Treatment should be repeated at 24-hour intervals for a total of three consecutive days.Sheep Administer to sheep by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at 24-hour intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recov ered) after the initial three treatments. Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner’s judgement of severity of disease (i.e., extent of elevated body tem perature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite).Goats Administer to goats by intramuscular injection at the dosage of 0.5 to 1.0 mg ceftiofur per pound (1.1 to 2.2 mg/kg) of body weight (1-2 mL reconstituted sterile solution per 100 lbs body weight). Treatment should be repeated at

24-hour intervals for a total of three consecutive days. Additional treatments may be given on days four and five for animals which do not show a satisfactory response (not recov ered) after the initial three treatments. Selection of dosage (0.5 to 1.0 mg/lb) should be based on the practitioner’s judgement of severity of disease (i.e., extent of elevated body tem perature, depressed physical appearance, increased respiratory rate, coughing and/or loss of appetite). Pharmacokinetic data indicate that elimination of the drug is more rapid in lactating does. For lactating does, the high end of the dose range is recommended.Horses Administer to horses by intramuscular injection at the dosage of 1.0 to 2.0 mg ceftiofur per pound (2.2 to 4.4 mg/kg) of body weight (2-4 mL reconstituted sterile solution per 100 lbs body weight). A maximum of 10 mL may be administered per injection site. Treatment should be repeated at 24-hour intervals, continued for 48 hours after clinical signs have disappeared and should not exceed 10 days. Dogs Administer to dogs by subcutaneous injection at the dosage of 1.0 mg ceftiofur per pound (2.2 mg/kg) of body weight (0.1 mL reconstituted sterile solution per 5 lbs body weight). Treatment should be repeated at 24-hour intervals for 5-14 days. Reconstituted NAXCEL Sterile Powder is to be administered to dogs by subcutaneous injection. No vial closure should be entered more than 20 times. Therefore, only the 1 gram vial is approved for use in dogs.Day-Old Chicks Administer by subcutaneous injection in the neck region of day-old chicks at the dosage of 0.08 to 0.20 mg ceftiofur/chick. One mL of the 50 mg/mL reconstituted solution will treat approximately 250 to 625 day-old chicks. Reconstituted NAXCEL Sterile Powder is to be administered by subcutaneous injection only. A sterile 26 gauge needle and syringe or properly cleaned automatic injection machine should be used.Day-Old Turkey Poults Administer by subcutaneous injection in the neck region of day-old turkey poults at the dosage of 0.17 to 0.5 mg ceftiofur/poult. One mL of the 50 mg/mL reconstituted solution will treat approximately 100 to 294 day-old turkey poults.Reconstituted NAXCEL Sterile Powder is to be administered by subcutaneous injection only.

CONTRAINDICATIONS As with all drugs, the use of NAXCEL Sterile Powder is contraindicated in animals previously found to be hypersensitive to the drug.

WARNINGSNOT 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) or to report any adverse event please call Zoetis Inc. at 1-888-963-8471.

RESIDUE WARNINGS: Cattle: When used according to label indications, dosage and routes of administration, treated cattle must not be slaughtered for 4 days following the last treatment. When used according to label indications, dosage and routes of administration, a milk discard time is not required. Use 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 in milk.Swine: When used according to label indications, dosage and route of administration, treated pigs 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.Sheep: Neither a pre-slaughter drug withdrawal interval nor a milk discard time is required when this product is used according to label indications, dosage, and route of administration. Use 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 in milk.Goats: Neither a pre-slaughter drug withdrawal interval nor a milk discard time is required when this product is used according to label indications, dosage, and route of administration. Use 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 in milk.Horses: Do not use in horses intended for human consumption.

PRECAUTIONS The effects of ceftiofur on the reproductive performance, pregnancy, and lactation of cattle, swine, sheep, and goats have not been determined.Cattle Following subcutaneous administration of ceftiofur sodium in the neck, small areas of discoloration at the site may persist beyond five days, potentially resulting in trim loss of edible tissues at slaughter. As with any parenteral injection, localized post-injection bacterial infections may result in abscess formation. Attention to hygienic procedures can minimize their occurrence.Swine The safety of ceftiofur has not been determined for swine intended for breeding.Horses The safety of ceftiofur has not been determined for horses intended for breeding. The administration of antimicrobials to horses under conditions of stress may be associated with acute diarrhea that could be fatal. If acute diarrhea is observed, discontinue use of this anti microbial and initiate appropriate therapy. Dogs The safety of ceftiofur has not been determined for dogs intended for breeding, or pregnant dogs.

ADVERSE REACTIONS The use of ceftiofur may result in some signs of immediate and transient local pain to the animal.

CLINICAL MICROBIOLOGY Summaries of MIC data are presented in Tables 1 and 2. Testing followed Clinical and Laboratory Standards Institute (CLSI) Guidelines.

*Minimum inhibitory concentration (MIC) for 90% of the isolates.

Table 1. Ceftiofur MIC Values of Bacterial Isolates from Clinical Field Studies in the USA

Animal Organism Number Date MIC90* MIC Range Tested Tested (µg/mL) (µg/mL)Bovine Mannheimia haemolytica 461 1988-1992 0.06 ≤0.03-0.13 Mannheimia haemolytica 42 1993 0.015 ≤0.003-0.03 Pasteurella multocida 318 1988-1992 0.06 ≤0.03-0.25 Pasteurella multocida 48 1993 ≤0.003 ≤0.003-0.015 Histophilus somni 109 1988-1992 0.06 ≤0.03-0.13 Histophilus somni 59 1993 ≤0.0019 no range Fusobacterium necrophorum 17 1994 ≤0.06 no rangeSwine Actinobacillus pleuropn. 83 1993 ≤0.03 ≤0.03-0.06 Pasteurella multocida 74 1993 ≤0.03 ≤0.03-0.06 Streptococcus suis 94 1993 0.25 ≤0.03-1.0 Salmonella choleraesuis 50 1993 1.0 1.0-2.0 beta-hemolytic Streptococcus spp. 24 1993 ≤0.03 ≤0.03-0.06 Actinobacillus suis 77 1998 0.0078 0.0019-0.0078 Haemophilus parasuis 76 1998 0.06 0.0039-0.25Sheep Mannheimia haemolytica 39 1992 0.13 ≤0.03-0.13 Pasteurella multocida 23 1992 ≤0.03 no rangeCanine Escherichia coli 44 1992 4.0 0.06-64.0 Escherichia coli 18 1990 0.25 0.13-0.5 Proteus mirabilis 17 1990 ≤0.06 ≤0.06-0.5 Proteus mirabilis 23 1992 1.0 ≤0.06-4.0Turkey Escherichia coli 1204 1995 1.0 0.13->32.0

