Resflor (Canada)

Company: Merck Animal Health

Florfenicol/Flunixin, as flunixin meglumine

DIN 02330997

FOR VETERINARY USE ONLY

Injectable Solution

Sterile Multi-dose Injectable Antibiotic/Non-steroidal Anti-inflammatory Solution

For Subcutaneous Use in Cattle Only

Description

Resflor is a sterile solution of a synthetic broad-spectrum antibiotic and a non- steroidal anti-inflammatory drug.

Each milliliter of Resflor contains: active ingredients: 300 mg florfenicol; 27.4 mg flunixin meglumine equivalent to 16.5 mg flunixin; non-medicinal ingredients: 250 mg N-methyl-2-pyrrolidone (NMP), 10 mg citric acid and polyethylene glycol q.s.; preservative: 150 mg propylene glycol.

Resflor Indications

Resflor is indicated for the treatment of bovine respiratory disease complex (BRD) associated with Mannheimia haemolytica, Pasteurella multocida and Histophilus somni and BRD associated pyrexia.

Dosage and Administration

Resflor should be administered as a single subcutaneous dose of 40 mg/kg florfenicol and 2.2 mg/kg flunixin (2 mL/15 kg body weight or 6 mL/100 lbs body weight). Do not administer more than 10 mL at each injection site.

The injection should be given only in the neck. Do not puncture the stopper more than 20 times.

It is recommended to treat animals in the early stages of the disease and to evaluate the response to treatment 72 hours after injection. If clinical signs of respiratory disease persist or increase, or if relapse occurs, treatment should be changed, using another antibiotic, and continued until signs have resolved.

Contraindications

Do not use in animals showing hypersensitivity to flunixin meglumine or florfenicol.

CAUTIONS: Do not exceed the recommended dose. Transient inappetence may occur with the use of this drug. As a class, cyclo-oxygenase inhibitory non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with gastrointestinal and renal toxicity. Use judiciously when renal impairment or gastric ulceration is suspected. Sensitivity to drug-associated adverse effects varies with the individual patient. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction. Since many NSAIDs may induce gastrointestinal ulceration, concomitant use of Resflor with other anti-inflammatory drugs, such as other NSAIDs and corticosteroids, should be avoided or closely monitored. Repeated Resflor daily dosing has been associated with abomasal erosions in the pre-ruminant calf. The product should be used with caution in this age group. Also see ADVERSE REACTIONS section. The safety of the product has not been tested in calves under 3 weeks of age.

Not for use in cattle of breeding age. The effects of florfenicol on bovine reproductive performance, pregnancy and lactation have not been determined. NSAIDs are known to have potential effects on both parturition and the estrous cycle. There may be a delay in the onset of estrus if flunixin is administered during the prostaglandin phase of the estrous cycle. The effects of flunixin on imminent parturition have not been evaluated in a controlled study. NSAIDs are known to have the potential to delay parturition through a tocolytic effect.

Warnings

Treated cattle must not be slaughtered for use in food for at least 60 days after the latest treatment with this drug. Not for use in lactating and dry dairy cows. Reproductive and developmental toxicities have been reported in laboratory animals following high, repeated exposures to NMP. Pregnant women should avoid handling this product. This product contains materials that can be irritating to skin and eyes. When handling the product, caution should be taken to avoid accidental self-injection and direct contact with skin and eyes. In case of accidental eye exposure, flush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Consult a physician if irritation persists. In case of accidental injection of this product, consult a physician immediately. KEEP OUT OF REACH OF CHILDREN.

Adverse Reactions

Although all adverse reactions are not reported, the following information is based on voluntary post-approval drug experience reporting. It is generally recognized that this results in significant under-reporting. The adverse reactions listed here reflect reporting and not necessarily causality. Adverse reactions are listed in decreasing order of frequency. All adverse reactions were reported as rare (less than 1/1,000) or very rare events (less than 1/10,000).

Lack of efficacy (rare), death, diarrhea, ataxia, injection site edema, injection site abscess, lethargy, anorexia, dyspnea, lameness (all very rare).

Anaphylaxis, incorrect injection technique and use of the product with other NSAIDs or when administered more than once, have been identified as risk factors for death in animals administered Resflor. Injection into the spinal cord or an artery may result in death. Adverse reactions reporting lack of efficacy are frequently reported in conjunction with other adverse events such as pyrexia, respiratory signs, and death, reflecting the nature and severity of the disease being treated.

Not every adverse event being reported after the use of a pharmaceutical product is due to the administration of the product. Adverse events may be due to underlying disease, medications or vaccinations used concomitantly, comorbidities, improper handling or administration, conditions during use, or off-label use.

