Flunazine (Canada)

Flunixin Meglumine Injection USP

Anti-inflammatory/Analgesic/Antipyretic

DIN 02240510

Veterinary Use Only

Sterile

50 mg/mL flunixin (equivalent to 83 mg flunixin meglumine)

For intravenous or intramuscular use in horses, for intravenous use only in cattle and for intramuscular use only in swine.

Description

Each milliliter of Flunazine^® contains:

Active Ingredients

50 mg flunixin (equivalent to 83 mg flunixin meglumine USP)

Non-Medicinal Ingredients: 0.1 mg edetate disodium, 2.2 mg sodium formaldehyde sulfoxylate, 4.0 mg diethanolamine, 207.2 mg propylene glycol, hydrochloric acid to adjust the pH and water for injection q.s.

Preservatives: 5.0 mg phenol

Therapeutic Classification

Nonsteroidal anti-inflammatory drug (NSAID); analgesic; antipyretic.

Structural Formula And Chemistry

Flunixin meglumine is the N-methyl-glucamine salt of (2 (2’-methyl-3’-trifluoromethyl-anilino) nicotinic acid).

Molecular Formula: C₁₄H₁₁F₃N₂O₂•C₇H₁₇NO₅

Molecular Weight: 491.46

Flunazine Indications

Horses: Flunazine^® is recommended for the alleviation of inflammation and associated pain in musculoskeletal disorders in the horse.

Flunazine^® is also recommended for the alleviation of visceral pain associated with colic in the horse.

Cattle: Flunazine^® is indicated for the control of pyrexia associated with Bovine Respiratory Disease (BRD), endotoxemia and acute bovine mastitis. Flunazine^® is also indicated for the control of inflammation associated with endotoxemia.

Swine: Flunazine^® is indicated as an aid in reducing pyrexia associated with swine respiratory disease.

Flunazine Dosage And Administration

Do not exceed the recommended dose.

Horses: The recommended dose is 1.1 mg flunixin per kg (1 mL/45 kg) of body weight once daily. Treatment may be given by intravenous or intramuscular injection and repeated for up to 5 days for musculoskeletal disorders. Intravenous administration is recommended for prompt relief of colic. Should colic symptoms recur, treatment may be repeated as necessary.

Cattle: The recommended dose is 2.2 mg flunixin per kg (2 mL/45 kg) of body weight as a single dose for acute bovine mastitis and once a day for up to 3 days for BRD and endotoxemia. Avoid rapid intravenous administration of the drug. Twenty-four (24) hours after administration, check if animal is febrile. Readminister only if the fever is 40°C (104°F) or higher.

Swine: The recommended dose is 2.2 mg flunixin per kg (2 mL/45 kg) of body weight given by a single intramuscular administration. The injection should be given only in the neck musculature with a maximum of 10 mL per site.

Contraindications

Flunixin is contraindicated in animals with hepatic disease, renal and cardiovascular impairment, gastrointestinal ulceration and/or platelet disorders. Do not use in animals showing hypersensitivity to flunixin. Do not exceed the recommended dose.

Horse and Cattle: Do not administer intra-arterially.

Flunazine Cautions

Use with caution in dehydrated animals.

Concurrent administration of potentially nephrotoxic drugs should be carefully approached.

NSAIDs may inhibit prostaglandins that maintain normal homeostatic function. Such prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease that has not been previously diagnosed. Due to the potential for NSAIDs to induce gastrointestinal ulceration, concomitant use of this drug with other anti-inflammatory drugs, such as other NSAIDs and corticosteroids should be avoided.

With the exception of the antibiotic oxytetracycline in cattle and swine, studies to determine the activity of flunixin meglumine when administered concomitantly with other drugs have not been conducted. Drug compatibility should be monitored closely. Discontinue use if hematuria or fecal blood is observed. Avoid rapid intravenous administration of the drug.

Horses: The effect of Flunazine^® on reproduction in horses has not been determined (see Adverse Reactions).

Cattle: The effect of Flunazine^® on reproduction in bulls has not been determined. NSAIDs are known to have the potential to delay parturition and prolong labour. Caution should be used when giving this product within 48 hours of expected parturition. Cows should be monitored carefully for placental retention if Flunazine^® is used within 24 hours after parturition.

Swine: The effect of Flunazine^® on reproduction in swine has not been determined (see Adverse Reactions).

Warnings

Treated animals must not be slaughtered for use in food for at least 6 days for cattle and 13 days for swine after the latest treatment with this drug. Milk taken from treated animals during treatment and within 36 hours after the latest treatment must not be used as food. Not for use in veal calves. The withdrawal period has not been established in pre-ruminating calves. This drug is not to be administered to horses that are to be slaughtered for food. The withdrawal period has not been established in pre-ruminating calves.

KEEP OUT OF REACH OF CHILDREN.

Adverse Reactions

Flunixin can be irritating to tissue at the injection site.

Inadvertent intra-arterial injection may cause adverse reactions such as ataxia, incoordination, hyperventilation, convulsion, and muscle weakness. Signs are transient and disappear without antidotal medication within a few minutes.

The use of NSAIDs may be associated with gastrointestinal, hepatic and renal toxicity.

As NSAIDs 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. NSAIDs are known to have the potential to delay parturition through a tocolytic effect. The use of NSAIDs in the immediate post-partum period may interfere with uterine involution and expulsion of fetal membranes.

