Flunixin meglumine is an NSAID that is approved by the FDA for the treatment of inflammatory conditions in cattle, horses, and swine and alleviation of pain associated with musculoskeletal disorders and colic in horses; it is not labeled for alleviation of pain in food-producing animals. Currently, there are no FDA-approved drugs for the treatment of pyrexia, inflammatory conditions, or pain in minor food-producing species such as sheep and goats. Owing to the lack of alternatives, veterinarians often administer food-producing animals products containing flunixin in an extralabel manner for the treatment of signs of pain. In the United States, NSAIDs are among the most frequently administered drugs for analgesia in cattle; however, such use is considered extralabel and must be in accordance with AMDUCA.1 In a 1995 survey2 of dairy veterinarians, NSAIDs (eg, flunixin, aspirin, phenylbutazone, and dipyrone) were the second most frequently prescribed class of drugs behind antimicrobials, and the majority of respondents listed flunixin as one of the top 20 most frequently prescribed drugs. Nonsteroidal anti-inflammatory drugs possess analgesic, antipyretic, and anti-inflammatory activities, which are produced through inhibition of prostaglandin synthesis secondary to inhibition of the cyclooxygenase enzyme.3,4
Frequent extralabel use of flunixin for the treatment of unlabeled species or conditions or by routes or at doses other than those on the label has resulted in violative residues in tissues of treated animals.5,6 In 2012, the USDA Food Safety and Inspection Service reported the identification of 1,166 drug residue violations in 928 cattle, sheep, and swine; 101 (9%) of those residues were caused by flunixin.6 All 101 flunixin residues were detected in cattle, of which 64 were detected in dairy cattle, 22 were detected in veal calves, and 15 were detected in beef cattle (Table 1).6 In a study7 that involved screening for 5OHF in milk samples obtained from large tanker trucks that transport milk to dairy processing plants, the marker residue (ie, the residue monitored in milk or tissues for regulatory purposes; can be the parent drug or a metabolite of that drug8) for flunixin, 1 of 500 (0.2%) samples contained 5OHF concentrations > 2 ppb, the tolerance for flunixin residues in milk in the United States. Although flunixin is approved for use in cattle, it is consistently one of the most frequently identified violative residues in meat and milk products obtained from cattle.6
Summary of US animals with violative drug residues detected at the time of slaughter in 2012 as reported by the USDA Food Safety and Inspection Service.6
| Species | Production class | No. (%) of animals with violative residue for any drug | No. of animals with violative flunixin residues |
|---|---|---|---|
| Cattle | Dairy cows, heifers, and bulls | 452 (49) | 64 |
| Â | Veal calves* | 307 (33) | 22 |
| Â | Beef cows and steers | 95 (10) | 15 |
| Sheep | Lambs†| 2 (0.2) | 0 |
| Swine | Sows and market hogs‡ | 72 (7.8) | 0 |
| Total | Â | 928 (100) | 101 |
Veal calves were defined as immature cattle lacking a functional rumen intended for meat production and included both beef and dairy breeds.
Lambs were defined as sheep < 14 months old.
Market hogs were defined as pigs approximately 6 months old with a live body weight of approximately 91 to 136 kg (200 to 300 lb).
As a reminder to readers, there is an important distinction between WDI and WDT. The WDI is a scientifically derived recommended withholding time for meat or milk products from animals following administration of a drug in an extralabel manner.9 Accurate prediction of appropriate WDIs for flunixin following extralabel administration to food-producing animals is essential to help producers minimize the incidence of violative flunixin residues in products intended for human consumption and is in the best interest for consumer health and safety.1 The WDT is defined as the time required after administration of a drug in accordance with its label for tissue concentrations of the drug or its metabolites to decrease below approved tolerances or MRLs established by a regulating body.9 Mathematically, the WDT is the point following administration of the labeled dosage of a drug after which there is 95% confidence that 99% of treated animals in the reference population will have tissue or milk residues less than the tolerance or MRL for that drug.10 The tolerance (established by the FDA in the United States) or MRL (established by the FDA equivalent in foreign countries) is the highest concentration of a chemical, drug, or drug metabolite that is legally acceptable in animal tissues or milk intended for human consumption (ie, the highest concentration that can be consumed without any adverse risk to health).10 Tissue drug concentrations below established tolerances or MRLs are generally considered indicative of correct drug use and ensure compliance with legal requirements for low drug residues in unprocessed food. The tolerances and MRLs for flunixin are established for target tissues (liver and muscle) and milk on the basis of assessment of risk to human health and flunixin residue data.11 In cattle and swine, the liver is used as the primary target tissue for establishing tolerances or MRLs for flunixin-free acid. Although the tolerance (United States) and MRL (other countries) are both defined as the highest legally acceptable concentration of a drug in tissues or milk intended for human consumption, the magnitude of those limits frequently varies among countries or jurisdictions (Table 2),12,13 and US veterinarians should be cognizant of those differences when treating food-producing animals that are destined for export to a foreign country. Tolerances established by the FDA for drugs approved for use in food-producing animals are published in the US Code of Federal Regulations Title 21 part 556.12 The aims of this FARAD digest are to discuss the pharmacokinetics and tissue residue data for flunixin and to establish appropriate conservative recommendations for meat and milk WDIs following extralabel use of flunixin in cattle and swine.