Clinical Pharmacology

The pharmacokinetic disposition of florfenicol after subcutaneous injection of RESFLOR to beef cattle is described in Table 1.

Table 1 Mean Pharmacokinetic Parameters of Florfenicol in Male and Female Ruminating Beef Cattle Administered Resflor Subcutaneously at a Florfenicol Dose of 40 mg/kg Body Weight

C_max: Maximum plasma concentration

T_max: Time at which C_max was observed

T _1/2: Elimination half-life

AUC_0-∞: Area Under the Curve

AUC_0-LOQ: Area Under the Curve to the limit of quantification

T_MIC90: Time at which the value of the MIC₉₀ is obtained

MIC₉₀: The minimum inhibitory concentration for 90% of the isolates

Comparable plasma concentrations of florfenicol were demonstrated in a comparative pharmacokinetic study in cattle administered either Resflor (florfenicol and flunixin meglumine combined formulation) or Nuflor (florfenicol only formulation). Following subcutaneous injection of Resflor (test article) or Nuflor (reference article) at florfenicol nominal concentration of 40 mg/kg body weight, the bioequivalence criteria were met for AUC_0-LOQ and T_MIC90. However, Resflor provided a higher C_max of florfenicol when compared to Nuflor.

MICROBIOLOGY: Florfenicol is a synthetic, broad-spectrum antibiotic active against many gram-negative and gram-positive bacteria isolated from domestic animals. It acts by binding to the 50S ribosomal subunit and inhibiting bacterial protein synthesis. In vitro studies of florfenicol demonstrate bactericidal activity against commonly isolated pathogens involved in bovine respiratory disease (BRD) including Mannheimia haemolytica, Pasteurella multocida and Histophilus somni. The minimum inhibitory concentrations (MICs) of florfenicol for BRD organisms were determined using US isolates obtained in 2006 from natural infections (Table 2).

Table 2 Florfenicol MIC Values* of Indicated Pathogens Isolated From US Cattle With Naturally-Occurring BRD

*The correlation between the in vitro susceptibility data (MIC values) and clinical response has not been determined.

**The minimum inhibitory concentration for 50% and 90% of the isolates.

Table 3 Clinical and Laboratory Standards Institute (CLSI) Recommended Susceptibility Interpretive Criteria and MIC Breakpoints for Florfenicol

S = Susceptible, I = Intermediate, R = Resistant.

Standardized procedures require the use of laboratory control organisms for both standardized disk diffusion assays and standardized dilution assays. The 30 µg florfenicol disk should give the following zone diameters and florfenicol powder should provide the following MIC values for reference strains.

Table 4 Recommended Quality Control Strains for Florfenicol Susceptibility Testing

ANIMAL SAFETY: Safety studies were conducted in ruminating and preruminating cattle using 1X, 3X and 5X the recommended dose for 3X the duration of treatment. Ruminating calves: Decreased food consumption was observed in the 3X and 5X groups. Decreased body weights were observed in the 5X group (secondary to decreased food consumption). Decreased water consumption was observed in the 5X group which was associated with an increased urine specific gravity. As expected, swelling at the site of injection was noted and resolved with time. Pre-ruminating calves: Abomasal erosions were observed in pre-ruminating calves after three times the recommended treatment duration with 1x doses. Abomasal ulcerations were observed after three times the recommended treatment duration with 3 x and 5 x doses. Clinically none of the animals exhibited any signs of illness and continued to grow normally. In a field trial with pre-ruminating calves some animals that received additional treatment with NSAIDs developed ulceration of the stomach.

EFFICACY: The effectiveness of Resflor in the control of pyrexia associated with naturally occurring bovine respiratory disease was confirmed in several well controlled studies conducted in North America and the EU for ruminating and pre-ruminating calves respectively. At 6 hours post-dose Resflor-treated cattle exhibited a more rapid antipyretic response than Nuflor-treated cattle. There was no difference in Day 10 treatment failure rates between animals treated with Resflor and Nuflor.

Storage

Store at or below 25 °C. Do not freeze. Use within 28 days of first puncture. The solution is light yellow to straw colored. Color does not affect potency.

How Supplied

Resflor Injection is available in 100, 250 and 500 mL glass sterile multiple dose vials.

Intervet Canada Corp., Kirkland, Qc H9H 4M7

1-866-683-7838

Intervet Canada Corp. is a subsidiary of Merck & Co., Inc.

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

Version February 14, 2023

CPN: 1208215.6