Animal Organism Number Date MIC90** MIC Range Tested Tested (µg/mL) (µg/mL)Bovine Mannheimia haemolytica 110 1997-1998 0.06 ≤0.03-0.25 Mannheimia haemolytica 139 1998-1999 ≤0.03 ≤0.03-0.5 Mannheimia haemolytica 209 1999-2000 ≤0.03 ≤0.03-0.12 Mannheimia haemolytica 189 2000-2001 ≤0.03 ≤0.03-0.12 Pasteurella multocida 107 1997-1998 ≤0.03 ≤0.03-0.25 Pasteurella multocida 181 1998-1999 ≤0.03 ≤0.03-0.5 Pasteurella multocida 208 1999-2000 ≤0.03 ≤0.03-0.12 Pasteurella multocida 259 2000-2001 ≤0.03 ≤0.03-0.12 Histophilus somni 48 1997-1998 ≤0.03 ≤0.03-0.25 Histophilus somni 87 1998-1999 ≤0.03 ≤0.03-0.125 Histophilus somni 77 1999-2000 ≤0.03 ≤0.03-0.06 Histophilus somni 129 2000-2001 ≤0.03 ≤0.03-0.12 Bacteroides fragilis group 29 1994 16.0 ≤0.06->16.0 Bacteroides spp., non-fragilis group 12 1994 16.0 0.13->16.0 Peptostreptococcus anaerobius 12 1994 2.0 0.13-2.0Swine Actinobacillus pleuropn. 97 1997-1998 ≤0.03 no range Actinobacillus pleuropn. 111 1998-1999 ≤0.03 ≤0.03-0.25 Actinobacillus pleuropn. 126 1999-2000 ≤0.03 ≤0.03-0.06 Actinobacillus pleuropn. 89 2000-2001 ≤0.03 ≤0.03-0.06 Pasteurella multocida 114 1997-1998 ≤0.03 ≤0.03-1.0 Pasteurella multocida 147 1998-1999 ≤0.03 ≤0.03-0.5 Pasteurella multocida 173 1999-2000 ≤0.03 ≤0.03-0.06 Pasteurella multocida 186 2000-2001 ≤0.03 ≤0.03-0.12 Streptococcus suis 106 1997-1998 0.5 ≤0.03-4.0 Streptococcus suis 142 1998-1999 0.25 ≤0.03-1.0 Streptococcus suis 146 1999-2000 0.06 ≤0.03-4.0 Streptococcus suis 167 2000-2001 0.06 ≤0.03-4.0 Salmonella choleraesuis 96 1999-2000 1.0 0.03->4.0 Salmonella choleraesuis 101 2000-2001 1.0 0.5-2.0Equine Streptococcus equi subsp. equi 12 1994 ≤0.0019 no range Streptococcus equi subsp. equi 29 2002 ≤0.03 ≤0.03-0.05 Streptococcus zooepidemicus 48 1994 ≤0.0019 no range Streptococcus zooepidemicus 59 2002 ≤0.03 ≤0.03-0.25 Rhodococcus equi 66 1998 4.0 ≤0.03-16.0 Rhodococcus equi 42 2002 8.0 ≤0.03->32.0 Bacteroides fragilis group 32 1995 >16.0 0.13->16.0 Bacteroides spp., non-fragilis group 12 1995 4.0 0.25-4.0 Fusobacterium necrophorum 16 1995 ≤0.06 no rangeCanine Escherichia coli 26 2000 32 0.25->32 Proteus mirabilis 14 2000 0.25 0.06-0.25Turkey Escherichia coli 17 1998-1999 1.0 0.25-1.0 Escherichia coli 25 1999-2000 0.50 0.12-0.5 Escherichia coli 20 2000-2001 2.0 0.12-16.0 Citrobacter spp. 37 1995 32.0 0.5->32.0 Enterobacter spp. 51 1995 >32.0 0.13->32.0 Klebsiella spp. 100 1995 1.0 0.13-2.0 Proteus spp. 19 1995 1.0 0.06-32.0 Pseudomonas spp.*** 31 1995 >32.0 0.06->32.0 Salmonella spp. 24 1995 1.0 0.5-1.0 Staphylococcus spp. (coagulase positive) 17 1995 2.0 1.0-2.0 Staphylococcus spp. (coagulase negative) 26 1995 8.0 0.13->32.0Chicken Escherichia coli 62 1997-1998 0.50 0.25-2.0 Escherichia coli 53 1998-1999 4.0 0.25->4.0 Escherichia coli 67 1999-2000 0.50 0.12-16.0 Escherichia coli 90 2000-2001 1.0 ≤0.03-8.0 * The following in vitro data are available but their clinical significance is unknown.** Minimum inhibitory concentration (MIC) for 90% of the isolates.*** MIC50 is 32 µg/mL

Table 2. Ceftiofur MIC Values of Bacterial Isolates from Diagnostic Laboratories in the USA and Canada*

Based on the pharmacokinetic studies of ceftiofur in swine and cattle after a single intramuscular injection of 1.36 to 2.27 mg ceftiofur equivalents/lb (3.0 to 5.0 mg/kg) BW (swine) or 0.5 to 1.0 mg ceftiofur equivalents/lb (1.1 to 2.2 mg/kg) BW (cattle) and the MIC and disk (30 µg) diffusion data, the following breakpoints are recommended by CLSI.

Zone Diameter (mm) MIC (µg/mL) Interpretation ≥ 21 ≤ 2.0 (S) Susceptible 18-20 4.0 (I) Intermediate ≤ 17 ≥ 8.0 (R) Resistant

A report of “Susceptible” indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of “Intermediate” is a technical buffer zone and isolates falling into this category should be retested. Alternatively the organism may be successfully treated if the infection is in a body site where drug is physiologically concentrated. A report of “Resistant” indicates that the achievable drug concentrations are unlikely to be inhibitory and other therapy should be selected. Based on the pharmacokinetic studies of ceftiofur in horses after a single intramuscular injection of 1 mg ceftiofur equivalents/lb (2.2 mg/kg) BW, clinical effectiveness data and MIC data, the following breakpoint is recommended by CLSI.

Zone Diameter (mm) MIC (µg/mL) Interpretation ≥ 22 ≤ 0.25 (S) Susceptible

The susceptible only category is used for populations of organisms (usually one species) for which regression analysis (disk vs. MIC) cannot be performed. These breakpoints will permit detection of strains with decreased susceptibility as compared to the original population. Standardized procedures1 require the use of laboratory control organisms for both stan dardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strain. Ceftiofur sodium disks or powder reference standard is appropriate for both ceftiofur salts.

ANIMAL SAFETYCattle Results from a five-day tolerance study in normal feeder calves indicated that formulated ceftiofur was well tolerated at 25 times (25 mg/lb/day) the highest recommended dose of 1.0 mg/lb/day for five consecutive days. Ceftiofur administered intramuscularly had no adverse systemic effects. In a 15-day safety/toxicity study, five steer and five heifer calves per group were intramuscularly administered formulated ceftiofur at 0 (vehicle control), 1, 3, 5 and 10 times the highest recommended dose of 1.0 mg/lb/day to determine the safety factor. There were no adverse systemic effects indicating that the formulated ceftiofur has a wide margin of safety when injected intramuscularly into the feeder calves at 10 times (10 mg/lb/day) the recommended dose for three times (15 days) the recommended three to five days of therapy. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at 1 and 3 times the highest recommended dose of 1.0 mg/lb/day. The histopathological evaluations were conducted at posttreatment days 1, 3, 7 and 14. The injection of NAXCEL Sterile Powder at the recommended dose admin-istered SC in the neck of cattle was well tolerated. However, a several square centimeter area of yellow-red discoloration resulting from a single SC injection persisted in many of the cattle beyond 4.5 days post-injection. Also, one of the animals developed an abscess at the injection site.Swine Results from a five-day tolerance study in normal feeder pigs indicated that formulated ceftiofur was well tolerated when administered at 57 mg/lb (more than 25 times the highest recommended daily dosage of 2.27 mg/lb of body weight) for five consecutive days. Ceftiofur administered intramuscularly to pigs produced no overt adverse signs of toxicity. To determine the safety factor and to measure the muscle irritancy potential in swine, a safety/toxicity study was conducted. Five barrows and five gilts per group were intramuscularly administered formulated ceftiofur at 0, 2.27, 6.81 and 11.36 mg/lb of body weight for 15 days which is 0, 1, 3 and 5 times the highest recommended dose of 2.27 mg/lb of body weight/day and 5 times the recommended treatment length of 3 days. There were no adverse systemic effects indicating that formulated ceftiofur has a wide margin of safety when injected intramuscularly into feeder pigs at the highest recommended dose of 2.27 mg/lb/day for 3 days or at levels up to 5 times the highest recommended dose for 5 times the recommended length of treatment. The formulation was shown to be a slight muscle irritant based on results of histopathological evaluation of the injection sites at posttreatment days 1, 2, 3 and 4. By day 10 post injection the muscle reaction was subsiding and at day 15 post injection there was little evidence of muscle damage in any of the pigs in any of the treatment groups.

