Ketoprofen

Overview

Ketoprofen (Ketofen®) is a nonsteroidal anti-inflammatory drug (NSAID) used in dogs and cats for its anti-inflammatory, analgesic, and antipyretic effects.

It is used for the relief of acute pain associated with musculoskeletal and other painful disorders in dogs and cats. In dogs, it may also be used for the management of chronic pain associated with osteoarthritis.

Mechanism of Action (MOA): Ketoprofen is a nonselective, reversible inhibitor of cyclooxygenase, blocking both COX-1 and COX-2 and so reducing the synthesis of prostaglandins in tissues. It has also been reported to inhibit the lipoxygenase pathway, with effects on both the vascular and cellular phases of inflammation, although the evidence for this action is weak. These actions contribute to its anti-inflammatory, analgesic, and antipyretic properties.

Indications

Ketoprofen is used in dogs and cats for the management of pain and inflammation associated with acute musculoskeletal and other painful conditions. In dogs, it may also be used for the management of chronic pain associated with osteoarthritis.

• Acute pain relief: Management of pain associated with musculoskeletal disorders and other painful conditions in dogs and cats.
• Anti-inflammatory therapy: Reduction of inflammation associated with acute painful disorders.
• Chronic osteoarthritis pain (dogs): Management of chronic pain associated with osteoarthritis.

Dosage (Reference)

Dog

Ketoprofen may be used for the management of acute pain and inflammation or for chronic osteoarthritis-associated pain. Duration of therapy depends on the clinical condition and route of administration.

Cat

Accurate dosing is important in cats. Ketoprofen may be used for acute pain management and, at lower oral doses, for chronic pain control.

Warnings & Precautions

Ketoprofen is a nonselective NSAID with anti-inflammatory, analgesic, and antipyretic properties. Careful patient selection and monitoring are important to reduce the risk of adverse effects, particularly during repeated administration.

• Perioperative use: Do not administer before surgery. Treatment should be delayed until the patient has fully recovered from anesthesia and is normotensive.
• Renal disease: Use should be carefully evaluated in patients with renal disease due to the potential for NSAID-associated renal adverse effects.
• Hepatic disease: Liver dysfunction may prolong drug metabolism, increasing the risk of accumulation and overdose with repeated dosing.
• Accurate dosing in cats: Careful dose calculation is essential to minimize the risk of toxicity and adverse effects.
• Hydration and blood pressure status: Avoid use in dehydrated, hypovolaemic, or hypotensive patients.
• Gastrointestinal disease: Do not use in patients with pre-existing gastrointestinal disease because NSAIDs may increase the risk of gastrointestinal adverse effects.
• Coagulation disorders: Avoid use in animals with blood clotting abnormalities.
• Pregnancy and young animals: Contraindicated in pregnant animals and animals less than 6 weeks of age; some references restrict the contraindication to late pregnancy, when prostaglandin inhibition may close the ductus arteriosus, and otherwise advise that it should be used when the maternal benefits outweigh the potential risks to the offspring.
• Hypersensitivity: Contraindicated in animals known to be hypersensitive to ketoprofen.
• Cardiac disease: Renal, cardiovascular or hepatic dysfunction requires careful benefit-risk assessment; some current product labels contraindicate ketoprofen in animals with these diseases.
• Hypoproteinemia: Use with caution in hypoproteinemic patients.
• Aged animals: Use in aged animals may involve additional risk; a reduced dose and careful clinical management may be required.
• Masking of infection: Ketoprofen may mask the clinical signs of infection, including inflammation and pyrexia.
• NSAID wash-out period: Allow a 3 to 5 day wash-out period before starting another NSAID after stopping ketoprofen.
• Injection technique: Avoid intra-arterial and perivenous injection, and do not mix ketoprofen with other substances in the same syringe.
• Lactation: Ketoprofen enters canine milk; use with caution in nursing animals, and avoid use late in pregnancy.

Drug Interactions

The following interactions have been reported or are considered theoretically significant in patients receiving ketoprofen. Concurrent use may increase the risk of adverse effects and may require additional monitoring.