Comparison of US tolerances12 and European Union MRLs13 for flunixin-free acid in various tissues of cattle and swine and 5OHF in milk of cattle.
| Species | Tissue | US tolerance (ppb) | European Union MRL (ppb) |
|---|---|---|---|
| Bovine | Liver | 125 | 300 |
| Â | Muscle | 25 | 20 |
|  | Kidney | — | 100 |
|  | Fat | — | 30 |
| Â | Milk | 2 | 40 |
| Swine | Liver | 30 | 200 |
| Â | Muscle | 25 | 50 |
|  | Kidney | — | 30 |
|  | Fat | — | 10 |
— = Not established.
Cattle
Flunixin is the only NSAID approved by the FDA for use in beef and dairy cattle for the control of pyrexia associated with bovine respiratory tract disease and inflammation associated with endotoxemia and mastitis. The FDA has placed it on a list of drugs of high regulatory concern because of its extensive use in veterinary medicine and the potential risk consumption of food with flunixin residues poses to human health.14 Flunixin is commercially available under the trade names of Banamine, Flunixamine, Prevail, Citation, Equileve, and Meflosyl Solution in the United States; Flunixin, Finadyne, and Cronyxin in the United Kingdom; Finadyne in South Africa and Australia; and Megludyne in India. In the United States, the FDA-approved preparations for cattle contain flunixin meglumine salt, which is to be administered by the IV route only. Intravenous administration can be stressful for treated animals and requires more time, skill, and training by the drug administrator. Unfortunately, on the basis of the number and nature of requests submitted to FARAD, it appears that flunixin is frequently administered by the IM or SC routes in field settings, and the number of beef and dairy cattle with violative tissue residues of flunixin at the time of slaughter associated with administration of the drug by an extralabel (IM or SC) route has been increasing.15,16 In the United States, the labeled dosage for flunixin in cattle is 1.1 to 2.2 mg/kg (0.5 to 1.0 mg/lb), IV, every 24 hours or divided into 2 doses every 12 hours for 3 days with a WDT of 4 days for meat and 36 hours for milk.17 However, there is a combination product containing florfenicol and flunixina that is approved by the FDA for SC administration to beef and nonlactating (< 20 months old) dairy cattle for the treatment of bovine respiratory tract disease; this product has a longer meat WDT (38 days)18 than flunixin-only products because of its florfenicol component.19 In the European Union, a transdermal formulation of flunixinb has been approved for pour-on application to cattle for the treatment of pyrexia associated with bovine respiratory tract disease and acute mastitis at a dosage of 3.3 mg/kg (1.5 mg/lb), topically, once, with a WDT of 7 days for meat and 36 hours for milk.20
In the United States, extralabel drug use is allowed under AMDUCA. It is important to note that AMDUCA allows administration of a drug by an extra-label route for therapeutic purposes only; it expressly prohibits administration of a drug by an extralabel route for convenience purposes.1 Therefore, administration of flunixin by any route other than IV because it is easier is illegal. Nevertheless, the fact is that flunixin is commonly administered to cattle by routes other than I V, and until recently, the FARAD-recommended WDIs were 30 days for meat and 72 hours for milk following a single IM injection and 8 days for meat and 48 hours for milk following a single PO administration of flunixin at the labeled dose (1.1 to 2.2 mg/kg).15 However, review of the existing data6,15,21–25 suggests that the WDI for meat may need to be extended to as long as 60 days following administration of multiple IM or SC doses of flunixin to ensure that violative residues are not detected in treated cattle. The WDI for milk following administration of multiple IM or SC doses of flunixin has not been established.
Effect of administration route on WDI
Multiple studies21–23,26–35,c have been conducted in which the pharmacokinetics of flunixin following administration by various routes to cattle have been determined, and the apparent plasma t1/2s for those studies were summarized (Table 3). The t1/2 of flunixin following IV administration varies substantially among studies,21–23,26–29,32,33,35,c which probably is a reflection of differences among those studies in production class, age, and health status of study animals; dosage administered; and methods used to determine the pharmacokinetics, particularly the terminal portion of the drug concentration versus time curve. The mean apparent plasma t1/2 of flunixin following IV administration of 1 dose (1.1 to 2.2 mg/kg) of the drug to healthy mature cattle (lactating and nonlactating dairy cows and beef cattle) ranged from 3.14 to 5.70 hours in all studies21–23,26,27,35,c except one.28 In the exception,28 the mean ± SD apparent t1/2 of flunixin (11.6 ± 8.0 hours) was 2 to 3 times as long as that in the other studies,21–23,26,27,35,c probably because the cows in that study28 were administered 2.2 mg of flunixin/kg, IV, once daily for 3 days, whereas the cows in the other studies21–23,26,27,35,c were administered the drug only once and blood samples were collected for 96 hours after the last dose of flunixin was administered. Also, the t1/2 in that study28 was influenced by a fairly long concentration-time curve because the plasma flunixin concentrations were quantifiable for a longer duration owing to the increased sensitivity of the detection method (limit of quantification, 0.5 ng/mL [0.5 ppb]) used, compared with that of the other studies.21–23,26,27,35,c
Apparent plasma t1/2 (hours) of flunixin meglumine in cattle following IV, IM, SC, or PO administration.