Horses: Isolated reports of local reactions following intramuscular injection, particularly in the neck, have been received. These include localized swelling, sweating, induration, and stiffness. In very rare instances in horses, fatal or nonfatal clostridial infections or other infections have been reported in association with intramuscular use of flunixin.

Cattle: A temporary head thrashing can occur if the drug is injected too rapidly.

Horses and Cattle: Very rare instances of anaphylactic-like reactions, some of which have been fatal, have been reported, primarily following intravenous use.

Swine: Intramuscular injection may cause local tissue irritation and damage. In an injection-site irritation study, the tissue damage did not resolve in all animals by Day 28 post-injection. This may result in trim loss of edible tissue at slaughter.

Clinical Pharmacology

Flunixin meglumine is a potent, non-narcotic, non-steroidal, analgesic agent with anti-inflammatory activity. Antipyretic activity has been demonstrated in cattle, swine and in laboratory animals. It is significantly more potent than pentazocine, meperidine and codeine as an analgesic in the rat yeast paw test.

Horses: Flunixin is four times as potent on a mg per mg basis as phenylbutazone as measured by the reduction in lameness and swelling in the horse. Plasma half-life in horse serum is 1.6 hours following a single dose of 1.1 mg flunixin per kg. Measurable amounts are detectable in horse plasma at 8 hours post injection. Intravenous studies show that the onset of activity is within 2 hours. Peak response occurs between 12 and 16 hours and duration of activity is 24 to 36 hours following intravenous and intramuscular administration. Clinical studies show that pain symptoms were alleviated in 37% of treated horses within 15 minutes, and 74% within 30 minutes.

Cattle: Flunixin meglumine is a weak acid (pKa = 5.82) which exhibits a high degree of plasma protein binding (approximately 99%). However, free (unbound) drug appears to readily partition into body tissues (V_ss predictions range from 297 to 782 mL/kg). Total body water is approximately 570 mL/kg. In cattle, elimination occurs primarily through biliary excretion. This may, at least in part, explain the presence of multiple peaks in the blood concentration/time profile following IV administration.

In healthy cattle, total body clearance has been reported to range from 90 to 150 mL/kg/hr. These studies also report a large discrepancy between the volume of distribution at steady state (V_ss) and the volume of distribution associated with the terminal elimination phase (V_β). This discrepancy appears to be attributable to extended drug elimination from a deep compartment. The terminal half-life has been shown to vary from 3.14 to 8.12 hours.

Model and field studies have shown that flunixin can have short-term effects in the control of some inflammatory factors associated with endotoxemia and irritation (carregeenan). Flunixin persists in inflammatory tissues and is associated with anti-inflammatory properties which extend well beyond the period associated with detectable plasma drug concentrations. These observations account for the counterclockwise hysteresis associated with flunixin’s pharmacokinetic/pharmacodynamic relationship. Therefore, prediction of drug concentrations based on the estimated plasma terminal half-life will likely underestimate both the duration of drug action and the concentration of drug remaining at the site of activity.

Swine: The pharmacokinetic profiles were found to follow a 2-compartmental model, although a deep (third) compartment was observed in some animals. The mean terminal elimination half-life (β half-life) of flunixin after a single intramuscular injection of flunixin (2.2 mg per kg) to pigs was between 3 and 4 hours. The mean observed maximum plasma concentration was 2944 ng/mL, achieved at a mean time of approximately 0.4 hours. The mean AUC(0-LOQ) was 6431 ng*hr/mL. Following IM administration of flunixin, quantifiable drug concentration could be measured up to 18 hours post dose. The mean volume of distribution was 2003 mL/kg and the mean total clearance was 390 mL/hr/kg. The mean absolute bioavailability of flunixin following an intramuscular injection in the neck was 87%.

Studies on reproduction in rats and rabbits have shown no teratogenicity.

Toxicity

No toxic effects were observed in rats given intramuscular flunixin 4 mg/kg/day for 28 days. No adverse effects were seen in dogs given a single intramuscular injection of 50 mg flunixin per kg. Higher doses resulted in salivation, panting, emesis, and tremors. No toxic effects were observed in monkeys given intramuscular doses between 3 and 30 mg flunixin per kg per day for 28 days.

Horses: Prolonged parenteral treatment in horses at 4.4 mg flunixin per kg body weight showed no untoward effects.

Cattle: No flunixin-related changes (adverse reactions) were noted in cattle administered a 1X (2.2 mg flunixin per kg) dose for 9 days (three times the maximum recommended duration). Toxicity, such as blood in feces and/or urine, manifested itself at moderately elevated doses (3X and 5X) when flunixin was administered daily for 9 days (three times the maximum recommended duration for BRD and endotoxemia).

Storage

Store between 15°C and 30°C (59°F and 86°F). Do not use the opened product after 28 days.

How Supplied

Flunazine^® 50 mg flunixin/mL (equivalent to 83 mg flunixin meglumine/mL) is available in 100 and 250 mL multidose vials.

Manufactured by: Bimeda-MTC Animal Health Inc., Cambridge, ON N3C 2W4

^®Registered Trademark

Bimeda-MTC Animal Health Inc.

Distributed by: Vetoquinol N.-A. Inc., 2000, ch. Georges, Lavaltrie, QC, CANADA J5T 3S5

CPN: 1194094.13