Zuprevo (Canada)

Company: Merck Animal Health

Tildipirosin Injection, 180 mg/mL

DIN 02387719

VETERINARY USE ONLY

Antibiotic

For Subcutaneous Use in Beef and Non-lactating Dairy Cattle Only.

Description

ZUPREVO is a clear yellowish ready-to-use sterile injectable solution containing tildipirosin, a semi-synthetic macrolide antibiotic. Each mL of ZUPREVO contains: ACTIVE INGREDIENT: 180.0 mg of tildipirosin as the free base; NON-MEDICINAL INGREDIENTS: citric acid monohydrate, propylene glycol, and water qs.

Zuprevo Indications

ZUPREVO is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. ZUPREVO is also indicated for the reduction of morbidity associated with BRD in feedlot calves, caused by Mannheimia haemolytica, Pasteurella multocida and Histophilus somni, during the first 14 days in the feedlot, when administered at the time of arrival.

Dosage and Administration

ZUPREVO should be administered in the neck of cattle by a single subcutaneous injection at a dose rate of 4 mg/kg body weight (1 mL/45 kg). Do not inject more than 10 mL into a single site. Do not puncture the stopper more than 20 times. Most animals will respond to treatment within 3 to 5 days. If no improvement is observed, the diagnosis should be re-evaluated.

Note: To limit the development of antimicrobial resistance, ZUPREVO should only be used as an arrival treatment in feedlot calves when BRD has been diagnosed and calves are 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 sales 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); and, recent weaning and poor vaccination history.

CONTRA-INDICATIONS: ZUPREVO is contraindicated in animals previously found to be hypersensitive to macrolide antibiotics. Do not use concurrently with other macrolides as cross-resistance may occur.

CAUTIONS: Do not use ZUPREVO (tildipirosin 180 mg/mL) in swine. Fatal adverse events have been reported following the use of tildipirosin in swine. Not for use in breeding cattle. The effects of tildipirosin on bovine reproductive performance, pregnancy and lactation have not been assessed. Subcutaneous injection can cause a local tissue reaction that may result in trim loss of edible tissue at slaughter.

Warnings

Treated animals must not be slaughtered for use in food for at least 42 days after the latest treatment with this drug. Do not use in female dairy cattle 20 months of age or older. To limit the development of antimicrobial resistance, ZUPREVO should only be used as an arrival treatment in feedlot calves when BRD has been diagnosed and calves are at high risk of developing BRD.

Tildipirosin may cause sensitization by skin contact. Avoid direct contact with skin, eyes and clothes. In case of accidental eye exposure, flush with water for 15 minutes. If accidental skin exposure occurs, wash with soap and water. Remove contaminated clothing. Consult a physician if irritation persists. Wash hands after use. Special precaution should be taken to avoid self-injection. In case of accidental self-injection, seek medical advice immediately and show the package insert to the physician. Do not use in automatically powered syringes which have no additional protection system. Keep out of the reach of children.

Adverse Reactions

Swelling and inflammation at the injection site, which may be severe, is commonly observed after administration and can cause transient signs of pain in cattle. As with other macrolide antibiotics, individual hypersensitivity reactions may occur.

Clinical Pharmacology

ZUPREVO is a 16-membered, tribasic semi-synthetic macrolide antibiotic. Tildipirosin has shown in vitro and in vivo antibacterial activity against the bacteria Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, three pathogens associated with bovine respiratory disease (BRD). 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 1 PK characterization of subcutaneously administered tildipirosin in calves (4 mg/kg)

* Value based on all 14 animals; ** Value based on 8 animals that were slaughtered at 504 hr post-treatment.

C_max: maximum observed plasma concentration; T_max: Time at which C_max was observed

AUC_0-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

AUC_0-inf: AUC estimated from time zero to time infinity

t_1/2: Terminal elimination half life; SD: standard deviation

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 free drug concentrations underestimate concentrations at the site of action¹. 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 2 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

SD: standard deviation

Tildipirosin concentrations in bronchial fluid collected in vivo from non-anesthetized cattle reflect the bacterial exposure to drug concentrations at the site of action. Drug concentrations in lung homogenate or bronchial fluid collected post mortem are unlikely to reflect the effective concentrations of active drug available at the site of infection.