| Â | Â | Â | Â | Â | Route of administration | |||
|---|---|---|---|---|---|---|---|---|
| Reference | Production class | No. of animals | Dose (mg/kg) | Frequency | IV | IM | SC | PO |
| 29 | Calf | 8 | 2.2 | Once | 6.87 ± 0.49 | — | — | — |
| 31 | Calf | 6 | 2.2 | Once | — | 6.25 ± 0.81 | — | — |
| 34 | Beef cattle | 32 | 2.2 | Once | — | — | 8.8 | — |
| 27 | Beef cattle | 8 | 2.2 | Once | 4.8 ± 1.0 | — | 6.3 ± 3.2 | — |
| 26 | Lactating cattle | NA | 1.1 | Once | 3.7 ± 0.7 | — | — | — |
| c | Lactating cattle | 3 | 2.2 | Every 24 h for 3 d | 4.0 | 4.4 | — | 7.1 |
| 21 | Lactating cattle | 6 | 1.1 | Once | 3.14 | 5.20 | — | — |
| 35 | Lactating cattle | 6 | 2.2 | Once | 5.70 ± 2.6 | — | — | — |
| 22 | Lactating cattle | 12 | 1.1 | Every 12 h for 1 d | 3.42 ± 0.98 | 4.48 ± 1.77 | 5.39 ± 2.47 | — |
| 28 | Lactating cattle | 5 | 2.2 | Every 24 h for 3 d | 11.6 ± 8 | 15.5 ± 8 | — | — |
| 30 | Nonlactating cattle | 10 | 2.2 | Once | — | 5.18 ± 0.98 | 7.46 ± 2.6 | — |
| 23 | Nonlactating cattle | 1 | 2.2 | Once | 3.80* | — | — | — |
| 23 | Nonlactating cattle | 3 | 2.2 | Every 12 h for 14 d | — | 6.4–9.0†|  |  |
| 23 | Nonlactating cattle | 3 | 2.2 | Every 6 h for 14 d | — | 12.1–24.8†| — | — |
| 33 | Heifer | 6 | 1.1 | Once | 8.12 | — | — | — |
| 23 | Heifer | 1 | 2.2 | Once | 4.30* | — | — | — |
| 32 | Heifer | 6 | 2.2 | Once | 3.9–8.9†| — | — | 5.3–6.7†|
Values represent mean ± SD (when available) unless otherwise noted.
Calculated value for 1 animal.
Range.
— = Not calculated. NA = Not available.
In general, the apparent plasma t1/2 (range, 4.4 to 6.25 hours)21,30,31,c of flunixin following IM administration of the labeled dose (1.1 to 2.2 mg/kg) once was longer than that following a single IV injection of the same dose, and the apparent t1/2 (range, 6.9 to 24.8 hours)23,28 following IM administration of multiple doses of flunixin (2.2 mg/kg) was even longer (Table 3). The apparent positive association between the plasma t1/2 and number of IM doses of flunixin administered is likely a function of drug retention in tissues damaged by injection of the drug. Drug absorption is frequently delayed by tissue damage, and persistent drug concentrations at an injection site may create a phenomenon known as flip-flop kinetics.15 This issue warrants further investigation in regard to flunixin because, to our knowledge, a significant increase in serum creatine kinase activity, an indicator of skeletal muscle damage, following IM administration of flunixin has been reported by the investigators of only 2 studies.36,37
The fact that the mean apparent plasma t1/2 of flunixin following SC or PO administration of a single dose of the drug was approximately 1.5 to 2 times as long as that following IV administration of a single dose in beef and lactating cattle (Table 3) suggests that administration of the drug by an extralabel route is a contributing factor associated with violative tissue residues in cattle at slaughter.22,27,30,32,38 That observation was supported by results of another study,28 in which the MRT (ie, the mean time that drug molecules stay in the body before elimination) of flunixin in lactating dairy cattle following IM administration (44.3 hours) was substantially longer than that following IV administration (36.7 hours). Collectively, the results of those studies22,27,28,30,32,38 suggest that, in cattle, tissue elimination of flunixin varies with route of administration.
In the United States, the tolerance for 5OHF, the marker residue for flunixin, in milk is 2 ppb,12 and the WDT for milk following administration of the labeled dosage of flunixin is 36 hours.17 In a study39 in which 8 lactating Holstein cows were administered14C-flunixin (2.2 mg/kg, IV, q 24 h for 3 days), the mean total radioactive flunixin residues in milk were 66, 20, and 14 ppb at 12, 24, and 36 hours, respectively, after the last flunixin injection. The mean milk 5OHF concentration was 6 ppb at 36 hours after the last injection; however, the investigators attributed that high mean concentration to exceptionally high 5OHF concentrations in the milk of 1 cow.39 In a study22 with a crossover design, 12 lactating Holstein cows were administered 2 doses of flunixin (1.1 mg/kg) with a 12-hour interval between doses by each of 3 routes (IV, IM, and SC). A milk 5OHF concentration > 2 ppb was detected at 36 hours after the last flunixin injection for 1 cow following IM administration and 1 cow following SC administration but was not detected in any of the cows following IV administration; however, the milk 5OHF concentration was < 2 ppb at 48 hours after the last flunixin injection for all cows following all 3 routes of administration.22 Thus, the investigators concluded that administration of flunixin to lactating cows in accordance with the label consistently resulted in milk 5OHF concentrations less than the tolerance at the WDT, whereas milk 5OHF concentrations greater than the tolerance could persist at the WDT if flunixin was administered by an extralabel (IM or SC) route.22 In yet another study,28 20 lactating dairy cattle underwent an IV infusion of either LPS (n = 10) or sterile saline (0.9% NaCl) solution (10) and then 5 cows in each group were administered flunixin (2.2 mg/kg) by either the IV or IM route once daily for 3 days. The milk 5OHF concentration was > 2 ppb for 6 and 2 cows at 36 and 48 hours, respectively, after the last flunixin injection.28 Collectively, the results of those studies22,28,39 indicate that administration of flunixin by an extralabel (IM or SC) route, particularly if multiple doses are administered by that route, can result in violative flunixin residues in the milk of dairy cattle.