Sheep In a 15-day safety/toxicity study in sheep, three wether and three ewe lambs per group were given formulated ceftiofur sodium by the intramuscular route 0 (sterile water vehicle), 1, 3 or 5 times the recommended dose of 1.0 mg/lb/day for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in sheep. Based on examination of injection sites from study days 9, 11, 13 and 15, a low incidence of visual changes and histopathologic findings of mild, reversible inflammation from all groups including the controls indicated that the formulation is a slight muscle irritant.Goats In a 15-day safety/toxicity study 5 lactating does, 5 dry does, and 5 wethers were given formulated ceftiofur by the intramuscular route with 11 mg/kg/day for 15 days. This con stitutes 5 times the recommended dose for 3 times the recommended maximum duration of 5 days of treatment. There were no adverse systemic effects indicating that formulated ceftiofur is well tolerated and has a wide margin of safety in goats.Horses In a safety study, horses received a daily intramuscular injection of either 0 mg/lb/day (saline control), 1.0 mg/lb/day (50 mg/mL), 3.0 mg/lb/day (100 mg/mL), or 5.0 mg/lb/day (200 mg/mL) of an aqueous solution of ceftiofur sodium for 30 or 31 days. Ceftiofur sodium was well tolerated when administered intra-muscularly to male and female horses at doses up to 5.0 mg/lb/day for 30 or 31 days. No clinical evidence of irritation was noted at any dose. The drug-related changes detected in this study were limited to a transient decrease in food consumption in horses receiving 3.0 or 5.0 mg/lb/day ceftiofur, and general mild skeletal muscle irritation at the injection sites which resolved by regener-ation of muscle fibers. In a tolerance study, horses received a single daily intravenous infusion of either 0 (saline), 10.0 or 25.0 mg/lb/day of an aqueous solution (50 mg/mL) of ceftiofur for 10 days. The results indicated that ceftiofur administered intrave-nously at a dose of 10.0 or 25.0 mg/lb/day apparently can change the bacterial flora of the large intestine thereby leading to inflammation of the large intestine with subsequent diarrhea and other clinical signs (loose feces, eating bedding straw, dehydration, rolling or colic and a dull, inactive demeanor). Decreased food consumption, a loss of body weight, hematologic changes related to acute inflammation and stress, and serum chemistry changes related to decreased food consumption and diarrhea were also associated with treatment at these doses. The adverse effects were most severe a few days after dosing was initiated and tended to become less severe toward the end of the 10-day dosing period.Dogs Ceftiofur sodium was well tolerated at the therapeutic dose and is safe for the treatment of urinary tract infections in dogs. In the acute safety study, ceftiofur was well tolerated by dogs at the recommended level (1.0 mg/lb) for 5-14 days. When administered subcutaneously for 42 consecutive days, one of four females developed thrombocytopenia (15 days) and anemia (36 days). Thrombocytopenia and anemia also occurred at the 3X and 5X dose levels. In the reversibility phase of the study (5X dose), the thrombocytopenia reversed within 8 days, and of the two anemic animals the male recovered within 6 weeks and the female was sacrificed due to the severity of the anemia. In the 15-day tolerance study in dogs, high subcutaneous doses (25 and 125 times the recommended therapeutic dose) produced a progressive and dose-related thrombocytopenia, with some dogs also exhibiting anemia and bone marrow changes. The hematopoietic changes noted in dogs treated with ceftiofur were similar to those associated with long-term cephalosporin admin-istration in dogs and also man. The hematopoietic effects are not expected to occur as a result of recommended therapy.Day-Old Chicks In an acute toxicity study of ceftiofur in day-old chicks, a total of 60 male and 60 female chicks were each given single subcutaneous injections of 10, 100 or 1,000 mg/kg of body weight. Treatment on day 1 was followed by 6 days of observation; body weight was determined on days 1, 4 and 7; and selected hematology parameters were evaluated on day 4. No meaningful differences were noted among the treated and control groups of chicks for the parameters evaluated. Histopathologic evaluation of all deaths and chicks surviving to termination did not reveal a target organ or tissue of potential toxicity of ceftiofur when administered at up to 20 times (100 mg/kg) the intended highest use dosage.Day-Old Turkey Poults In an acute toxicity study of ceftiofur in day-old turkey poults, a total of 30 male and 30 female poults were each administered single subcutaneous injections of 100, 400 or 800 mg/kg body weight. Injection on day 1 was followed by 6 days of observation; body weight on days 1, 4, and 7; and selected hematology parameters on day 4. No meaningful differences were noted between the treated groups at 100 or 400 mg ceftiofur/kg and a negative control group for the parameters evaluated. Histopathologic evaluation of all deaths and poults surviving to termination did not reveal a target organ or tissue of potential toxicity of ceftiofur when administered at up to 50 times (400 mg/kg) the highest use dosage. A dose of 800 mg/kg (100 times the intended highest use dosage) was toxic, resulting in clinical signs and deaths accompanied by gross and microscopic morphologic tissue alterations.

TISSUE RESIDUE DEPLETIONCattle A radiolabeled residue metabolism study established tolerances for ceftiofur residues in cattle kidney, liver and muscle. These tolerances of 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 an intramuscular 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 tissues such as kidney, liver and muscle by 4 days after dosing. These data collectively support a 4-day pre-slaughter withdrawal period in cattle when used according to label directions.Swine Radiolabeled residue metabolism studies established tolerances for ceftiofur residues in swine kidney, liver, and muscle. These tolerances of 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.

STORAGE CONDITIONS Store unreconstituted product at controlled room temperature 20° to 25° C (68° to 77° F). Store reconstituted product either in a refrigerator 2° to 8° C (36° to 46° F) for up to 7 days or at controlled room temperature 20° to 25° C (68° to 77° F) for up to 12 hours. Protect from light. Color of the cake may vary from off-white to a tan color. Color does not affect potency.

ONE-TIME SALVAGE PROCEDURE FOR RECONSTITUTED PRODUCT At the end of the 7-day refrigeration or 12-hour room temperature storage period following reconstitution, any remaining reconstituted product may be frozen for up to 8 weeks without loss in potency or other chemical properties. This is a one-time only salvage procedure for the remaining product. To use this salvaged product at any time during the 8-week storage period, hold the vial under warm running water, gently swirling the container to accel erate thawing, or allow the frozen material to thaw at room temperature. Rapid freezing or thawing may result in vial breakage. Any product not used immediately upon thawing should be discarded.

HOW SUPPLIED NAXCEL Sterile Powder is available in the following package sizes: 1 gram vial 4 gram vial

1 Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Anti microbial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals; Approved Standard – Second Edition. NCCLS document M31-A2. CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, 2002.

NADA # 140-338, Approved by FDA


Revised: January 2014

30146300A&P

* All testing performed using a 30µg disk.** Quality control ranges are applicable only to tests performed by disk diffusion

test using a chocolate Mueller-Hinton agar, incubated in 5-7% CO2 for 20-24 hours.

*** MIC quality control ranges are applicable only to tests performed by broth microdilution procedures using veterinary fastidious medium (VFM).

