NAPROXEN
Chemistry - Naproxen is a propionic acid derivative, and has similar structure and pharmacologicprofiles as ibuprofen and ketoprofen. It is a white to off-white crystalline powder with an apparentpKa of 4.15. It is practically insoluble in water and freely soluble in alcohol. The sodium salt is alsoavailable commercially for human use.
In dogs, absorption after oral dosing is rapid and bioavailability is between 68-100%. The drug ishighly bound to plasma proteins. The average half-life in dogs is very long at 74 hours.
In humans, naproxen is highly bound to plasma proteins (99%). It crosses the placenta and entersmilk at levels of about 1% of those in serum.
Uses, Indications - The manufacturer lists the following indications: ".... for the relief of inflammation and associated pain and lameness exhibited with myositis and other soft tissue diseases ofthe musculoskeletal system of the horse." (Package Insert; Equiproxen®¯Syntex). It has alsobeen used as an antiinflammatory/analgesic in dogs for the treatment of osteoarthritis and othermusculoskeletal inflammatory diseases (see adverse reactions below).
Contraindications/Precautions - Naproxen is relatively contraindicated in patients with a historyof, or preexisting hematologic, renal or hepatic disease. It is contraindicated in patients with active
GI ulcers or with a history of hypersensitivity to the drug. It should be used cautiously in patientswith a history of GI ulcers, or heart failure (may cause fluid retention). Animals suffering frominflammation secondary to concomitant infection, should receive appropriate antimicrobial therapy.
In studies in rodents and in limited studies in horses, no evidence of teratogenicity or adverseeffects in breeding performance have been detected following the use of naproxen. However, thepotential benefits of therapy must be weighed against the potential risks of its use in pregnant animals.
Reports of GI ulcers and perforation associated with naproxen has occurred in dogs. Dogs mayalso be overly sensitive to the adverse renal effects (nephritis/nephrotic syndrome) and hepatic(increased liver enzymes) effects with naproxen. Because of the apparent very narrow therapeuticindex and the seriousness of the potential adverse reactions that can be seen in dogs, manyclinicians feel that the drug should not be used in this species.
Overdosage - There is very limited information regarding acute overdoses of this drug in humansand domestic animals. The reported oral LD50 in dogs is >1000 mg/kg. Treatment should followstandard overdose procedures (empty gut following oral ingestion, etc.). Animal studies havedemonstrated that activated charcoal may bind significant amounts of naproxen. Supportivetreatment should be instituted as necessary. Because naproxen may cause renal effects, monitorelectrolyte and fluid balance carefully and manage renal failure using established guidelines.
One report of a dog who received 5.6 mg/kg for 7 days has been published (Gilmour and Walshaw 1987). The dog presented with symptoms of melena, vomiting, depression, regenerativeanemia, and pale mucous membranes. Laboratory indices of note included, neutrophilia with a leftshift, BUN of 66 mg/dl, serum creatinine of 2.1 mg/dl, serum protein:albumin of 4.0:2.1 g/dls. Thedog recovered following treatment with fluids/blood, antibiotics, vitamin/iron supplementation, oralantacids and cimetidine.
When aspirin is used concurrently with naproxen, plasma levels of naproxen may decrease aswell as an increased likelihood of GI adverse effects (blood loss) developing. Concomitant administration of aspirin with naproxen is not recommended.
Probenicid may cause a significant increase in serum levels and half-life of naproxen.
Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate;use together with extreme caution.
Naproxen may reduce the saluretic and diuretic effects of furosemide. Use with caution in patients with severe cardiac failure.
Storage, Stability, Compatibility
Naproxen should be stored in well-closed, light resistant containers and stored at room temperature. Temperatures above 40° C (104°F) should be avoided.Pharmacology - NAPROXEN
Like other NSAIDs, naproxen exhibits analgesic, anti-inflammatory, and antipyrexic activity probably through its inhibition of cyclooxygenase with resultant impediment ofprostaglandin synthesis.Pharmacokinetics - NAPROXEN
In horses, the drug is reported to have a 50% bioavailability after oral dosingand a half-life of approximately 4 hours. Absorption does not appear to be altered by the presenceof food. It may take 5-7 days to see a beneficial response after starting treatment. Following a dose, the drug is metabolized in the liver. It is detectable in the urine for at least 48 hours in the horseafter an oral dose.In dogs, absorption after oral dosing is rapid and bioavailability is between 68-100%. The drug ishighly bound to plasma proteins. The average half-life in dogs is very long at 74 hours.