The apparent t1/2s of flunixin in milk, liver, and kidneys of cattle following IV administration of the drug as reported in the scientific literature13,24,25,39–41 were summarized (Table 4). Following IV administration of flunixin (2.2 mg/kg, q 24 h for 3 days) to adult cattle, the apparent t1/2 in the liver (9 to 51 hours)25 and kidneys (22 to 37 hours)25 is substantially longer than the apparent t1/2 in plasma (11.6 ± 8 hours).28 Given that the apparent plasma t1/2 of flunixin in adult cattle tends to be longer following IM or SC administration than that following IV administration (Table 3), it is likely that the apparent t1/2s of flunixin in the liver and kidneys follow the same pattern. In the study28 in which lactating dairy cows were administered flunixin for 3 days by the IV or IM route after IV infusion of LPS or saline solution, the mean concentrations of flunixin residues in liver, kidney, muscle, and other tissues following IV administration were similar or slightly lower than those following IM administration, and all liver and kidney residues were below the respective tolerances at 96 hours after the last IV dose. However, the flunixin residues at the IM injection sites were 100 to 300 times those at the IV injection sites.28 Intramuscular or SC administration of flunixin-only formulations generally causes extensive tissue damage but SC administration of a florfenicol-flunixin combination does not because of differences in the vehicles used in the respective formulations. Flunixin accumulates in damaged tissue and is slowly released from that tissue into the systemic circulation, which results in extended retention of the drug in the body15,36 and possible violative residues in tissues used for human consumption. It is also one of the reasons that, in cattle, flunixin is approved for IV administration only.
Apparent t1/2 in the milk, liver, and kidneys of cattle following IV administration of flunixin.
| Â | Â | Â | Â | Â | t1/2 (h) | ||
|---|---|---|---|---|---|---|---|
| Reference | Production class | No. of animals | Dose (mg/kg) | Frequency | Milk | Liver | Kidneys |
| 25 | Cattle | 3 | 2.2 | q 24 h for 3 d | — | 34.2–36.3* | 29.6–31.7* |
| 13 | Cattle | 3 | 3.6 | q 24 h for 3 d | — | 115.6 | 52.7 |
| 24 | Lactating cow | 2 | 2.2 | q 24 h for 2 d | — | 27.9–30.3* | 21.5–27.6* |
| 40 | Lactating cow | 4 | 2.0 | q 24 h for 3 d | 6.68–22.7* | — | — |
| 39 | Lactating cow | 8 | 2.2 | q 24 h for 3 d | 26.9 | — | — |
| 41 | Lactating cow | 8 | 2.2 | q 24 h for 3 d | 13.82 | — | — |
Range. — = Not determined.
The apparent plasma t1/2 of flunixin in calves and heifers is generally longer than that for adult cattle following IV administration of the same dose of the drug (Table 3). This suggests that the flunixin elimination rate may increase as the age of the animal increases.
Effect of disease on WDI
Sick cattle are frequently treated with flunixin and other drugs concurrently, and some of those drugs may alter the pharmacokinetic profile of flunixin and result in violative drug residues in milk or meat products from treated cattle.42 For example, the apparent plasma t1/2 of flunixin (4.35 ± 1.82 hours) in cows with naturally occurring mastitis that were treated with flunixin (2.2 mg/kg, I V, once), ceftiofur sodium (2.2 mg/kg, IM, q 24 h for 3 days), and ceftiofur hydrochloride (10 mL/mammary gland, intramammary, q 24 h for 5 days) or cephapirin sodium (10 mL/mammary gland, intramammary, q 12 h for 3 days) was longer than that (3.68 ± 1.97 hours) for healthy control cows that received the same treatments.42
In the study28 in which lactating dairy cows were administered flunixin after IV infusion of LPS or saline solution, the MRT of flunixin for the LPS-treated cows (41.1 hours) was longer, although not significantly so, than that for the saline-treated cows (36.7 hours) following IV administration, whereas the MRT of flunixin for LPS-treated cows (62 hours) was significantly longer than that for saline-treated cows following IM administration (44 hours). Also, 1 LPS-treated cow had a liver flunixin concentration (177 ppb) that exceeded the tolerance (125 ppb) at 96 hours after IM administration of the drug, and the flunixin concentrations in other tissues of that cow were greater than those for the other cows of that study.28 The investigators of that study28 concluded that LPS inhibits the metabolism of flunixin in cattle, but that phenomenon does not appear to be unique to cattle. Following IV administration of 1 dose of flunixin (2.2 mg/kg), the plasma clearance rate was significantly slower and the apparent t1/2 was significantly longer in rats with experimentally induced endotoxemia, compared with healthy control rats.43