Table 3. Acceptable quality control ranges for ceftiofur against Clinical and Laboratory Standards Institute recommended American Type Culture Collection (ATCC) reference strains

Organism Name (ATCC Number) Zone Diameter* MIC Range (mm) (µg/mL)

Escherichia coli (25922) 26–31 0.25–1.0

Staphylococcus aureus (29213) — 0.25–1.0

Staphylococcus aureus (25923) 27–31 —

Pseudomonas aeruginosa (27853) 14–18 16.0–64.0

Actinobacillus pleuropneumoniae (27090) 34–42** 0.004–0.015***

Histophilus somni (700025) 36–46** 0.0005–0.004***

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Pirsue® Sterile Solution (Pirlimycin hydrochloride)For Intramammary Infusion in Lactating Cows Only

FOR USE IN ANIMALS ONLY - NOT FOR HUMAN USE


DESCRIPTIONPirlimycin hydrochloride is a lincosaminide antibiotic.

Chemical Structure of Pirlimycin Hydrochloride

Chemical Name of Pirlimycin Hydrochloride

Methyl(2S-Cis)-7-chloro-6,7,8-trideoxy-6[[(4-ethyl-2-piperidinyl)carbonyl]amino]-1-thio-L-threo-a-D-galacto-octo-pyranoside monohydrochloride hydrate.

PIRSUE Sterile Solution is a clear solution.Each 10 mL PLASTET® Disposable Syringe contains:Pirlimycin free base equivalents ………………………………………… 50 mgAqueous vehicle ………………………………………………………………… q.s.

INDICATIONS FOR USE PIRSUE Sterile Solution (pirlimycin hydrochloride) is indicated for the treatment of clinical and subclinical mastitis in lactating dairy cattle associated with Staphylococcus species such as Staphylococcus aureus and Streptococcus species such as Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis.

DOSAGEInfuse one (1) syringe into each affected quarter. Use proper teat end preparation and sanitation and proper intramammary infusion technique (see ADMINISTRATION). Repeat treatment after 24 hours. Daily treatment may be repeated at 24-hour intervals for up to 8 consecutive days.

ADMINISTRATIONTeat End Preparation: Wash teats thoroughly with water containing a suitable dairy antiseptic. Dry the teats thoroughly. Milk out the udder completely. Using the alcohol pad provided, wipe the teat end of the affected quarters, using a separate pad for each teat. Allow sufficient time (at least 5 to 10 seconds) for the alcohol to dry. Use of protective gloves by persons applying treatment is recommended as part of aseptic infusion technique.Important Considerations for Extended Therapy: For extended duration of therapy, infuse only quarters known to be infected with label pathogens. Do not concurrently infuse uninfected low SCC quarters of the same cow. Prepare the teats using the above instructions, and then infuse PIRSUE Sterile Solution using aseptic infusion technique and partial insertion (see diagram below).

Infusion: The Plastet disposable syringe is designed to provide the choice of either insertion of the full cannula as has traditionally been practiced, or insertion of no more than 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al., 1987. Current Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA.a. Full insertion: Remove the white end cap by pulling straight up as shown. Gently insert the full cannula into the teat canal.b. Partial insertion: Remove the white end cap by pulling straight up as shown. Gently insert the exposed white tip into the teat canal.

Choose the desired insertion length (full or partial) and gently insert the tip into the teat canal. Carefully push the plunger to infuse the entire contents, and then massage the quarter to distribute the solution into the milk cistern. Following infusion, dip all quarters with an antiseptic teat dip. Cows with systemic clinical signs caused by mastitis should receive other appropriate therapy under the direction of a licensed veterinarian.Reinfection: After treatment, reinfection may occur unless good herd management, sanitation, and mechanical safety measures are practiced. Affected cows should be watched carefully to detect recurrence and possible spread of infection to other animals.

WARNING Repeated infusion during extended duration therapy regimens, even with adequate teat end preparation and sanitation, can result in elevated somatic cell counts and/or clinical mastitis, which can result in animal death. If acute clinical mastitis or other clinical signs of illness develop during extended duration therapy with PIRSUE, discontinue therapy immediately and contact your veterinarian.

Discard Empty Container; DO NOT REUSEKEEP OUT OF REACH OF CHILDREN

RESIDUE WARNINGS 1. Milk taken from animals during treatment and for 36 hours after the last treatment must not

be used for food regardless of treatment duration. 2. Following infusion twice at a 24-hour interval, treated animals must not be slaughtered for 9 days. 3. Following any extended duration of therapy (infusion longer than twice at a 24-hour interval,

up to 8 consecutive days), animals must not be slaughtered for 21 days. 4. Use of this product in a manner other than indicated under DOSAGE might result in violative residues.

PRECAUTIONWhen using extended duration therapy with PIRSUE Sterile Solution, failure to thoroughly clean quarters and to use aseptic infusion technique can result in the infusion of environmental mastitis pathogens not sensitive to pirlimycin.

ADVERSE REACTIONSAs demonstrated in the pivotal target animal safety study, even with adequate pre-treatment preparation, repeated infusion of PIRSUE Sterile Solution resulted in elevated SCC and clinical mastitis due to infection with Gram-negative environmental pathogens. For a complete listing of adverse reactions for pirlimycin reported to the Center for Veterinary Medicine (CVM) see http://www.fda.gov/cvm/ade_cum.htm. For technical assistance, to report suspected adverse reactions, or to request a Material Safety Data Sheet (MSDS), call 1-888-963-8471.

MICROBIOLOGYPirlimycin is a lincosaminide antibiotic that has activity against Gram-positive mastitis pathogens. Pirlimycin functions by binding to the 50S ribosomal subunit of bacterial ribonucleic acid, which interferes with protein synthesis within the bacteria. In vitro activity of pirlimycin has been demonstrated against Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae, and Streptococcus uberis, four pathogens associated with clinical and subclinical mastitis in lactating dairy cattle.

Utilizing data that included isolates from cows with mastitis, zone diameter interpretive criteria 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 pirlimycin against Gram-positive mastitis pathogens are shown in Table 1.

Table 1. CLSI-Accepted Interpretive Criteria for Pirlimycin Against Bovine Mastitis Pathogens*

Pathogen Disk Potency Zone Diameter MIC Breakpoint

Interpretive Standards (mm) (mg/mL)

S R S R

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus dysgalactiae 2 mg ≥13 ≤12 ≤2.0 ≥4.0

Streptococcus uberis

S - Susceptible

R - Resistant

* These interpretive criteria are only intended for use when CLSI M31-A2 performance standards are used to deter-mine antimicrobial susceptibility.

EFFECTIVENESSThe effectiveness of pirlimycin was demonstrated in a field dose response study in lactating dairy cattle with clinical mastitis. Three investigators enrolled 486 cows from 39 herds. Cows with abnormal milk (clots, flakes) and with or without udder clinical signs (swelling, redness, or soreness) were enrolled and treated, regardless of the mastitis pathogen isolated or the pre-treatment somatic cell count. Cows were treated in the affected quarter(s) with 50, 100, or 200 mg of pirlimycin twice at a 24-hour interval. A non-treated control group was included. In this study, an individual quarter was cured if it had normal milk, no udder clinical signs, and if the milk was negative for any mastitis pathogen at 10 days post-treatment. If no bacteria were isolated pre-treatment, a decrease in somatic cell count was required. A cow was cured if all enrolled quarters in that cow were cured. All three treatment levels had significantly greater cow cure rates than the non-treated control group. Based on this study, the dose of 50 mg of pirlimycin per quarter administered twice at a 24-hour interval was determined to be the effective dose for the treatment of clinical mastitis.

ANIMAL SAFETYTwo pivotal studies addressing the safety of pirlimycin administered at dosages of 50 mg or 200 mg (4X) into all four quarters twice at a 24-hour interval indicate that the formulation is safe and non-irritating to the bovine udder. Safety observations were also made during the clinical effectiveness study. No udder irritation was noted due to intramammary infusion with pirlimycin during these studies.

