Resflor (Canada)

Manufacturer: 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, 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.

Resflor 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 BW or 6 mL/100 lbs BW). 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.

Resflor Dosage Guide
Animal Weight		Resflor Dosage 2 Ml/15 Kg Body Weight (ml)
(kg)	(lbs)
45	100	6.0
90	200	12.0
135	300	18.0
180	400	24.0
225	500	30.0
270	600	36.0
315	700	42.0
360	800	48.0
405	900	54.0
450	1000	60.0

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

Use judiciously when renal impairment or gastric ulceration is suspected. Do not use in animals showing hypersensitivity to flunixin meglumine or florfenicol.

Resflor 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. 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.

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. Do not use in calves to be processed for veal as a withdrawal period has not been established in pre-ruminating calves. KEEP OUT OF REACH OF CHILDREN. This product contains material that can be irritating to skin and eyes. Avoid direct contact with skin, eyes and clothes. 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. Consult a physician if irritation persists. In case of accidental injection of this product, consult a physician immediately.

Adverse Reactions

Of 175 calves treated with Resflor in a field trial no animal experienced any adverse reactions.

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 Beef Cattle Administered Resflor Subcutaneously At A Florfenicol Dose Of 40 Mg/kg Bw

	Cmax (µg/ml)	Tmax (hr)	Auc0-loq (µg*hr/ml)	Auc0-∞ (µg*hr/ml)	Tmic90 (hr)	T1/2 (hr)
N	28	28	28	28	28	28
Mean	4.31	5.46	132.76	156.04	39.54	53.68
STD ERR	0.21	0.32	3.92	3.94	1.73	3.98
% CV	25.24	31.30	15.64	13.38	23.13	39.19

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 BW, 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

Organism	Year Of Isolation	Isolate Numbers	Mic50** (µg/ml)	Mic90** (µg/ml)	Mic Range (µg/ml)
Mannheimia haemolytica	2006	158	1.00	1.00	0.5 to 32
Pasteurella multocida	2006	103	0.50	0.50	≤ 0.125 to 16
Histophilus somni	2006	85	≤ 0.125	≤ 0.125	≤ 0.125 to 0.25

*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

Bovine Respiratory Pathogens	Zone Diameter (mm, 30 µg Disk)			Mic Breakpoint (µg/ml)
	S	I	R	S	I	R
Mannheimia haemolytica Pasteurella multocida Histophilus somni	≥ 19	15-18	≤ 14	≤ 2	4	≥ 8

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

Qc Strains For Florfenicol	Atcc #	Nctc Or Ncimb #	Acceptable Zone Diameter (mm, 30 µg Disk)	Acceptable Mic (µg/ml)
Staphylococcus aureus	29213	Not available	Not defined	2-8
Staphylococcus aureus	25923	12702	22-29	Not defined
Enterococcus faecalis	29212	12697	Not defined	2-8
Escherichia coli	25922	12241	22-28	2-8
Pseudomonas aeruginosa	27853	10896	Not defined	> 16
Streptococcus pneumoniae	49619	Not available	24-31	1-4
Histophilus somni	700025	Not available	34-44	0.125-0.5
Actinobacillus pleuropneumoniae	27090	Not available	31-40	0.25-1

Animal Safety

A safety study was conducted in cattle using 1X, 3X, 5X the recommended dose for 3X the duration of treatment. 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.

Efficacy

The effectiveness of Resflor in the control of pyrexia associated with naturally occurring bovine respiratory disease was confirmed in a well controlled pivotal study conducted under commercial feedlot conditions in North America. Resflor exhibited a more rapid antipyretic response than Nuflor and saline-treated cattle.

Storage Information

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 May 15, 2012

134274 R2

12-0038INS

Nac No.

12082153