MECLOFENAMIC ACID
Chemistry - An anthranilic acid derivative (fenamate), meclofenamic acid is a white, crystallinepowder that is practically insoluble in water. The sodium salt of meclofenamic acid is availablecommercially for human use. It is freely soluble in water.
It also has a transient effect on platelet aggregation, but unlike aspirin, does not appear to affectbleeding times.
In studies done with monkeys, highest meclofenamic acid levels were detected in the plasma, liver, and kidneys. Lower levels were detected in skeletal muscle, fat, spleen, heart, and brain. At plasmalevels of 1 micrograms/ml, the drug was 99.8% bound to albumin. It rapidly crosses the placenta, but it is unknown whether it is distributed into milk.
The plasma half-life has been reported to range from 1-8 hours in horses. Therapeutic efficacydoes not seem to be closely related with blood levels, however, as the onset of action may take 36-96 hours and significant efficacy may be seen for days following a dose.
Meclofenamic acid is metabolized in the liver primarily by oxidation to an active hydroxymethylmetabolite which may be further oxidized to an inactive metabolite (carboxyl). In humans, meclofenamic acid and its metabolites are then excreted by the kidneys (approx. 70% within 7days) or eliminated with the feces (20-30%). In horses, meclofenamic acid can be detected in theurine for at least 96 hours following the final dose.
In horses, it is indicated for the "oral treatment of acute or chronic inflammatory diseases involving the musculoskeletal system..." (Package Insert; Arquel®¯Parke-Davis). Meclofenamicacid has also been used for the treatment of laminitis, with varying degrees of success.
Contraindications/Precautions - The manufacturer states that meclofenamic acid is contraindicated in animals with "active gastrointestinal, hepatic or renal diseases" (Package Insert;
Arquel®¯Parke-Davis). Additionally, meclofenamic acid is contraindicated in patients demonstrating previous hypersensitivity reactions to it or salicylates. It is relatively contraindicated inpatients with active or historical hemorrhagic disorders, or bronchospastic disease. Becausemeclofenamic acid is highly bound to plasma proteins, patients with hypoproteinemia may requirelower dosages to prevent symptoms of toxicity.
Meclofenamic acid has been shown to delay parturition in some species and therefore should beavoided during the last stages of pregnancy. It has caused teratogenic effects (minor skeletal abnormalities, delayed ossification) in rodents. Some preliminary studies have shown no effects withregard to either mare or stallion reproductive performance and no gross defects were seen in foalsborn to mares who received meclofenamic acid during pregnancy. It should, nevertheless, be used inpregnancy only when the potential benefits outweigh the potential risks of therapy.
However, hematologic changes (decreased hematocrit/PCV) and GI effects (buccal erosions, diarrhea, colic, anorexia, changes in stool consistency) have been reported. The diarrheal and colicreactions may be more likely in horses that have a heavy infestation of bots (Gasterophilus sp.)
With chronic therapy, decreases in plasma protein concentrations may occur.
In dogs, vomiting, decreased hemoglobin, leukocytosis, tarry stools, and small intestinal ulcershave all been reported following therapy at usual effective doses. Clients should be counseled withregard to these potential adverse effects and instructed to monitor their animal carefully forsymptoms associated with them.
In humans, NSAIDs have caused hepatotoxicity and it is recommended that human patients receiving chronic meclofenamate sodium therapy undergo occasional liver function tests. Although itdoes not appear that this adverse reaction is of major concern in either dogs or horses, the potentialfor hepatotoxicity does exist.
Overdosage - There is very limited information regarding acute overdoses of this drug in humansand no information was located regarding overdoses in domestic animals. Following an acute, massive overdose in humans, generalized CNS stimulation initially occurs, with seizures possible.
After this initial phase, acute renal failure may occur with secondary azotemia and anuria.
Treatment should follow standard overdose procedures (empty gut following oral ingestion, etc.).
Supportive treatment should be instituted as necessary and IV diazepam used to help controlseizures. Because meclofenamic acid may cause renal effects, monitor electrolyte and fluid balancecarefully and manage renal failure using established guidelines.
When aspirin is used concurrently with meclofenamic acid, plasma levels of meclofenamic acidmay decrease as well as a likelihood of increased GI adverse effects (blood loss) developing.
Concomitant administration of aspirin with meclofenamic acid is not recommended.
Storage, Stability, Compatibility
Should be stored in tight, light-resistant packaging at temperatures below 30°C (86°F).Pharmacology - MECLOFENAMIC ACID
Meclofenamic acid exhibits pharmacologic actions similar to those of aspirin. It isa potent inhibitor of cyclooxygenase, thereby inhibiting the release of prostaglandins. Like aspirin, meclofenamic acid (sodium salt administered IV) has been demonstrated to reduce the cardiovascular and respiratory effects of experimentally induced anaphylaxis in ponies and calves byits antagonistic effects at high concentrations on histamine, kinins, and prostaglandins.It also has a transient effect on platelet aggregation, but unlike aspirin, does not appear to affectbleeding times.