• ACE inhibitors (e.g., benazepril, enalapril): May increase the risk of renal dysfunction and may reduce blood pressure control.
• Aminoglycosides (e.g., gentamicin, amikacin): May increase the risk of nephrotoxicity.
• Angiotensin II receptor blockers (e.g., telmisartan): May increase the risk of renal dysfunction and may reduce blood pressure control.
• Anticoagulants (e.g., heparin, enoxaparin, warfarin): May increase the risk of bleeding; some current product labels prohibit concurrent administration.
• Aspirin: May increase the risk of gastrointestinal adverse effects and bleeding.
• Corticosteroids (e.g., dexamethasone, prednisolone): May significantly increase the risk of gastrointestinal, platelet, and renal adverse effects, particularly in dogs.
• Other NSAIDs (e.g., carprofen, meloxicam, robenacoxib): Do not give another NSAID concurrently or within 24 hours; combined use significantly increases the risk of NSAID-related adverse effects.
• Beta-blockers (e.g., atenolol, propranolol): May increase blood pressure.
• Bisphosphonates (e.g., alendronate): May increase the risk of gastrointestinal ulceration.
• Clopidogrel: May increase the risk of bleeding.
• Cyclosporine: May increase the risk of nephrotoxicity.
• Desmopressin: May increase the risk of hyponatremia.
• Digoxin: May increase serum digoxin concentration and prolong its half-life.
• Diuretics (e.g., furosemide, spironolactone): May increase the risk of renal toxicity and reduce diuretic efficacy; some current product labels prohibit concurrent administration.
• Highly protein-bound drugs: Ketoprofen is highly protein bound and may transiently displace other highly protein-bound drugs such as phenytoin, oral anticoagulants, sulfonamides and sulfonylureas, although this is unlikely to be of clinical concern because free drug concentrations equilibrate through increased clearance.
• Methotrexate: Use together with extreme caution – severe toxicity has occurred in humans when NSAIDs and methotrexate were used concurrently.
• Probenecid: Reduces ketoprofen clearance and decreases its protein binding, significantly increasing ketoprofen serum concentrations and half-life; concurrent use is not recommended.
• SSRIs (e.g., fluoxetine, paroxetine, sertraline): May increase the risk of bleeding.
• Trazodone: May increase the risk of bleeding.
• Tricyclic antidepressants (e.g., amitriptyline, clomipramine): May increase the risk of bleeding.

Side Effects & Overdose

Side Effects

Gastrointestinal adverse effects may occur following ketoprofen administration. Some animals may develop adverse effects with one NSAID but not with another.

• Gastrointestinal signs: Vomiting is the most common adverse effect; diarrhea and other gastrointestinal disturbances may also occur, and these signs disappear rapidly when treatment is stopped. Therapy should be discontinued if signs persist beyond 1–2 days.
• Gastrointestinal bleeding: Treatment should be stopped immediately if gastrointestinal bleeding is suspected.
• Cardiac effects: NSAIDs have been associated with a small risk of precipitating cardiac failure in humans; the significance of this risk in animals is unknown.
• Anorexia and ulceration: Reported adverse effects include gastric mucosal damage and gastrointestinal ulceration, renal crest necrosis, hepatitis, vomiting and anorexia.
• Platelet function and surgical bleeding: Perioperative use in dogs can decrease platelet aggregation, although its clinical significance may be limited; bleeding problems may occur when ketoprofen is given before or after surgery.
• Renal effects and dose dependence: Reduced creatinine clearance has been reported in healthy dogs given 2 mg/kg orally daily for 10 days; reducing the regimen to 1 mg/kg subcutaneously followed by 0.25 mg/kg orally daily eliminated the renal effects and reduced gastrointestinal bleeding during long-term administration.
• Prolonged oral dosing in dogs: Dogs given 0.25 mg/kg daily for 30 consecutive days developed pyloric lesions and fecal occult blood.
• Age dependence in cats: In cats given 2 mg/kg subcutaneously daily for 3 days, fewer gastrointestinal effects were seen in cats under 3 months of age than in cats over 6 months, suggesting the effects may be age dependent.
• Injection-site reactions: Slight transient swelling or local edema is occasionally seen after subcutaneous or intramuscular injection.