Flunixin persists in inflamed tissues and has anti-inflammatory activity that extends beyond the period associated with detectable plasma concentrations of the drug.29 Following administration, most NSAIDs are highly bound to plasma proteins, and the percentage of flunixin bound to plasma protein can exceed 99% in some cases.23 Although protein binding can limit the passage of a drug from plasma into interstitial fluid, it also facilitates the sequestration of NSAIDs in inflamed tissues because protein readily leaks into those tissues.29,44 It is likely that inflammation alters the metabolism or disposition of flunixin, which results in a prolonged MRT of flunixin residues in milk and other tissues.28,42 Detectable flunixin concentrations persisted in milk for up to 60 hours after administration in 3 of 10 cows with clinical mastitis that were treated with 1 (labeled) dose of flunixin in conjunction with parenteral and intramammary administration of antimicrobials (mean ± SD flunixin concentration, 13.02 ± 10.93 ppb), whereas flunixin was detectable in milk for only 24 hours after administration in all 10 like-treated healthy control cows.42 In that study,42 the ratios of 5OHF concentration (marker residue) to flunixin concentration (parent drug) in milk for healthy control cows (range, 1.25 to 2.5; ie, the concentration of the marker residue was greater than that of the parent drug) were several times greater than those for cows with mastitis (range, 0.023 to 0.167; ie, the concentration of the marker residue was less than that of the parent drug) within 24 hours after flunixin administration, which further suggests that flunixin is metabolized quicker in healthy cows than in diseased cows. Results of a study8 in which a physiologically based pharmacokinetic computation model was developed to predict the M/D for flunixin and other drugs (ceftiofur, enrofloxacin, and sulfamethazine) in cattle and swine and evaluate how disease effects that ratio in various tissues (plasma, liver, kidneys, and muscle) similarly indicate the M/D for healthy animals is generally greater than that for diseased animals, regardless of the drug or tissue evaluated. Also, the M/D is not a fixed value; it changes over time.8 Those findings challenge the wisdom of regulatory policies that use a fixed M/D determined from a limited number of studies involving healthy animals to establish tolerances or MRLs because, in practice, drugs are generally not administered to healthy animals.8
In a survey45 of cull dairy cows performed at 21 US abattoirs between July 2003 and July 2004, the liver flunixin concentration was greater than the tolerance for 50 of 710 (7.04%) cows that appeared diseased, compared with only 2 of 251 (0.80%) cows that appeared healthy. In rats with experimentally induced acute liver or kidney disease that were treated with 1 dose of flunixin (2.2 mg/kg, IV), the apparent t1/2 and total body clearance rate of flunixin were significantly longer, compared with those of control rats without experimentally induced liver or kidney disease.46 In diseased animals, inflammation and infection alter liver and kidney function, which can decrease the clearance rate of flunixin,46–48 most likely because flunixin accumulates at inflammatory sites owing to its affinity for binding to inflammatory proteins.49 The distribution of flunixin within the central and peripheral compartments may also be altered during certain disease conditions. In septic animals, the distribution of body fluid shifts such that the distribution of flunixin into the peripheral compartment increases while the distribution of flunixin into the central compartment decreases,50 which can lead to violative residues. Thus, it is likely that the current flunixin WDT, which was determined on the basis of pharmacokinetic data obtained from a reference population of healthy animals, likely underestimates the time required for tissue clearance of the drug to below tolerances in diseased animals. Therefore, data obtained from both healthy and diseased animals should be used to more accurately estimate the WDT for drugs administered to food-producing species under normal practice conditions.
For cattle treated with the labeled dosage of flunixin, the WDT for meat is 4 days.17 In a study51 in which a population pharmacokinetic model was developed to predict tissue residues and the WDI for flunixin in cattle on the basis of data obtained from a diverse population (healthy and diseased animals of various ages) of cattle that were administered various dosages of the drug, the estimated WDI for meat was 7 days. In another study,42 cows with mastitis had mean total flunixin concentrations in milk that exceeded the tolerance for > 60 hours after administration, whereas the mean 5OHF concentrations in milk exceeded the tolerance for only 36 hours after administration. The findings from that study42 suggest that total flunixin concentration may be a better marker residue than 5OHF in milk in some cases. As previously mentioned, the M/D is not a fixed value,8 and concentration data for the drug or drug metabolite that persists the longest in the target tissue of interest will provide the most conservative estimate of the WDI.
Recommendations
Following administration of a single labeled dose of flunixin (1.1 to 2.2 mg/kg) to adult cattle by an IV or extravascular (IM, SC, or PO) route, FARAD currently recommends a WDI of 84 and 96 hours, respectively, for milk22,42 and 7 and 10 days, respectively, for meat.28,51 Administration of multiple doses of flunixin by an extravascular route may require extending the WDI for meat to as long as 60 days to ensure that violative residues are not detected in treated cattle.6,15,21–25 These recommendations were made on the basis of a review of the currently available pharmacokinetic data for flunixin in cattle and should be revisited as new data become available.
