Elephant specific information, if available, is in blue.

Chemistry – A propionic acid derivative nonsteroidal anti-inflammatory agent, ketoprofen occurs as an off white to white, fine to granular powder. It is practically insoluble in water, but freely soluble in alcohol at 20°C. Ketoprofen has a pKa of 5.9 in a 3:1 methanol:water solution.

 

Storage/Stability/Compatibility – Ketoprofen oral capsules should be stored at room temperature in tight, light resistant containers. The veterinary injection should be stored at room temperature. Compatibility studies with injectable ketoprofen and other compounds have apparently not been published.

 

Pharmacology – Ketoprofen exhibits actions similar to that of other nonsteroidal antiin­flammatory agents in that it possesses antipyretic, analgesic and antiinflammatory activity. Its purported mechanism of action is the inhibition of cyclooxygenase catalysis of arachidonic acid to prostaglandin precursors (endoperoxides), thereby inhibiting the synthesis of prostaglandins in tissues. Ketoprofen purportedly has inhibitory activity on lipoxygenase, whereas flunixin reportedly does not at therapeutic doses.

 

Uses/Indications – Ketoprofen is labeled for use in horses for the alleviation of inflamma­tion and pain associated with musculoskeletal disorders. Like flunixin (and other NSAIDs), ketoprofen potentially has many other uses in a variety of species and condi­tions; however well controlled studies for these uses are generally unavailable.

 

Pharmacokinetics – In species studied (rats, dog, man), ketoprofen is rapidly and nearly completely absorbed after oral administration. The presence of food or milk decreases oral absorption. Oral absorption characteristics in horses was not located. It has been reported that when comparing IV vs. IM injections in horses, the areas under the curve are rela­tively equivalent.

 

While distribution characteristics are not well described, the drug does enter synovial fluid and is highly bound to plasma proteins (99% in humans, and approximately 93% in horses). In horses, the manufacturer reports that the onset of activity is within 2 hours and peak effects 12 hours post dose.

 

Ketoprofen is eliminated via the kidneys both as a conjugated metabolite and unchanged drug. The elimination half life in horses is approximately 1.5 hours.

 

Contraindications/Precautions/Reproductive Safety – While the manufacturer states that there are no contraindications to the drug’s use (other than previous hypersensitivity to ketoprofen), it should be used only when the potential benefits outweigh the risks in cases where GI ulceration or bleeding is evident or in patients with significant renal or hepatic impairment. Ketoprofen may mask the signs and symptoms (inflammation, hyper­pyrexia) of infection. Because ketoprofen is highly protein bound, patients with hypopro­teinemia may have increased levels of free drug, thereby increasing the risks for toxicity.

 

The manufacturer cautions against ketoprofen’s use in breeding animals, because effects on fertility, pregnancy or fetal health have not been established in horses. However, rat and mice studies have not demonstrated increased teratogenicity or embryotoxicity. Rabbits receiving twice the human dose exhibited increased embryotoxicity, but not ter­atogenicity. Because non-steroidal antiinflammatory agents inhibit prostaglandin synthe­sis, adversely affecting neonatal cardiovascular systems (premature closure of patent duc­tus), ketoprofen should not be used late in pregnancy. Studies in male rats demonstrated no changes in fertility.

 

It is presently unknown whether ketoprofen enters equine milk. Ketoprofen does enter canine milk.

 

Adverse Effects/Warnings – Because ketoprofen is a relatively new agent, its adverse ef­fect profile in horses has not been clearly elucidated. Preliminary studies and reports indi­cate that ketoprofen appears relatively safe to use in horses and may have a lower inci­dence of adverse effects than either phenylbutazone or flunixin. Potentially, gastric mu­cosal damage and GI ulceration, renal crest necrosis, and mild hepatitis may occur.

 

Do not administer intra-arterially and avoid SubQ injections. While not labeled for IM use in horses, it reportedly is effective and may only cause occasional inflammation at the injection site.

 

Overdosage/Acute Toxicity – Horses given ketoprofen at doses up to 11 mg/kg adminis­tered IV once daily for 15 days exhibited no signs of toxicity. Severe laminitis was ob­served in a horse given 33 mg/kg/day (15X over labeled dosage) for 5 days. Anorexia, depression, icterus, and abdominal swelling was noted in horses given 55 mg/kg/day (25X labeled dose) for 5 days. Upon necropsy, gastritis, nephritis and hepatitis were diagnosed in this group.