Overdose

Repeated administration in patients with impaired hepatic function may increase the risk of drug accumulation and overdose due to prolonged metabolism.

• Drug accumulation: Liver disease may delay ketoprofen metabolism, increasing the potential for accumulation with repeated dosing.
• Increased toxicity risk: Inaccurate dosing, particularly in cats, may increase the risk of overdose and adverse effects.
• Reported toxicity thresholds: The oral LD50 in dogs has been reported as 2000 mg/kg, but exposures as low as 0.44 mg/kg have caused gastrointestinal ulcers in dogs, and cats have developed renal toxicity at doses as low as 0.7 mg/kg.
• Management: Decontamination with emetics and/or activated charcoal is appropriate; gastrointestinal protectants such as omeprazole, famotidine or sucralfate can be considered, and fluid diuresis is warranted if renal effects are suspected.
• Poison consultation: For a known or suspected overdose, consult a 24-hour poison consultation service specializing in veterinary-specific information.
• Tested tolerance margins: Reported tolerance and toxicity figures differ markedly by source and by product: the 1% injectable is reported to be well tolerated in dogs and cats at twice the recommended dose, and the tablets at three times the 1 mg/kg dose in both species and, in dogs, at five times the 0.25 mg/kg chronic dose for up to 90 days – while gastrointestinal ulceration has been reported in dogs at exposures as low as 0.44 mg/kg and renal toxicity in cats at doses as low as 0.7 mg/kg.

Key Notes

Practical points to consider when using ketoprofen in dogs and cats:

• Dual pathway inhibition: In addition to cyclooxygenase inhibition, ketoprofen has been reported to inhibit the lipoxygenase pathway, although the evidence for this action is weak.
• Multiple therapeutic effects: Ketoprofen provides anti-inflammatory, analgesic, and antipyretic effects.
• Acute and chronic use: Dosing protocols differ between acute pain management and long-term treatment of chronic pain.
• Half-life and duration of action: The active S-isomer has a half-life of about 3.5 hours in dogs and 1.5 hours in cats; despite that short half-life the duration of action may reach 24 hours, and elimination is more rapid in the cat than in the dog.
• Oral absorption: In dogs, ketoprofen is rapidly and almost completely absorbed after oral administration, but food or milk decreases oral absorption.
• Protein binding: Ketoprofen is highly protein bound – the 99% figure is reported in humans – and may transiently displace other highly protein-bound drugs, although this is unlikely to be clinically important because free drug concentrations equilibrate through increased clearance.
• Monitoring: Monitor the response – level of analgesia, reduced inflammation and resolution of pyrexia – and watch for vomiting, diarrhea, decreased appetite, hematemesis, hematochezia and melena. Take a baseline physical examination, CBC, serum chemistry panel including renal and liver parameters and urinalysis, consider fecal occult blood testing where appropriate, and repeat after the first few weeks and periodically during long-term use; monitor renal function during chronic treatment.
• Laboratory interferences: Ketoprofen can interfere with laboratory assays: it may falsely raise blood glucose measured by the glucose oxidase and peroxidase method using ABTS as a chromogen and serum bilirubin measured with DMSO as a reagent, and may falsely raise serum iron measured by the Ramsey method or falsely lower it when bathophenanthroline disulfonate is used.
• Antipyretic use: In dogs and cats ketoprofen has been shown to be effective for treating pyrexia.
• Licensing and availability: Ketoprofen is not approved for dogs or cats in the United States, where approved NSAIDs are available and its extra-label use is not recommended; it is licensed for dogs and cats in the United Kingdom and other countries. Human over-the-counter ketoprofen is available in the United States and those forms have been given to dogs and cats.
• Storage: Requirements are product-specific: the 100 mg/mL injection is stored below 25 °C, with brief excursions permitted between 0 °C and 40 °C, and used within 4 months of first vial puncture. Store oral products in tight, light-resistant containers at room temperature; the stability of compounded oral formulations has not been evaluated.