An additional study was conducted to determine the safety of extended duration therapy. Twenty lactating Holstein cows, first lactation or greater, at various milk production levels, and with no evidence of clinical mastitis were enrolled and treated with pirlimycin administered at a dosage of 50 mg/quarter in all four quarters daily for eight consecutive days. Cows were monitored for general health, changes in milk production and quality, and signs of udder irritation for a total of 14 days, beginning three days prior to the first treatment. Milk production was not affected by treatment. SCCs of tre-ated cows were statistically significantly increased post-treatment relative to the pre-treatment level. A total of 24 pirlimy-cin-treated quarters (32%) in 15 cows had increased SCCs (>200,000 cells/mL) for at least two consecutive milkings. Of these, six treated cows (8 quarters) had a concurrent bacterial infection attributable to a mastitis pathogen. Udder irritation occurred in seven pirlimycin-treated cows (10 quarters). Abnormal strip cup scores occurred in six pirlimycin-treated cows (9 quarters). Most of the abnormal udder and strip cup observations were seen in quarters where bacte-ria were also isolated.

Corroborative data from field studies and field use reports indicate that although intramammary infusion of pirlimycin hydrochloride at 50 mg/quarter administered from two to eight consecutive days was well tolerated, repeated infusion with pirlimycin increases the potential for intramammary infections and subsequent clinical mastitis due to environmental bacteria, including coliform bacteria. Adverse reactions, including clinical signs of mastitis (udder swelling and abnor-mal milk), increased SCCs, and death from coliform mastitis have been reported in cows following extended therapy with pirlimycin. Some, but not all, adverse reactions were associated with failure to thoroughly clean quarters and to use aseptic infusion technique.

MILK AND TISSUE RESIDUE DEPLETION The established tolerance of pirlimycin in milk is 0.40 ppm. Milk residue depletion studies were conducted in cows with clinical mastitis. In one study, cows were infused with 50 mg of pirlimycin twice at a 24-hour interval into all quarters regardless of the number of affected quarters. In a second study, cows with a single mastitic quarter were infused with 50 mg of pirlimycin twice at a 24-hour interval into only the affected quarter. In a third study, normal cows were infused with 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. As a result of these three studies, milk taken from cows during treatment and for 36 hours following treatment must not be used for food and must be discarded. For extended duration of therapy (once daily for up to 8 consecutive days), a milk residue study was conducted where cows received 50 mg of pirlimycin per quarter into all four quarters for 8 consecutive days. This study confirmed that milk taken from cows during treatment and for 36 hours following the last treatment must not be used for food and must be discarded.

The established tolerance for pirlimycin in liver (the target tissue) is 0.5 ppm. A pivotal tissue residue study was conducted following administration of 50 mg of pirlimycin twice at a 24-hour interval into all four quarters. Following receipt of the 50 mg of pirlimycin twice at a 24-hour interval into all four quarters, the liver residue decline data from this study supports a 9-day pre-slaughter withdrawal period.

For extended duration of therapy, a second tissue residue study was conducted. Each lactating cow received 50 mg pirlimycin per quarter into all four quarters, once daily for 8 consecutive days. Using the established tolerance for pirlimycin of 0.5 ppm in the liver, these data support a 21-day pre-slaughter withdrawal period for extended duration pirlimycin therapy. Extended duration of therapy is considered as any treatment period longer than 2 days (up to 8 consecutive days) of therapy.

EFFECT ON MILK MANUFACTURING STARTER CULTURES A study was conducted to examine the effect of varying concentrations of pirlimycin in milk on the growth of bacterial starter cultures used to produce fermented milk products. Pirlimycin did not adversely affect bacterial starter cultures used for the production of fermented milk products at concentrations found following normal label use including proper milk discard periods. Violative levels of pirlimycin (>0.40 ppm) can adversely affect the growth of bacterial starter cultures.

PIR

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STORAGE CONDITIONSStore at Controlled Room Temperature 20 to 25°C (68 to 77°F).Store Plastets in Carton or Pail Until Used.

HOW SUPPLIEDPIRSUE Sterile Solution is available in unbroken packages of 12-10 mL Plastet Disposable Syringes with 12 individually wrapped 70% isopropyl alcohol pads. The Plastet Disposable Syringes are packaged in Cartons (12-10 mL Plastet Disposable Syringes per carton) and in Pails (12 packages of 12-10 mL Plastet Disposable Syringes or 144 Plastets per pail).


PAA036273



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5” x 24” Folds to: 5” x 1.5” PD2194 1475000 Insert

11395 PAA036273 Pirsue USA

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Project No. Artwork Number Description Country

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69

For Intramammary Infusion in Dry Dairy Cattle Only

FOR USE IN ANIMALS ONLY — NOT FOR HUMAN USE

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 dry dairy cattle for disease prevention purposes; at unapproved doses, frequencies, durations, or routes of administration; and in unapproved major food producing species/production classes.

DESCRIPTION: Ceftiofur hydrochloride is a cephalosporin antibiotic.

Chemical Structure of Ceftiofur Hydrochloride

U-64279A

Chemical Name of Ceftiofur Hydrochloride5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7 - [[2-(2- amino-4-thiazolyl) - 2 -(methoxyimino)acetyl]amino]-3-[[(2-furanyl-carbonyl)thio]methyl]-8-oxo, hydrochloride. Ceftiofur Hydrochloride Sterile Suspension is an oil based sterile suspen-sion. Each 10 mL PLASTET® Disposable Syringe Contains:Ceftiofur Equivalents (as the hydrochloride salt) ................................... 500 mgMicrocrystalline Wax............................................................................. 700 mgOleoyl Polyoxylglyceride ....................................................................... 500 mgCottonseed Oil ............................................................................................ q.s.

INDICATIONS FOR USE SPECTRAMAST® DC Ceftiofur Hydrochloride Sterile Suspension is indicated for the treatment of subclinical mastitis in dair cattle at the time of dry off associated with Staphylo coc cus aureus, Streptococcus dysgalactiae, and Streptococcus uberis. SPECTRAMAST® DC Ceftiofur Hydrochloride Sterile Suspension has been proven effective against Staph y lo coc cus aureus, Streptococcus dysgalactiae, and Streptococcus uberis.

DOSAGE Infuse one (1) syringe into each affected quarter at the time of dry off.

DIRECTIONS FOR USING THE PLASTET® DISPOSABLE SYRINGE The syringe is designed to provide the choice of either insertion of the full cannula as has traditionally been practiced, or insertion of no more than 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al. 1987. Current Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA.a. Full insertion: Remove the red end cap by pulling straight up as

shown. Gently insert the full cannula into the teat canal; carefully infuse the product.

b. Partial insertion: Remove the red end cap by pulling straight up as shown. Gently insert the exposed white tip into the teat canal; carefully infuse the product.

ADMINISTRATION

Treatment: Wash teats thoroughly with warm water containing a suitable dairy antiseptic. Dry teats thoroughly. Milk out udder completely. Using an alcohol pad provided, wipe off the end of the affected teat using a separate pad for each teat. Choose the desired insertion length (full or partial) and insert tip into teat canal; push plunger to dispense entire contents, massage the quarter to distribute the suspension into the milk cistern.Reinfection: After successful treatment, reinfection may occur unless good herd management, sanitation, and mechanical safety measures are practiced. Affected cows should be watched carefully to detect recurrence of infection and possible spread to other animals.CONTRAINDICATIONS As with all drugs, the use of SPECTRAMAST® DC Sterile Suspension is contraindicated in animals previously found to be hypersensitive to the drug.

