Carprofen (with special reference to Ruminants, Hedgehogs, Bears, Lagomorphs, Ferrets and Great Apes)

White, crystalline. (B263, J289.27S1.w1)

• Practically insoluble at 25°C. (B263, J289.27S1.w1)

• Freely soluble in ethanol at room temperature. (B263, J289.27S1.w1)

• Inhibits cyclo-oxygenase, phospholipase A₂ and prostaglandin synthesis. (B263)
  • Weak inhibitor of cyclo-oxygenase. (B201.10.w10, J35.152.w4)
• The mechanisms of action of carprofen are not clear. (J35.152.w3, J35.152.w4, J289.27S1.w1)
• At a dosage of 4 mg/kg in sheep, both racemic and S(+) carprofen effectively inhibited cyclooxygenase (COX) isoenzymes, suggesting that at this dose rate at least part of the effect of carprofen is via inhibition of COX. (J289.26.w2)
• Racemic carprofen at 4 mg/kg or S(+) enantiomer carprofen at 2 mg/kg was shown to be a potent inhibitor of cyclooxygenase in vivo in sheep. (J13.63.w1)
• Note: chiral inversion of the enantiomers of carprofen apparently does not occur in various species including humans, dogs, horses, cattle, rats and cats. (J289.20.w2, J289.27S1.w1)

• Store at room temperature (15-30°C). (B263)

Associated Techniques

• Analgesic, anti-inflammatory and antipyretic activity. (B263, J289.27S1.w1)
• Note: The S(+) enantiomer has considerably higher activity than the R(-) enantiomer, with a potency ration in various in vitro and in vivo tests of 3.8 to more than 24. (J289.20.w2)

• Inflammation, pain. (B201.10.w10, B263)
• May provide post-operative pain control comparative to that given by opioid analgesics. (B201.10.w10)
• In calf pneumonia to suppress pulmonary oedema. (B201.10.w10)
• In young cattle less than 12 months old "indicated as an adjunct therapy for the control of acute inflammation associated with respiratory disease." (B266)
• Unlike other NSAIDs, use during or prior to anaesthesia, or in individuals with pre-existing renal disease, is not contra-indicated. This drug is licensed for preoperative use. (B322.3.w3)

• Dog: oral administrated carprofen is about 90% bioavailable; peak serum levels at one to three hours after administration.
• Following administration of carprofen to lactating cows at 0.7 mg/kg intravenously daily for five days peak plasma concentrations, reached following the fifth injection, were about 45 µg/mL. (J171.131.w2)

• Dog: volume of distribution is low: 0.12-0.22 l/kg. (B263)

Cattle:

• Following administration to healthy cows at 0.7 mg/kg bodyweight t_1/2α was 1.81 +/- 0.36 h (mean +/- SEM) and the volume of distribution at steady state Vd_ss was 0.091 +/- 0.003 L/kg. In the same cows with endotoxin induced mastitis, t_1/2α was 1.01 +/- 0.16 h (mean +/- SEM) (significantly lower, P<0.05) and the volume of distribution at steady state Vd_ss was 0.086 +/- 0.004 L/kg. (J289.14.w2)
• Following administration to calves of eight to 10 weeks old at 0.7 mg/kg, the half-life of the distribution phase, t_1/2α  was 0.828+/- 0.264 h (mean +/-SEM); values for the R(-) and S(+) enantiomers were not significantly different from one another: 0.883 +/- 0.247 h and 0.742 +/- 0.261 h respectively. The volume of distribution (area method) Vd_(area) was 151.8 +/4.3 mL/kg for total carprofen and was significantly (P<0.01) lower for R(-) than for S(+) carprofen, with values of 144.8 +/- 4.8 mL/kg and 162.3 +/- 2.5 mL/kg respectively. Volume of distribution at steady state (Vd_ss) for total carprofen was 154.7 +/- 2.7 mL/kg and again was significantly (P<0.001) lower for R(-) than for S(+) carprofen with values of 147 +/- 3.4 mL/kg and 162.8 +/- 2.2 mL/kg respectively. (J35.152.w3)
• Following administration to calves of 16-17 weeks old at 0.7 mg/kg, the half-life of the distribution phase, t_1/2α was 0.546+-0.081 h (mean +/-SEM); values for the R(-) and S(+) enantiomers were not significantly different from one another: 0.624 +/- 0.089 h and 0.476 +/- 0.067 h respectively. The volume of distribution (area method) Vd(area) was 147.0 +/- 4.4 mL/kg for total carprofen and was significantly (P<0.01) lower for R(-) than for S(+) carprofen, with values of 136.2 +/- 2.9 mL/kg and 154.4 +/- 5.4 mL/kg respectively. Volume of distribution at steady state (Vd_ss) for total carprofen was 146.0 +/- 5.0 mL/kg and again was significantly (P<0.05) lower for R(-) than for S(+) carprofen with values of 140.2 +/- 4.2 mL/kg and 154.0 +/- 7.5 mL/kg respectively. In tissue cages, penetration into transudate was poor while penetration into exudate was good, for both enantiomers. (J35.152.w4)
• Following administration of carprofen to lactating cows at 0.7 mg/kg, the volume of distribution was 0.09 L/kg. (J171.131.w1)