 

Humans have survived oral ingestions of up to 5 grams. The LD50 in dogs after oral in­gestion has been reported to be 2000 mg/kg. General drug removal and supportive mea­sures have been recommended in cases of oral overdosage.

 

Drug Interactions – Because ketoprofen is highly bound to plasma proteins, it can dis­place or be displaced by other highly protein bound drugs, including warfarin, phenylbutazone, etc.  Because ketoprofen may inhibit platelet aggregation and also cause gastrointestinal ul­ceration, when used with other drugs that alter hemostasis (e.g., heparin, warfarin, etc.) and/or cause gastrointestinal erosion (e.g., aspirin, flunixin, phenylbutazone, corticos­teroids, etc.), increased likelihood of bleeding or ulceration may occur. Ketoprofen and probenecid are not recommended to be used together. Probenecid re­duces renal clearance of ketoprofen and also reduces its protein binding; thereby increas­ing the risk of toxicity. NSAIDs (including ketoprofen) may potentially significantly reduce the excretion of methotrexate and cause toxicity.

 

Laboratory Considerations – Ketoprofen may cause falsely elevated blood glucose val­ues when using the glucose oxidase and peroxidase method using ABTS as a chromogen; falsely elevated serum bilirubin values when using DMSO as a reagent; falsely elevated serum iron concentrations using the Ramsey method, or falsely decreased serum iron concentrations when using bathophenanthroline disulfonate as a reagent.

 

Doses –

Horses:

For labeled indications: 2.2 mg/kg (1 ml/100 lbs) IV once daily for up to 5 days. (Package insert – Ketofen®)

 

Elephants:

a) 1 mg/kg every 48 hours to 2 mg/kg every 24 hours in Asian elephants (Hunter et.al. 2003).

 

Elephant references:

a) Hunter,R.P., Isaza,R., and Koch,D.E. 2003. Oral bioavailability and pharmacokinetic characteristics of ketoprofen enantiomers after oral and intravenous administration in Asian elephants (Elephas maximus). Am J Vet Res 64:(1):109-114  Abstract: OBJECTIVE: To assess oral bioavailability (F) and pharmacokinetic characteristics of the R- and S-enantiomers of ketoprofen administered IV and orally to captive Asian elephants (Elephas maximus). ANIMALS: 5 adult Asian elephants. PROCEDURE: Elephants received single treatments of racemic ketoprofen at a dose of 2.2 mg/kg, administered IV and orally, in a complete crossover design. Blood samples were collected at intervals during the 24 hours following treatment. At least 4 weeks elapsed between drug administrations. Samples were analyzed for R- and S-ketoprofen with a validated liquid chromatography-mass spectroscopic assay. Pharmacokinetic parameters were determined by use of noncompartmental analysis. RESULTS: The enantiomers of ketoprofen were absorbed well after oral administration, with median F of 101% for R-ketoprofen and 85% for S-ketoprofen. Harmonic mean half-life ranged from 3.8 to 5.5 hours, depending on route of administration and enantiomer. The area under the concentration-time curve, mean residence time, apparent volume of distribution, plasma clearance, and maximum plasma concentration values were all significantly different between the 2 enantiomers for both routes of administration. CONCLUSIONS AND CLINICAL RELEVANCE: Ketoprofen has a long terminal half-life and complete absorption in this species. Based on the pharmacokinetic data, a dosage of ketoprofen of 1 mg/kg every 48 hours to 2 mg/kg every 24 hours, PO or IV, is recommended for use in Asian elephants, although the safety and efficacy of ketoprofen during long-term administration in elephants have not been determined.

Monitoring Parameters – 1) Efficacy; 2) Adverse Effects (in humans, occasional liver function tests are recommended with long term therapy)

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products:

Ketoprofen Injection 100 mg/ml in 50 ml and 100 ml multi-dose vials; Ketofen® (Fort Dodge); (Rx) Approved for use in horses not intended for food.

 

Human-Approved Products:

Ketoprofen Oral Capsules 25 mg, 50 mg, 75 mg;Orudis® (Wyeth-Ayerst), generic; (Rx)

Ketoprofen 12.5 mg Tablets Orudis KT® (Whitehall-Robins) (OTC);Actron Caplets® (Bayer) (OTC)

Ketoprofen Extended Release 100 mg, 150 mg, 200 mg Capsules Oruvail® (Wyeth-Ayerst) (Rx)