Discard Empty Container: DO NOT REUSEKEEP OUT OF REACH OF CHILDREN

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. Sen si ti za tion 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 report adverse effects in users, to obtain more information or to obtain a material safety data sheet, call Zoetis Inc. at 1-888-963-8471.

RESIDUE WARNINGS1. Milk taken from cows completing a 30-day dry cow

period may be used for food with no milk discard due to ceftiofur residues.

2. Following label use, no pre-slaughter withdrawal period is required for neonatal calves born from treated cows regardless of colostrum consumption.

3. Following intramammary infusion, a 16-day pre-slaughter withdrawal period is required for treated cows.

4. Use of this product in a manner other than indicated under DOSAGE might result in violative residues.

CLINICAL MICROBIOLOGY Ceftiofur is a broad-spectrum cephalosporin antibiotic that exerts its effect by inhibiting bacterial cell wall synthesis. Like other ß-lactam antimicrobial agents, the cephalosporins inhibit cell wall synthesis by interfering with the enzymes essential for peptidoglycan synthesis. This effect results in lysis of the bacterial cell and accounts for the bactericidal nature of these agents. Ceftiofur has demonstrated in vitro activity against clinical isolates and isolates from diagnostic laboratories. The results of susceptibility testing of these isolates against ceftiofur are presented in Tables 1 and 2. Appropriate reference strains were also susceptibility tested and their minimum inhibitory concentration (MIC) values and zone of inhibition with a 30 µg disk are presented in Table 4.

Table 1. Ceftiofur MIC values for isolates from a multi-site clinical field study evaluating subclinical mastitis

in dry dairy cows in the U.S. during 2000

Organism No. MIC90*(µg/mL)MIC range

(µg/mL)

Staphylococcus aureus 300 1.0 ≤0.06 to 2.0

Streptococcus dysgalactiae 55 ≤0.06 ≤0.06 to >64.0

Streptococcus uberis 58 1.0 ≤0.06 to 4.0

* The MIC for 90% of the isolates.

Table 2. Ceftiofur MIC values* for mastitis pathogens from diagnostic laboratories in the U.S. and Canada

Organism No. Date isolated

MIC90**(µg/mL)

MIC range(µg/mL)


135 1991–1992 1.0 0.13 to 2.0

10 1993 1.0 0.25 to 1.0

107 1995 1.0 0.25 to 2.0

61 2000 1.0 ≤0.06 to 2.0

Coagulase (-) staphylococci

139 2000–2001 1.0 ≤0.06 to 2.0

Streptococcus dysgalactiae

15 1991–1992 1.0 ≤0.06 to 2.0

15 1993 ≤0.0039 No range†

152 1997–1999 0.25 0.25 to 4.0

64 2000 ≤0.06 ≤0.06 to 0.5


22 1991–1992 0.5 ≤0.06 to 4.0

15 1993 0.03 ≤0.0039 to 0.06

133 1997–1999 0.5 0.5 to 8.0

20 2000 1.0 <0.06 to 2.0

Escherichia coli

39 1991–1992 1.0 0.25 to 1.0

40 1993 0.5 0.13 to 1.0

52 2000 0.5 ≤0.06 to 1.0

* The above in vitro data are available, but their clinical significance is unknown.** The MIC for 90% of the isolates. † No range, all isolates yielded the same value.

Based on pharmacokinetic, milk residue and clinical effectiveness studies in dairy cattle following intramammary infusion of ceftiofur and the MIC and disk (30 µg) diffusion data from mastitis pathogens, the following breakpoints are recommended by the National Committee for Clinical Laboratory Standards [now the Clinical and Laboratories Standards Institute (CLSI)] (Table 3).

Table 3. Current recommended interpretive criteria established by CLSI for ceftiofur for Bovine Mastitis

Bovine Mastitis Organisms

Disk Content

Zone Diameter

(mm)

MIC break-point (μg/

mL)

S I R S I RStaphylococcus aureusStreptococcus dysgalactiaeStreptococcus uberisStreptococcus agalactiaeEscherichia coli

30 µg ≥21 18–20 ≤17 ≤2.0 4.0 ≥8.0

S–Susceptible I–Intermediate R–Resistant

Standardized procedures require the use of laboratory control organisms for both standardized diffusion techniques and standardized dilution techniques. The 30 µg ceftiofur sodium disk should give the following zone diameters and the ceftiofur sodium standard reference powder (or disk) should provide the following MIC values for the reference strain. The ceftiofur sodium disks or standard reference powder is appropriate for ceftiofur hydrochloride (Table 4).

SPECTRAMAST® DCbrand of ceftiofur hydrochloridesterile suspension

Table 4. Acceptable quality control ranges for ceftiofur against CLSI recommended American Type

Culture Collection (ATCC) reference strains

Organism (ATCC No.) Zone Diameter*

(mm)

MIC range

(μg/mL)

Escherichia coli (25922) 26 to 31 0.25 to 1.0

Staphylococcus aureus (29213) --- 0.25 to 1.0

Staphylococcus aureus (25923) 27 to 31 ---

Pseudomonas aeruginosa (27853) 14 to 18 16.0 to 64.0

*All testing performed using a 30 µg disk.

EFFECTIVENESS The effectiveness of a single intramammary (IMM) infusion of ceftiofur hydrochloride for the treatment of subclinical mastitis present at the time of dry off was demonstrated in a randomized block design study. Nineteen veterinary investigators enrolled cows in 21 herds and from these 21 herds, 431 cows and 1708 quarters met enrollment criteria in the study and calved within a 45 to 60 day period following enrollment. The enrollment criteria were whole udder somatic cell counts greater than 400,000 cells/mL or a linear somatic cell count score greater than or equal to 5. Milk microbiologic samples were obtained prior to treatment and at Days 3 and 5 post-calving. There were 5 treatment groups including a negative control group. There were 43 cows in the negative control group and 51 cows in the 500 mg ceftiofur group that had a positive pre-treatment milk culture that were evaluated for treatment success. The primary decision variable was the microbiologic (therapeutic) cure in which bacteria isolated pre-treatment were absent from both post-treatment samples. In another study in eleven study herds, 446 cows with a somatic cell count (SCC) greater than or equal to 400,000 cells/mL or a linear score greater than or equal to 5 were enrolled. Cows with a dry period of at least 45 days were blocked by lactation (1st + 2nd or ≥3rd). A single quarter milk sample was aseptically obtained from all four quarters for bacterial culture prior to treatment and on Days 3 and 5 post-calving. There were 4 treatment groups including a negative control. There were 84 cows in the negative control and 73 in the 500 mg ceftiofur group that had a positive pre-treatment milk culture that were evaluated for treatment success. The primary decision variable was the microbi-ologic (therapeutic) cure in which bac-teria isolated pre-treatment were absent from both post-treatment samples. Ceftiofur was found to be effective against Staphylococcus aureus, Streptococcus dysgalactiae, and Streptococcus uberis, when compared to negative controls. This intramammary ceftiofur formulation was well tolerated. No adverse formulation related events were noted during the entire study. A large multi-location field dose confirmation study and a pilot study demonstrated that 500 mg of ceftiofur infused once per quarter at the time of dry off was effective for the treatment of subclinical mastitis in dairy cattle at the time of dry off.

ANIMAL SAFETY An udder irritation study was conducted in 22 healthy lactating dairy cows to assess udder irritation following a single intramammary infusion of a sterile oil-based suspension containing 500 mg of ceftiofur into all four quarters followed by milk-out 12 hours later. Throughout the 10 day post-treatment observation period there was a clinically insignificant rise in SCC to mean levels <200,000 cells/mL from the pre-infusion level of <69,000 cells/mL. No clinical signs of udder irritation (swelling, pain, or redness), changes in rectal temperature, or changes in milk production were noted in this study. Clinical observations were made during a GLP residue depletion study of 36 cows following a single intramammary infusion of a sterile oil based suspension containing 500 mg of ceftiofur into all four quarters at the end of lactation. No report of udder irritation or adverse reaction was noted in the daily visual observations over the 14 days immediately following treatment. Collectively, these studies demonstrate that the intramammary infusion of an oil-based sterile suspension containing 500 mg of ceftiofur once into all four quarters at the end of lactation is clinically safe and non-irritating to the udder of non-lactating dairy cows.