Swine
In swine, flunixin is approved for control of pyrexia associated with respiratory tract disease at a dosage of 2.2 mg/kg, IM, once, and the WDT for meat is 12 days.52 Lameness is a frequent complication associated with low growth rate and poor reproductive performance in breeding-age swine, which represents a welfare concern and has a large negative economic impact for producers.53 In the United States, lameness is the third most common reason cited for culling sows, and lame sows comprise 15% of the cull market.54 Appropriate pain management, regardless of the etiology, is critical for veterinarians and producers.53–55 Currently, there are no analgesics approved for use in swine in the United States. Review of the FARAD inquiry database suggests that flunixin is frequently used in swine, and it is frequently administered by extralabel (PO or SC) routes. In a study56 with a crossover design in which the pharmacokinetics of flunixin was determined following administration of a target dose of 2.2 mg/kg to adult swine by I V, IM, and PO routes, the mean apparent plasma t1/2 did not differ significantly following IV (6.29 hours; range, 4.84 to 8.34 hours), IM (7.49 hours; range, 5.55 to 12.98 hours), and PO (7.08 hours; range, 5.29 to 9.15 hours) administration. In that study,56 the mean ± SD plasma flunixin concentration at 48 hours after IM administration (10.2 ± 8.8 ng/mL) was 3.8 and 4.6 times that following IV (2.68 ± 1.80 ng/mL) and PO (2.2 ± 1.1 ng/mL) administration, respectively. The bioavailability of flunixin following PO administration was 22% (range, 11% to 44%), whereas that following IM administration was 76% (range, 54% to 92%).56 In growing swine, the apparent t1/2 of flunixin was 7.7 to 7.8 hours after IV administration of the drug at doses ranging from 2.0 to 3.0 mg/kg.57,58 The mean apparent t1/2 of flunixin following IV administration (6.29 to 7.8 hours)56–58 is almost twice that following IM administration (3 to 4 hours).52 The difference in the t1/2 of flunixin following IV and IM administration is likely attributable, at least partially, to differences in assay sensitivity and breed, age, and health status of the study pigs.
In swine, protein binding of flunixin is > 98% at physiologically relevant plasma flunixin concentrations (0.30 to 10 μg/mL).57 The volume of distribution of flunixin at the steady state is fairly large (1.83 to 2.35 L/kg) in growing pigs,57,58 which is likely a reflection of the drug's high lipophilicity and protein binding characteristics. Unfortunately, aside from the data generated by the flunixin manufacturer during the FDA approval process,52 no studies have been conducted to determine tissue residues in swine following IV or extravascular routes of administration. Therefore, following extralabel use of flunixin, WDIs calculated solely on the basis of plasma drug concentrations may result in violative tissue residues, and further tissue residue studies need to be conducted.
Recommendations
Following administration of a flunixin formulation that does not have a swine label, even at the labeled dosage (2.2 mg/kg, IM, once), FARAD recommends a meat WDI of 13 to 15 days. That WDI was calculated by adding a safety factor of 10% to the label WDT (12 days) to be in compliance with AMDUCA stipulations.59 Following IV or PO administration of 1 or more doses of flunixin (2.2 mg/kg), FARAD recommends a meat WDI of 21 days. That WDI was calculated by use of the half-life multiplier technique as described.59 For swine, veterinarians are advised to prescribe flunixin formulations specifically labeled for swine at the labeled dosage to avoid greatly extended WDIs and violative tissue residues of the drug.
Acknowledgments
Supported by a USDA grant for the FARAD.
ABBREVIATIONS
| 5OHF | 5-hydroxy flunixin |
| FARAD | Food Animal Residue Avoidance and Depletion Program |
| LPS | Lipopolysaccharide |
| M/D | Marker residue–to–parent drug ratio |
| MRL | Maximum residue limit |
| MRT | Mean residence time |
| ppb | Parts per billion |
| t1/2 | Elimination half-life |
| WDI | Withdrawal interval |
| WDT | Withdrawal time |
Footnotes
Resflor Gold, Merck Animal Health, Summit, NJ.
Finadyne transdermal, MSD Animal Health, Kenilworth, NJ.
Cameron BD, Done JN, Young WR. The pharmacokinetics of flunixin (finadyne) in the plasma and milk of lactating cows: a comparison between formulations (abstr), in Proceedings. 3rd European Assoc Vet Pharmacol Toxicol Cong 1985;88.
References
1. Extralabel drug use in animals. 21 CFR 530.
2. Sundlof SF, Kaneene JB, Miller RA. National survey on veterinarian-initiated drug use in lactating dairy cows. J Am Vet Med Assoc 1995; 207: 347–352.
3. Espinasse J, Thouvenot JP, Dalle S, et al. Comparative study of the action of flunixin meglumine and tolfenamic acid on prostaglandinE2 synthesis in bovine inflammatory exudate. J Vet Pharmacol Ther 1994; 17:271–274.
4. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998; 104(suppl 3A):2S–8S.
5. USDA Food Safety and Inspection Service. United States national residue program for meat, poultry, and egg products. 2011 residue sample results. Available at: www.fsis.usda.gov/wps/wcm/connect/f511ad0e-d148-4bec-95c7-22774e731f7c/2011_Red_Book.pdf?MOD=AJPERES. Accessed Feb 13, 2015.
6. USDA Food Safety and Inspection Service. United States national residue program for meat, poultry, and egg products. 2012 residue sample results. Available at: www.fsis.usda.gov/wps/wcm/connect/be77fe0d-2295-417f-9472-6b43052068b9/2012-Red-Book.pdf?MOD=AJPERES. Accessed Feb 13, 2015.
7. Kissell LW, Baynes RE, Riviere JE, et al. Occurrence of flunixin residues in bovine milk samples from USA. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013; 30: 1513–1516.
8. Lin Z. vahl Cl, Riviere JE. Human food safety implications of variation in food animal drug metabolism. Sci Rep 2016; 6: 27907.
9. FARAD. Extralabel drug use (ELDU) resource page. Available at: www.farad.org/eldu/eldumain.asp. Accessed Oct 4, 2016.
10. FDA. Guidance for industry #3. General principles for evaluating the human food safety of new animal drugs used in food-producing animals (Draft revised guidance). July 2016. Available at: www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndusGui/ucm052180.pdf. Accessed Oct 10, 2016.