Pharmacokinetics - MECLOFENAMIC ACID
Meclofenamic acid is reported to be well absorbed following oral administration, with measurable plasma levels being reached in 30 minutes and peak levels in 1-4 hours.In studies done with monkeys, highest meclofenamic acid levels were detected in the plasma, liver, and kidneys. Lower levels were detected in skeletal muscle, fat, spleen, heart, and brain. At plasmalevels of 1 micrograms/ml, the drug was 99.8% bound to albumin. It rapidly crosses the placenta, but it is unknown whether it is distributed into milk.
The plasma half-life has been reported to range from 1-8 hours in horses. Therapeutic efficacydoes not seem to be closely related with blood levels, however, as the onset of action may take 36-96 hours and significant efficacy may be seen for days following a dose.
Meclofenamic acid is metabolized in the liver primarily by oxidation to an active hydroxymethylmetabolite which may be further oxidized to an inactive metabolite (carboxyl). In humans, meclofenamic acid and its metabolites are then excreted by the kidneys (approx. 70% within 7days) or eliminated with the feces (20-30%). In horses, meclofenamic acid can be detected in theurine for at least 96 hours following the final dose.
Uses, Indications
Meclofenamic acid is used clinically in dogs for the symptomatic relief ofsymptoms associated with chronic inflammatory disease of the musculoskeletal system; often in anattempt to improve mobility in animals with hip dysplasia or chronic osteoarthritis.In horses, it is indicated for the "oral treatment of acute or chronic inflammatory diseases involving the musculoskeletal system..." (Package Insert; Arquel®¯Parke-Davis). Meclofenamicacid has also been used for the treatment of laminitis, with varying degrees of success.
Contraindications/Precautions - The manufacturer states that meclofenamic acid is contraindicated in animals with "active gastrointestinal, hepatic or renal diseases" (Package Insert;
Arquel®¯Parke-Davis). Additionally, meclofenamic acid is contraindicated in patients demonstrating previous hypersensitivity reactions to it or salicylates. It is relatively contraindicated inpatients with active or historical hemorrhagic disorders, or bronchospastic disease. Becausemeclofenamic acid is highly bound to plasma proteins, patients with hypoproteinemia may requirelower dosages to prevent symptoms of toxicity.
Meclofenamic acid has been shown to delay parturition in some species and therefore should beavoided during the last stages of pregnancy. It has caused teratogenic effects (minor skeletal abnormalities, delayed ossification) in rodents. Some preliminary studies have shown no effects withregard to either mare or stallion reproductive performance and no gross defects were seen in foalsborn to mares who received meclofenamic acid during pregnancy. It should, nevertheless, be used inpregnancy only when the potential benefits outweigh the potential risks of therapy.
Adverse Effects, Warnings
Adverse reactions are reported to be fairly uncommon in horses.However, hematologic changes (decreased hematocrit/PCV) and GI effects (buccal erosions, diarrhea, colic, anorexia, changes in stool consistency) have been reported. The diarrheal and colicreactions may be more likely in horses that have a heavy infestation of bots (Gasterophilus sp.)
With chronic therapy, decreases in plasma protein concentrations may occur.
In dogs, vomiting, decreased hemoglobin, leukocytosis, tarry stools, and small intestinal ulcershave all been reported following therapy at usual effective doses. Clients should be counseled withregard to these potential adverse effects and instructed to monitor their animal carefully forsymptoms associated with them.
In humans, NSAIDs have caused hepatotoxicity and it is recommended that human patients receiving chronic meclofenamate sodium therapy undergo occasional liver function tests. Although itdoes not appear that this adverse reaction is of major concern in either dogs or horses, the potentialfor hepatotoxicity does exist.
Overdosage - There is very limited information regarding acute overdoses of this drug in humansand no information was located regarding overdoses in domestic animals. Following an acute, massive overdose in humans, generalized CNS stimulation initially occurs, with seizures possible.
After this initial phase, acute renal failure may occur with secondary azotemia and anuria.
Treatment should follow standard overdose procedures (empty gut following oral ingestion, etc.).
Supportive treatment should be instituted as necessary and IV diazepam used to help controlseizures. Because meclofenamic acid may cause renal effects, monitor electrolyte and fluid balancecarefully and manage renal failure using established guidelines.
Drug Interactions
Because meclofenamic acid is highly bound to plasma proteins and maydisplace other highly bound drugs, increased serum levels and duration of actions of phenytoin, valproic acid, oral anticoagulants, other anti-inflammatory agents, salicylates, sulfonamides, and the sulfonylurea antidiabetic agents can occur. If meclofenamic acid is used concurrently with warfarin, enhanced hypoprothrombinemic effects may transpire.When aspirin is used concurrently with meclofenamic acid, plasma levels of meclofenamic acidmay decrease as well as a likelihood of increased GI adverse effects (blood loss) developing.
Concomitant administration of aspirin with meclofenamic acid is not recommended.