MILK AND TISSUE RESIDUE DEPLETION A metabolism study in cattle using radiolabeled ceftiofur provided the data to establish tolerances for ceftiofur-related residues (as desfuroylceftiofur) in tissue and milk. These tolerances of ceftiofur residues are 0.1 ppm in milk, 0.4 ppm in kidney, 2.0 ppm in liver, and 1.0 ppm in muscle. Pivotal residue decline studies were conducted to assess the depletion of ceftiofur-related residues, measured as desfuroylcef-tio-fur using the official analytical method, in tissues of treated cows, in milk from treated cows, and in tissues of calves born to treated cows. In these studies, non-mastitic cows received 500 mg of ceftiofur per quarter into all four quarters once at dry off. The milk residue deple-tion study demonstrated that milk produced at calving may be used for human consumption with no discard period when the treatment to calv-ing interval is 30 days or more. The tissue depletion study measured residues in the tissues of treated cows and in the tissues of neonatal calves born to treated cows. In neonatal calves born to treated cows, tissue residues were less than the codified tolerances for kidney, liver and muscle. These data support a zero day pre-slaughter withdrawal period for calves born to treated cows when the treatment to calving interval is 30 days or more, regardless of colostrum consumption. The tissue residue depletion data support a 16-day pre-slaughter withdrawal period following intramammary infusion for treated cows.

STORAGE CONDITIONS Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect from light. Store plastets in carton until used.

HOW SUPPLIED SPECTRAMAST® DC Sterile Suspension is available in cartons containing 1 unbroken package of 12–10 mL PLASTET® Disposable Syringes with 12 individually wrapped 70% isopropyl alcohol pads and in pails containing 12 unbroken packages of 12-10 mL PLASTET Disposable Syringes with 144 individually wrapped 70% isopropyl alcohol pads.

NADA# 141-239, Approved by FDADistributed by:Zoetis Inc.Kalamazoo, MI 49007

www.spectramast.com or call 1-888-963-8471

Revised: September 2013 30150900A&P

70

SPECTRAMAST® LC(ceftiofur intramammary suspension)Sterile Suspension

For Intramammary Infusion in Lactating Cows OnlyFOR USE IN ANIMALS ONLY — NOT FOR HUMAN USE

CONTRAINDICATIONS As with all drugs, the use of SPECTRAMAST® LC Sterile Suspension is contraindicated in animals previously found to be hypersensitive to the drug.

Discard Empty Container: DO NOT REUSEKEEP OUT OF REACH OF CHILDREN

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 individu als. Repeated or prolonged exposure may lead to sensitization. Avoid direct contact of the prod-uct with the skin, eyes, mouth and clothing. Sen si ti za tion 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 safety data sheet contains more detailed occupa tional safety infor-mation. To report suspected adverse events, for technical assistance or to obtain a copy of the safety data sheet (SDS), contact Zoetis Inc. at 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 WARNINGS1. Milk taken from cows during treatment (a maximum of eight

daily infusions) and for 72 hours after the last treatment must not be used for human consumption.

2. Following label use for up to eight consecutive days, a 2-day pre-slaughter withdrawal period is required.

3. Use of this product in a manner other than indicated under DOSAGE might result in violative residues.

PRECAUTION Following intramammary infusion with antibiotics in lactating cows, milk obtained during treatment and during the milk discard period should be properly discarded and not fed to calves. SPECTRAMAST LC is intended for use in lactating dairy cattle with mastitis associated only with the speci-fied labeled pathogens. To assure responsible antimicrobial drug use, it is expected that subclinical mastitis will be diagnosed using a positive culture or other pathogen-specific test in addition to any other appropriate veteri-nary medical evaluation prior to treatment. Cows with systemic clinical signs caused by mastitis should receive other appropriate therapy under the direc-tion of a licensed veterinarian. After successful treatment, reinfection may occur unless good herd management, sanitation, and mechanical safety measures are practiced. Affected cows should be watched carefully to detect recurrence of infection and possible spread to other animals.

CLINICAL MICROBIOLOGY Ceftiofur is a broad-spectrum cephalosporin antibiotic that exerts its effect by inhibiting bacterial cell wall synthesis. Like other ß-lactam antimicrobial agents, cephalosporins inhibit cell wall synthesis by interfering with the enzymes essential for peptidoglycan synthesis. This effect results in lysis of the bacte-rial cell and accounts for the bactericidal nature of these agents. Ceftiofur has demonstrated in vitro activity against coagulase-negative staphylococci, Streptococcus dysgalactiae, and Escherichia coli. The minimum inhibitory concentrations (MICs) of ceftiofur against indicated pathogens collected from field studies conducted in 2000 were determined using methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS, M31-A) and are represented in Table 1, below:

Table 1. Ceftiofur Minimum Inhibitory Concentrations (MIC) Values* of Isolates from Field Studies Evaluating Clinical Mastitis in Dairy Cows in the U.S. During 2000

Pathogen Number of MIC90** MIC Range isolates (µg/mL) (µg/mL)Coagulase-negative 33 1.0 ≤0.06–2.0 staphylococci (CNS)Streptococcus dysgalactiae 32 ≤0.06 ≤0.06–0.5Escherichia coli 35 0.5 ≤0.06–1.0 * The correlation between in vitro susceptibility data and clinical effectiveness

is unknown.** The lowest MIC to encompass 90% of the most susceptible isolates.

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 lactating dairy cattle for disease prevention purposes; at unapproved doses, frequencies, durations, or routes of administration; and in unapproved major food producing species/production classes.

DESCRIPTION Ceftiofur hydrochloride is a cephalosporin antibiotic.

Chemical Structure of Ceftiofur HydrochlorideNH2

S N

C

COOH

N O

O

C

N

SNH

OCH3O CH2 S C

• HCl

O

U-64279A

Chemical Name of Ceftiofur Hydrochloride 5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, 7 -[[2-(2- amino-4-thiazolyl) - 2 -(methoxyimino)acetyl]amino]-3-[[(2-furanylcarbonyl)thio]methyl]-8-oxo, hydrochloride. SPECTRAMAST® LC Sterile Suspension is an oil based sterile suspension. Each 10 mL PLASTET® Disposable Syringe Contains:Ceftiofur Equivalents (as the hydrochloride salt) ................................125 mgMicrocrystalline Wax ..........................................................................700 mgOleoyl Polyoxylglyceride ....................................................................500 mgCottonseed Oil .........................................................................................q.s.

INDICATIONS FOR USE SPECTRAMAST® LC (ceftiofur intramammary suspension) Sterile Suspension is indicated for use in lactating dairy cattle for (1) the treatment of clinical mastitis associated with coagulase-negative staphylococci, Streptococcus dysgalactiae, and Escherichia coli and (2) the treatment of diagnosed subclinical mastitis associated with coagulase-negative staphylo-cocci and Streptococcus dysgalactiae.

DOSAGE Infuse one (1) syringe into each affected quarter. Repeat this treatment in 24 hours. For extended duration therapy, once daily treatment may be repeated for up to 8 consecutive days.