11. FDA. Freedom of information summary, supplemental new animal drug application NADA 101–479, Banamine injectable solution (flunixin meglumine). www.fda.gov/downloads/animalveterinary/products/approvedanimaldrugproducts/foiadrugsummaries/ucm064905.pdf. Accessed Jul 10, 2012.
12. Tolerances for residues of new animal drugs in food. 21 CFR 556.
13. European Medicines Agency Committee for Veterinary Medicinal Products. Flunixin: summary report (1). 1999. Available at: www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500014324.pdf. Accessed May 2, 2016.
14. FARAD. FARAD Newsletter 2007;9. Available at: www.farad.org/publications/newsletters/FARADNewsletter_9.pdf. Accessed Apr 29, 2016.
15. Smith GW, Davis JL, Tell LA, et al. Extralabel use of nonsteroidal anti-inflammatory drugs in cattle. J Am Vet Med Assoc 2008; 232: 697–701.
16. Leavens TL, Tell LA, Kissell LW, et al. Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus). Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2014; 31: 1506–1521.
17. FDA. Animal Drugs @ FDA. Flunixin meglumine. Available at: www.accessdata.fda.gov/scripts/animaldrugsatfda/. Accessed May 2, 2016.
18. Merck Animal Health. Resflor Gold product information. Summit, NJ: Merck Animal Health, 2009.
19. Hannon SJ, Perrett T, Wildman BK, et al. Efficacy of a florfenicol-flunixin meglumine combination product versus tulathromycin or ceftiofur crystalline free acid for the treatment of undifferentiated fever in feedlot calves. Vet Ther 2009; 10: E1–E18.
20. Health Products Regulatory Authority. Finadyne transdermal summary of product characteristics. Available at: www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_10996-272-001_18092015141937.pdf. Accessed Oct 10, 2016.
21. Anderson KL, Neff-Davis CA, Davis LE, et al. Pharmacokinetics of flunixin meglumine in lactating cattle after single and multiple intramuscular and intravenous administrations. Am J Vet Res 1990; 51: 1464–1467.
22. Kissell LW, Smith GW, Leavens TL, et al. Plasma pharmacokinetics and milk residues of flunixin and 5-hydroxy flunixin following different routes of administration in dairy cattle. J Dairy Sci 2012; 95: 7151–7157.
23. Odensvik K, Johansson M. High-performance liquid chromatography method for determination of flunixin in bovine plasma and pharmacokinetics after single and repeated doses of the drug. Am J Vet Res 1995; 56: 489–495.
24. Lichtenwalner DM, Cameron BD, Young C. The metabolism and pharmacokinetics of flunixin meglumine in cows and steers, in Proceedings. 14th World Cong Dis Cattle 1986; 1179–1183.
25. Clement RP, Simmons RD, Christopher RJ, et al. Design and conduct of studies to meet residue chemistry requirements. In: Hutson DH, Hawkins DR, Paulson GD, et al, eds. Xenobiotics and food-producing animals: metabolism and residues. Washington, DC: American Chemical Society, 1992; 37–48.
26. Benitz AM. Pharmacology and pharmacokinetics of flunixin meglumine in the bovine, in Proceedings. 13th World Cong Dis Cattle 1984; 928–930.
27. Shelver WL, Tell LA, Wagner S, et al. Comparison of ELISA and LC-MS/MS for the measurement of flunixin plasma concentrations in beef cattle after intravenous and subcutaneous administration. J Agric Food Chem 2013; 61: 2679–2686.
28. Smith DJ, Shelver WL, Baynes RE, et al. Excretory, secretory, and tissue residues after label and extra-label administration of flunixin meglumine to saline- or lipopolysaccharide-exposed dairy cows. J Agric Food Chem 2015; 63: 4893–4901.
29. Landoni MF, Cunningham FM, Lees P. Determination of pharmacokinetics and pharmacodynamics of flunixin in calves by use of pharmacokinetic/pharmacodynamic modeling. Am J Vet Res 1995; 56: 786–794.
30. Lacroix MZ, Gayrard V, Picard-Hagen N, et al. Comparative bioavailability between two routes of administration of florfenicol and flunixin in cattle. Rev Med Vet (Toulouse) 2011; 162: 321–324.
31. Gatne MM, Yadav MH, Mahale TR. Pharmacokinetics of flunixin in buffalo calves after single intramuscular administration. Buffalo Bull 2012; 31: 214–218.
32. Odensvik K. Pharmacokinetics of flunixin and its effect on prostaglandin F2 alpha metabolite concentrations after oral and intravenous administration in heifers. J Vet Pharmacol Ther 1995; 18: 254–259.
33. Hardee GE, Smith JA, Harris SJ. Pharmacokinetics of flunixin meglumine in the cow. Res Vet Sci 1985; 39: 110–112.
34. FDA. Freedom of information summary, original new animal drug application NADA 141–229, Resflor gold (florfenicol and flunixin meglumine [in 2-pyrrolidone and triacetin] injectable solution). Available at: www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSuFOIADru/UCM203309.pdf. Accessed Oct 10, 2016.
35. Rantala M, Kaartinen L, Välimäki E, et al. Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally induced Escherichia coli mastitis. J Vet Pharmacol Ther 2002; 25: 251–258.
36. Pyörälä S, Laurila T, Lehtonen S, et al. Local tissue damage in cows after intramuscular administration of preparations containing phenylbutazone, flunixin, ketoprofen and metamizole. Acta Vet Scand 1999; 40: 145–150.