In humans, naproxen is highly bound to plasma proteins (99%). It crosses the placenta and entersmilk at levels of about 1% of those in serum.
Uses, Indications - The manufacturer lists the following indications: ".... for the relief of inflammation and associated pain and lameness exhibited with myositis and other soft tissue diseases ofthe musculoskeletal system of the horse." (Package Insert; Equiproxen®¯Syntex). It has alsobeen used as an antiinflammatory/analgesic in dogs for the treatment of osteoarthritis and othermusculoskeletal inflammatory diseases (see adverse reactions below).
Contraindications/Precautions - Naproxen is relatively contraindicated in patients with a historyof, or preexisting hematologic, renal or hepatic disease. It is contraindicated in patients with active
GI ulcers or with a history of hypersensitivity to the drug. It should be used cautiously in patientswith a history of GI ulcers, or heart failure (may cause fluid retention). Animals suffering frominflammation secondary to concomitant infection, should receive appropriate antimicrobial therapy.
In studies in rodents and in limited studies in horses, no evidence of teratogenicity or adverseeffects in breeding performance have been detected following the use of naproxen. However, thepotential benefits of therapy must be weighed against the potential risks of its use in pregnant animals.
Adverse Effects, Warnings
Adverse effects are apparently uncommon in horses. The possibilityexists for GI (distress, diarrhea, ulcers), hematologic (hypoproteinemia, decreased hematocrit), renal(fluid retention) and CNS (neuropathies) effects.Reports of GI ulcers and perforation associated with naproxen has occurred in dogs. Dogs mayalso be overly sensitive to the adverse renal effects (nephritis/nephrotic syndrome) and hepatic(increased liver enzymes) effects with naproxen. Because of the apparent very narrow therapeuticindex and the seriousness of the potential adverse reactions that can be seen in dogs, manyclinicians feel that the drug should not be used in this species.
Overdosage - There is very limited information regarding acute overdoses of this drug in humansand domestic animals. The reported oral LD50 in dogs is >1000 mg/kg. Treatment should followstandard overdose procedures (empty gut following oral ingestion, etc.). Animal studies havedemonstrated that activated charcoal may bind significant amounts of naproxen. Supportivetreatment should be instituted as necessary. Because naproxen may cause renal effects, monitorelectrolyte and fluid balance carefully and manage renal failure using established guidelines.
One report of a dog who received 5.6 mg/kg for 7 days has been published (Gilmour and Walshaw 1987). The dog presented with symptoms of melena, vomiting, depression, regenerativeanemia, and pale mucous membranes. Laboratory indices of note included, neutrophilia with a leftshift, BUN of 66 mg/dl, serum creatinine of 2.1 mg/dl, serum protein:albumin of 4.0:2.1 g/dls. Thedog recovered following treatment with fluids/blood, antibiotics, vitamin/iron supplementation, oralantacids and cimetidine.
Drug Interactions
Because naproxen is highly bound to plasma proteins and may displace otherhighly bound drugs, increased serum levels and duration of actions of phenytoin, valproic acid, oral anticoagulants, other anti-inflammatory agents, salicylates, sulfonamides, and thesulfonylurea antidiabetic agents can occur. If naproxen is used concurrently with warfarin, enhanced hypoprothrombinemic effects have not been noted, but because of the tendency ofnaproxen to induce GI bleeding it should be used cautiously in patients on warfarin therapy.When aspirin is used concurrently with naproxen, plasma levels of naproxen may decrease aswell as an increased likelihood of GI adverse effects (blood loss) developing. Concomitant administration of aspirin with naproxen is not recommended.
Probenicid may cause a significant increase in serum levels and half-life of naproxen.
Serious toxicity has occurred when NSAIDs have been used concomitantly with methotrexate;use together with extreme caution.
Naproxen may reduce the saluretic and diuretic effects of furosemide. Use with caution in patients with severe cardiac failure.