DIRECTIONS FOR USING THE PLASTET® DISPOSABLE SYRINGE The syringe is designed to provide the choice of either insertion of the full cannula as has traditionally been practiced, or insertion of no more than 1/8 inch of the cannula, as reported by Eberhart, R.J., et. al. 1987. Current Concepts of Bovine Mastitis, 3rd Edition, National Mastitis Council, Arlington, VA.a. Full insertion: Remove the red end cap by pulling straight up as shown.

Gently insert the full cannula into the teat canal; carefully infuse the product.

b. Partial insertion: Remove the red end cap by pulling straight up as shown. Gently insert the exposed white tip into the teat canal; carefully infuse the product.

a.b.

ADMINISTRATIONTreatment: Wash teats thoroughly with warm water containing a suitable dairy antiseptic. Dry teats thoroughly. Milk out udder completely. Using an alcohol pad provided, wipe off the end of the affected teat using a separate pad for each teat. Choose the desired insertion length (full or partial) and insert tip into teat canal; push plunger to dispense entire contents, massage the quarter to distribute the suspension into the milk cistern.

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ANIMAL SAFETY A pivotal GLP udder irritation study was conducted in 40 cows to assess udder irritation following daily intramammary infusion of an oil-based suspen-sion containing 125 mg of ceftiofur for up to 8 consecutive days. A transient and clinically insignificant rise in SCC to levels <200,000 cell/mL was observed following infusion in normal cows with very low pre-infusion SCC (<10,000 cell/mL). This elevation is not unexpected with oil-based suspensions. The duration of therapy did not affect this elevation. No udder clinical signs of irritation (swelling, pain, or redness), changes in body temperature or in milk production were noted during this study. This pivotal GLP study demon-strated that this formulation is clinically safe and non-irritating to the udder of lactating dairy cows. In two clinical field efficacy studies in 971 lactating dairy cows, no reports of udder irritation or adverse events were noted following infusion. Collectively, these three studies demonstrate that the intramammary infusion of an oil-based suspension containing 125 mg of ceftiofur once daily into all four quarters for up to 8 consecutive days is clinically safe and non-irritating to the udder of lactating dairy cows.MILK AND TISSUE RESIDUE DEPLETION A metabolism study in cattle using radiolabeled ceftiofur provided the data to establish tolerances for ceftiofur-related residues (as desfuroylceftiofur) in tissue and milk. These tolerances are 0.1 ppm in milk, 0.4 ppm in kidney, 2.0 ppm in liver, and 1.0 ppm in muscle. Two pivotal milk residue decline studies were conducted. In these studies, non-mastitic cows received 125 mg of ceftiofur per quarter into all four quarters either twice at a 24-hour interval or once daily for 8 consecutive days. Regardless of treatment duration and using a tolerance of 0.10 ppm for ceftiofur-related residues in milk, these studies demonstrate that milk taken during treatment (a maximum of 8 consecutive daily infusions) and for 72 hours after the last treatment must not be used for human consumption and must be discarded. A pivotal tissue residue decline study in lactating dairy cattle provides tissue residue decline data. In this study, the cattle received an intramammary infusion of 125 mg of ceftiofur hydrochloride into each of four quarters once daily for 8 consecutive days. Ceftiofur residues were determined in the kidney (the target tissue) using the official analytical method. Kidney residues were less than the established tolerance (0.4 ppm) by 2 days after the last infusion. These data collectively support the assignment of a 2-day pre-slaughter withdrawal period regardless of treatment duration.STORAGE CONDITIONS Store at controlled room temperature 20° to 25° C (68° to 77° F). Protect from light. Store syringes in carton or pail until used.HOW SUPPLIED SPECTRAMAST® LC Sterile Suspension is available in cartons containing 1 unbroken package of 12–10 mL PLASTET® Disposable Syringes with 12 individually wrapped 70% isopropyl alcohol pads and in pails containing 12 unbroken packages of 12-10 mL PLASTET Disposable Syringes with 144 individually wrapped 70% isopropyl alcohol pads.

NADA# 141-238, Approved by FDA


www.spectramast.com or call 1-888-963-8471

Revised: February 2015

EFFECTIVENESS In 1999 to 2000, the efficacy of ceftiofur was demonstrated in a pivotal multi-location field trial in lactating dairy cattle with clinical mastitis in one quarter. Ceftiofur was formulated in stable cottonseed oil sterile suspension manufactured under GMP guidelines. Cows with mastitis were enrolled in the study if visually abnormal milk (clots, flakes, or watery secretion) or if udder swelling, heat, pain or redness were present and the milk was not yet visually abnormal but California Mastitis Test (CMT) gave results of 2 or greater. A total of 13 trial sites enrolled 352 cows in the study. Cows were assigned to one of three treatment groups: non-treated con trol, 62.5 mg ceftiofur, and 125 mg ceftiofur. Each treatment group received an intramammary infusion twice at a 24-hour interval in the affected quarter. The non-treated controls received no therapy. Three different definitions for cure were used for analysis purposes: 1) a clinical cure was defined as the milk and udder returning to normal 14 days after the last treatment and remaining normal at the 21 day time point; 2) a bacterial cure was defined as the absence of the pre-treatment pathogen at 14 and 21 days post-treatment; 3) a protocol cure was defined as the absence of the pre-treatment pathogen at 14 and 21 days post-treatment and return to normal of the milk and udder 14 days after the last treatment and remaining normal at the 21 day time point. Three hundred and thirty seven cows were analyzed for clinical cure rates, which were 54.7% (64/117) for the non-treated control group compared to 69.4% (75/108) for the 62.5 mg treatment group and 78.6% (88/112) for the 125 mg treatment group. The 125 mg treatment group’s clinical cure rate was signifi-cantly greater than the non-treated control (P=0.002). One hundred and forty six cows were analyzed for bac terial cure rates, which were 41.3% (19/46) for the non-treated control group, 45.6% (21/46) for the 62.5 mg treatment group and 70.4% (38/54) for the 125 mg treatment group. The 125 mg treatment group’s bacterial cure rate was significantly greater than the non-treated control group (P=0.006). One hundred and forty six cows were analyzed for protocol cure rates, which were 63.0% (34/54) for the 125 mg treatment group, 41.3% (19/46) for the 62.5 mg treatment group and 23.9% (11/46) for the non-treated control group. The 125 mg treatment group’s protocol cure rate was significantly better than the non-treated control (P<0.001) for treatment of clinical mastitis. Thus, 125 mg of ceftiofur administered via intra mammary infusion twice at a 24-hour interval was effective in the treatment of clinical mastitis in lactating dairy cows associated with coagulase-negative staphylococci, (CNS), Streptococcus dysgalactiae, and Escherichia coli. The effectiveness of ceftiofur for the treatment of subclinical mastitis was demonstrated in a 10-site field study in lactating dairy cattle in 2013. Cows with subclinical mastitis were enrolled in the study if milk and udders were visually normal, composite quantitative somatic cell count (SCC) was >400,000 cells/mL, and milk culture was positive for a mastitis-causing pathogen. Cows were assigned to one of two treatment groups: SPECTRAMAST LC (125 mg ceftiofur equivalents per dose) or an equivalent volume of saline. Each treatment group received an intramammary infusion twice at a 24-hour interval in the affected quarter. Treatment success (bacterial cure) was defined as the absence of the pre-treatment pathogen at 14 and 20 days post-treatment. Three hundred thirty-six cows were analyzed for bacterial cure rates. There was a statistically significantly different (P < 0.0001) overall proportion of treatment successes in the SPECTRAMAST LC-treated group (44%, 75/164) compared with the saline-treated group (4%, 8/172). Additionally, a clinically-relevant ratio of clinical successes to failures was observed in the SPECTRAMAST LC-treated group compared to the saline-treated group for evaluable cases of subclinical mastitis associated with CNS and with S. dysgalactiae.

30151801A&P

NOTES

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