37. Fajt VR, Wagner SA, Pederson LL, et al. The effect of intramuscular injection of dinoprost or gonadotropin-releasing hormone in dairy cows on beef quality. J Anim Sci 2011; 89: 1939–1943.
38. Damian P, Craigmill AL, Riviere JE. Extralabel use of nonsteroidal anti-inflammatory drugs. J Am Vet Med Assoc 1997; 211: 860–861.
39. Feely WF, Chester-Yansen C, Thompson K, et al. Flunixin residues in milk after intravenous treatment of dairy cattle with (14)C-flunixin. J Agric Food Chem 2002; 50: 7308–7313.
40. FDA. Freedom of information summary, supplemental new animal drug application NADA 101–479, Banamine injectable solution (flunixin meglumine). Available at: www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm064910.pdf. Accessed Oct 10, 2016.
41. Ngoh MA, Wislocki PG, Thompson K, et al. Residue depletion study and withdrawal period for flunixin-N-methyl glucamine in bovine milk following intravenous administration. J Agric Food Chem 2003; 51: 4701–4707.
42. Kissell LW, Leavens TL, Baynes RE, et al. Comparison of pharmacokinetics and milk elimination of flunixin in healthy cows and cows with mastitis. J Am Vet Med Assoc 2015; 246: 118–125.
43. Elmas M, Yazar E, Uney K, et al. Pharmacokinetics of flunixin after intravenous administration in healthy and endotoxaemic rabbits. Vet Res Commun 2006; 30: 73–81.
44. Galbraith EA, McKellar QA. Protein binding and in vitro serum thromboxane B2 inhibition by flunixin meglumine and meclofenamic acid in dog, goat and horse blood. Res Vet Sci 1996; 61: 78–81.
45. Deyrup CL, Southern KJ, Cornett JA, et al. Examining the occurrence of residues of flunixin meglumine in cull dairy cows by use of the flunixin cull cow survey. J Am Vet Med Assoc 2012; 241: 249–253.
46. Hwang YH, Yun H. Effects of acute hepatic and renal failure on pharmacokinetics of flunixin meglumine in rats. Exp Anim 2011; 60: 187–191.
47. Sarwari AR, Mackowiak PA. The pharmacologic consequences of fever. Infect Dis Clin North Am 1996; 10: 21–32.
48. Monshouwer M, Witkamp RF. Cytochromes and cytokines: changes in drug disposition in animals during an acute phase response: a mini review. Vet Q 2000; 22: 17–20.
49. Lees P, Higgins AJ. Flunixin inhibits prostaglandin E2 production in equine inflammation. Res Vet Sci 1984; 37: 347–349.
50. Holcomb SS. Third-spacing: when body fluid shifts. Nursing 2008; 38: 50–53.
51. Wu H, Baynes RE, Leavens T, et al. Use of population pharmacokinetic modeling and Monte Carlo simulation to capture individual animal variability in the prediction of flunixin withdrawal times in cattle. J Vet Pharmacol Ther 2013; 36: 248–257.
52. Merck Animal Health. Banamine-S (flunixin meglumine) injectable solution product bulletin. Summit, NJ: Merck Animal Health 2013.
53. Campler M, Pairis-Garcia MD, Stadler KJ, et al. Rubber mat placement in a farrowing and lactation facility: tips and techniques. J Swine Health Prod 2016; 24: 142–146.
54. Pluym LM, Van Nuffel A, van Weyenberg S, et al. Prevalence of lameness and claw lesions during different stages in the reproductive cycle of sows and the impact on reproduction results. Animal 2013; 7: 1174–1181.
55. Elmore MRP, Garner JP, Johnson AK, et al. A flooring comparison: the impact of rubber mats on the health, behavior, and welfare of group-housed sows at breeding. Appl Anim Behav Sci 2010; 123: 7–15.
56. Pairis-Garcia MD, Karriker LA, Johnson AK, et al. Pharmacokinetics of flunixin meglumine in mature swine after intravenous, intramuscular and oral administration. BMC Vet Res 2013; 9: 165.
57. Buur JL, Baynes RE, Smith GS, et al. Pharmacokinetics of flunixin meglumine in swine after intravenous dosing. J Vet Pharmacol Ther 2006; 29: 437–440.
58. Howard JT, Baynes RE, Brooks JD, et al. The effect of breed and sex on sulfamethazine, enrofloxacin, fenbendazole and flunixin meglumine pharmacokinetic parameters in swine. J Vet Pharmacol Ther 2014; 37: 531–541.
59. Gehring R, Baynes RE, Craigmill AL, et al. Feasibility of using half-life multipliers to estimate extended withdrawal intervals following the extralabel use of drugs in food-producing animals. J Food Prot 2004; 67: 555–560.
Appendix
List of useful websites that provide more detailed information regarding the use of flunixin meglumine in cattle and swine in the United States.
• FARAD (www.farad.org).
• Food and Drug Administration Center for Veterinary Medicine (www.fda.gov/AnimalVeterinary/default.htm).
• United States Department of Agriculture Food Safety and Inspection Service, Residue Testing, National Residue Program (www.fsis.usda.gov/wps/portal/fsis/topics/data-Collection-and-reports/chemistry/residue-chemistry).
• AVMA AMDUCA extralabel drug use algorithm (www.avma.org/KB/Resources/Reference/Pages/AMDUCA2.aspx).
