تيلديبيروسين

For the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni.

Federal law restricts this drug to use by or on the order of a licensed veterinarian. For subcutaneous injection in beef and non-lactating dairy cattle only. Not for use in female dairy cattle 20 months of age or older or in calves to be processed for veal. DO NOT USE ZUPREVO 18% IN SWINE. Fatal adverse events have been reported following the use of tildipirosin in swine. NOT FOR USE IN CHICKENS OR TURKEYS.

Zuprevo™

For the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef and non-lactating dairy cattle.

Federal law restricts this drug to use by or on the order of a licensed veterinarian. For subcutaneous injection in beef and non-lactating dairy cattle only. Not for use in female dairy cattle 20 months of age or older or in calves to be processed for veal. DO NOT USE ZUPREVO 18% IN SWINE. Fatal adverse events have been reported following the use of tildipirosin in swine. NOT FOR USE IN CHICKENS OR TURKEYS.

Zuprevo™

INDICATIONS: Zuprevo™18% is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni in beef and and non-lactating dairy cattle, and for the control of respiratory disease in beef and non-lactating dairy cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni.

ZUPREVO™ 18% (Tildipirosin) Injectable Solution for Cattle

CLINICAL PHARMACOLOGY: Similar to other macrolides, tildipirosin inhibits essential bacterial protein biosynthesis with selective binding to ribosomal subunits in a bacteriostatic and time-dependent manner. Tildipirosin may be bactericidal against certain isolates of Mannheimia haemolytica and Pasteurella multocida. The following plasma pharmacokinetic (PK) properties of tildipirosin have been observed following a subcutaneous injection at a dose of 4 mg/kg body weight in the neck: Table 2 Summary of pharmacokinetic characterization of tildipirosin administered subcutaneously to calves at a dose of 4 mg/kg BW. Parameter Average SD Cmax: maximum observed plasma concentration Tmax: Time at which Cmax was observed AUC0-last: Area under the plasma concentration versus time curve measured from time zero to the last sample with tildipirosin concentrations exceeding the limit of quantification of the analytical method AUC0-inf: AUC estimated from time zero to time infinity t1/2: Terminal elimination half life Cmax (ng/mL) 767Value based on all 14 animals 284 Tmax (hr) 0.75 0.43 AUC0-last (hr∙ng/mL) 21017Value based on 8 animals that were slaughtered at 504 hr post-treatment. 3499 AUC0-inf (hr∙ng/mL) 24934 3508 t1/2 (hr) 210 53 Due to the extensive partitioning of macrolides into tissues and because of their multi-fold greater concentrations in bronchial fluid relative to that observed in the blood, plasma drug concentrations underestimate concentrations at the site of actionNightingale, C.H. (1997) Pharmacokinetics and pharmacodynamics of newer macrolides. The Pediatric Infectious Disease Journal, 16, 438-443.. This is shown for tildipirosin in the following table, where bronchial fluid samples were collected in live, healthy calves, and compared to the concentrations in plasma observed in these same animals: Table 3 Bronchial fluid-to-plasma ratio of tildipirosin in non-anesthetized cattle following a subcutaneous injection at a dose of 4 mg/kg body weight in the neck Time (hours) Bronchial fluid (BF) concentration (ng/g) Plasma (P) concentration (ng/mL) BF/P Ratio Average SD Average SD 4 1543 895 297 81.8 5.20 10 2975 1279 242 96.7 12.3 24 3448 1433 136 53.9 25.4 72 3489 1712 70.7 29.0 49.3 96 1644 2024 60.2 29.0 27.3 120 1619 1629 52.3 19.9 30.9 240 1937 1416 27.1 10.8 71.5 336 1225 1682 26.1 9.2 47.0 504 935 1032 16.8 1.7 55.6 Tildipirosin concentrations in bronchial fluid collected in vivo from non-anesthetized cattle reflect the bacterial exposure to drug concentrations at the site of action.

ZUPREVO™ 18% (Tildipirosin) Injectable Solution for Cattle

WARNINGS: FOR USE IN ANIMALS ONLY. NOT FOR HUMAN USE. KEEP OUT OF REACH OF CHILDREN. TO AVOID ACCIDENTAL INJECTION, DO NOT USE IN AUTOMATICALLY POWERED SYRINGES WHICH HAVE NO ADDITIONAL PROTECTION SYSTEM. IN CASE OF HUMAN INJECTION, SEEK MEDICAL ADVICE IMMEDIATELY AND SHOW THE PACKAGE INSERT OR LABEL TO THE PHYSICIAN. Avoid direct contact with skin and eyes. If accidental eye exposure occurs, rinse eyes with clean water. If accidental skin exposure occurs, wash the skin immediately with soap and water. Tildipirosin may cause sensitization by skin contact. For technical assistance or to report a suspected adverse reaction, call: 1-800-219-9286. For customer service or to request a Material Safety Data Sheet (MSDS), call: 1-800-211-3573. For additional Zuprevo™18% information go to www.zuprevo.com. For a complete listing of adverse reactions for Zuprevo™18% reported to CVM see: http://www.fda.gov/AnimalVeterinary/SafetyHealth. DO NOT USE ZUPREVO 18% IN SWINE. Fatal adverse events have been reported following the use of tildipirosin in swine. NOT FOR USE IN CHICKENS OR TURKEYS.

ZUPREVO™ 18% (Tildipirosin) Injectable Solution for Cattle

RESIDUE WARNING: Cattle intended for human consumption must not be slaughtered within 21 days of the last treatment. Do not use in female dairy cattle 20 months of age or older. Use of this drug product in these cattle may cause milk residues. A withdrawal period has not been established in pre-ruminating calves. Do not use in calves to be processed for veal.

ZUPREVO™ 18% (Tildipirosin) Injectable Solution for Cattle

Inject subcutaneously as a single dose in the neck at a dosage of 4 mg/kg (1 mL/100 lb) body weight (BW).

Subcutaneous

Federal law restricts this drug to use by or on the order of a licensed veterinarian. For subcutaneous injection in beef and non-lactating dairy cattle only. Not for use in female dairy cattle 20 months of age or older or in calves to be processed for veal. DO NOT USE ZUPREVO 18% IN SWINE. Fatal adverse events have been reported following the use of tildipirosin in swine. NOT FOR USE IN CHICKENS OR TURKEYS.

Zuprevo™

DOSAGE AND ADMINISTRATION: Inject subcutaneously as a single dose in the neck at a dosage of 4 mg/kg (1 mL/100 lb) body weight (BW). Do not inject more than 10 mL per injection site. Do not puncture the stopper of the respective vial size more than the tested number of punctures, shown in Table 1. Clinical field studies indicate that administration of Zuprevo™ 18% (tildipirosin) Injectable Solution is effective for the control of respiratory disease in beef and non-lactating dairy cattle at "high risk" of developing BRD. Calves 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 and poor vaccination history Table 1 Number of punctures tested in the in-use study for the respective vial sizes Vial size [mL] Number of punctures tested in the in-use study 100 8 250 16

SUBCUTANEOUS

ZUPREVO™ 18% (Tildipirosin) Injectable Solution for Cattle