¹Nightingale, C.H. (1997) Pharmacokinetics and pharmacodynamics of newer macrolides. The Pediatric Infectious Disease Journal, 16, 438-443.

MICROBIOLOGY: Tildipirosin has shown in vitro and in vivo antibacterial activity against the bacteria Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni, three pathogens associated with bovine respiratory disease (BRD).

The minimum inhibitory concentrations (MICs) of tildipirosin against the indicated BRD pathogens were determined using the methods described in the M31-A2 standard of the Clinical and Laboratory Standards Institute (CLSI).

The MICs of tildipirosin were determined for isolates of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni obtained from two BRD field studies. In both studies, tested isolates of M. haemolytica and P. multocida were obtained from nasopharyngeal swabs taken prior to treatment from all study animals. Tested isolates of H. somni were obtained from nasopharyngeal swabs taken prior to treatment from all study animals and from nasopharyngeal swabs taken from saline-treated animals classified as treatment failures.

Table 3 Tildipirosin minimum inhibitory concentration (MIC) values* of indicated pathogens isolated from BRD field studies in the US.

* 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.

EFFICACY: In a multi-location US field study, calves with naturally occurring BRD were treated with ZUPREVO. The treatment success rate of the ZUPREVO treated group was compared to the treatment success rate in the saline-treated control group. A treatment success was defined as a calf not designated as a treatment failure from Day 1 to 13 and with normal attitude, normal respiration, and a rectal temperature of < 40°C on Day 14. The treatment success rate was significantly higher (p = 0.003) for the ZUPREVO treated group (229/300, 76%) compared to the saline-treated control group (96/200, 32%). There were no BRD-related deaths in the ZUPREVO treated group compared to a 7% (21/300) BRD-related mortality rate in the saline-treated group. This difference was statistically significant (p=0.034).

In another multi-location US field study, beef calves at high risk of developing BRD were administered ZUPREVO at the time of their arrival in the feedlot. The treatment success rate of the ZUPREVO treated group was compared to the treatment success rate in the saline-treated control group. A treatment success was defined as a calf not designated as a treatment failure based on clinical respiratory and attitude scoring and, if necessary, rectal temperature measurement of < 40°C through the end of the study (Day 14). The treatment success rate was significantly higher (p = 0.0001) for the ZUPREVO treated group (305/386, 79%) compared to the saline-treated group (197/387, 51%). There were three BRD-related deaths during the study (one ZUPREVO treated calf and two saline treated calves).

ANIMAL SAFETY: A target animal safety study was conducted using ZUPREVO in 5-month-old cattle administered as three subcutaneous doses of 4, 12, or 20 mg/kg body weight (BW) given 7 days apart. Animals remained clinically healthy during the study at the labeled dose. Injection site swelling and inflammation, initially severe in some animals and often associated with transient signs of pain, was observed that persisted to the last day of observation (21 days after injection). No other drug-related lesions were observed macroscopically or microscopically at the labeled dose.

A separate injection site tolerance study was conducted using ZUPREVO in 5 to 9 month-old cattle administered as a single subcutaneous injection of 10 mL. Injection site swelling and inflammation, initially severe in some animals, was observed that persisted to the last day of observation (35 days after injection). No other drug-related clinical signs were observed.

Storage

Do not store above 25°C. Once opened this product should be used within 28 days.

How Supplied

ZUPREVO is individually packaged in 20, 50, 100 and 250 mL multi-dose amber glass vials.

^®Registered trademark of Intervet International B.V. Used under license.

Intervet Canada Corp., subsidiary of Merck & Co., Inc., 16750, route Transcanadienne, Kirkland, QC H9H 4M7

1-866-683-7838

Version: 15MAR2017

CPN: 1208257.3