Sheep:

• Following intravenous administration of racemic carprofen at either 0.7 mg/kg or 4.0 mg/kg to adult Suffolk cross sheep, the volume of distribution was small: Vd_(area) was found to be 95.5 +/- 5.95 mL/kg (mean +/- SEM) and 118.4 +/- 3.53 respectively with volume of distribution at steady state Vd(ss) 92.7 +/- 5.77 mL/kg and 117.3 +/- 3.31 mL/kg respectively. It was commented that this indicated carprofen is not widely distributed throughout the body, and is probably related to high plasma protein binding. (J21.53.w2)
• Following intravenous administration in sheep of 4 mg/kg racemate carprofen, the half-life of the distribution phase, t_1/2α was 0.36 +/- 0.10 h (mean +/- SD) for R(-) and 0.43 +/- 0.09 h for S(+) while the volume at steady state V_ss was 122.1 +-14.6 mL/kg and 128.7 +/- 18.7 respectively; after administration of the individual enantiomers at 2 mg/kg the half-life of the distribution phase, t_1/2α was 0.31 +/- 0.16 h (mean +/- SD) for R(-) and 0.56 +/- 0.61 h for S(+) while the volume at steady state V_ss was 117.9 +/- 10.5 mL/kg and 127.3 +/- 13.7 mL/kg respectively. (J289.26.w2)

• Dog: highly (99%) plasma protein-bound. (B263)

• Metabolised in the liver, mainly by glucuronidation and oxidative processes. (B263)
• About 70-80% eliminated in faeces. (B263)
• About 10-20% eliminated in urine. (B263)
• Some enterohepatic recycling. (B263)
• Mainly eliminated by biotransformation in dogs, horses, rats and sheep, with both enantiomers converted to glucuronide metabolites. (J289.27S1.w1)

Cattle:

• In milk: Following administration to healthy cows or cows with endotoxin-induced mastitis at 0.7 mg/kg bodyweight, concentrations in milk of healthy cows was below the detection limit of the assay used (i.e. below 0.022 µg/mL milk) but concentrations in milk from the inflamed mastitic quarters were increased, up to 0.164 +/- 0.024 µg/mL, in the first 12 hours after induction of mastitis but were still lower than in plasma. Concentrations were reduced back to below 0.022 µg/mL milk at 24 to 48 hours. It was suggested that the increased concentration in mastitic milk may be due to damage to the blood/milk barrier. (J289.14.w2)
• In milk. Following administration of carprofen to lactating cows at 0.7 mg/kg daily for five days the concentration in milk was generally less than the sensitivity limit of the test used (25 ng/mL) and rarely reached 30 ng/mL in a few samples collected after the fourth or fifth injection. The data was considered to indicate poor excretion into milk. (J171.131.w1)

• Dog: approximately 13-18 hours (the S enantiomer has a longer half life than the R enantiomer). (B263)
• Horse: reported to be 22 hours. (B263)
• Human: 12 hours. (B135)
• Horse: S(+) 15 hours; R (-) 32 hours. (B340.10.w10)
• Cattle: S(+) 37 hours; R (-) 50 hours. (B340.10.w10)
• Dog: mixed drug 8-15 hours. (B340.10.w10)
• Cat: S(+) 15 hours; R (-) 20 hours. (B340.10.w10)

Cattle:

• Following administration to healthy cows at 0.7 mg/kg bodyweight there was a long elimination half-life (30.7 +/- 2.3 h) and a relatively low systemic clearance of 2.4 +/- 0.16 mL/h kg. In the same cows with endotoxin-induced mastitis, the elimination half life was significantly (P<0.01) longer at 43.0 +/- 2.3 h and the clearance was significantly lower (P<0.01) at 1.4 +/- 0.13mL/h kg. (J289.14.w2)
• Following administration to calves of eight to 10 weeks old at 0.7 mg/kg, the half-life of the elimination phase, t_{1/2 β}  was 43.4 +/- 2.3 h (mean +/-SEM); values for the R(-) and S(+) enantiomers were significantly (P<0.01) different from one another: 49.8 +/- 3.9 h and 37.4 +/- 2.4 h respectively. Clearance for total carprofen was 2.492 +/- 0.171 mL/h/kg and clearance was significantly (P<0.001) lower for R(-) than for S(+) with values of 2.073 +/- 0.145 mL/h/kg and 3.075 +/- 0.221 mL/h/kg respectively. (J35.152.w3)
• Following administration to calves of 16-17 weeks old at 0.7 mg/kg, the half-life of the elimination phase, t_1/2β  was 33.8 +/- 1,7 h (mean +/-SEM); values for the R(-) and S(+) enantiomers were significantly (P<0.01) different from one another: 37.7 +/- 1.8 h and 29.1 +/- 1.6 h respectively. Clearance for total carprofen was 2.984 +/- 0.094 mL/h/kg and clearance was significantly (P<0.001) lower for R(-) than for S(+) with values of 2.524 +/- 0.098 mL/h/kg and 3.696 +/- 0.113 mL/h/kg respectively. (J35.152.w4)
• Following repeated administration of carprofen to lactating cows at 0.7 mg/kg daily for five days, the elimination half life was in the range 44.5 to 64.6 h. Clearance after a single injection was 9.0 mL/min. (J171.131.w1)

Sheep: 

• Following intravenous administration of racemic carprofen at either 0.7 mg/kg or 4.0 mg/kg to adult Suffolk cross sheep, the elimination half-life t_1/2β was long at 26.1 h +/- 1.14 h (mean +/- SEM) and 33.7 h +/- 3.14 h respectively. Clearance Cl_b was slow: 2.5 +/- 0.1 mL/kg/h and 2.5 +/- 0.3 mL/kg/h respectively. Clearance in sheep may be slower than in other species. (J21.53.w2)
• Following intravenous administration in sheep of 4 mg/kg racemate carprofen or 2 mg/kg of either enantiomer, the drug was detectable in plasma consistently from five minutes to 144 hours after injection. After administration of the racemate the elimination half-life t_1/2β was 66.36 +/- 21.81 h (mean +/- SD) for R(-) and 24.17 +/- 5.98 for S(+); after administration of the individual enantiomers t_1/2β was 58.75 +/- 11.78 h and 25.09 +/- 5.50 for the R(-) and S(+) enantiomers respectively. After administration of the racemate, clearance CL_B was 1.42 +/- 0.36 mL/kg/h for R(-) and 4.00 +/- 1.22 mL/kg/h for S(+); after administration of the individual enantiomers clearance was 1.53 +/- 0.30 mL/kg/h for R(-) and 3.77 +/- 1.04 mL/kg/h for S(+). (J289.26.w2)

• May displace other drugs which are highly plasma protein-bound; could result in increased serum levels and duration of action for phenytoin, valproic acid, oral anticoagulants, other anti-inflammatory drugs, salicylates, sulfonamides, sulfonylurea antidiabetic agents. (B263)
• Use concurrently with aspirin may result in lowered plasma levels of carprofen and increased likelihood of gastro-intestinal effects with blood loss. (B263)
• Significant increase in both serum levels and half life of carprofen may be seen if probenecid is administered. (B263)
• Severe toxicity has been recorded with concurrent use of NSAIDs and methotrexate. (B263)
• May reduce the saluretic and diuretic effects of furosamide. (B263)
• May increase serum levels of digoxin. (B263)

• Rimadyl (Pfizer Limited). 
  • Rimadyl Granules: "White, free-flowing granules containing carprofen 8.75% w/w". (B266)
  • Rimadyl Small Animal Injection: "clear, sterile, mixed micelle solution for injection, containing 50 mg carprofen per ml (5% w/v) with Benzyl alcohol PhEur (1% w/v) as preservative." (B266)
  • Rimadyl Large Animal Solution: "clear, very pale straw coloured, sterile, aqueous solution for parenteral injection containing carprofen 5% w/v (50 mg/ml) with Ethanol PhEur 10% w/v as preservative." (B266)
  • Rimadyl Tablets: "round white tablets scored down the middle containing as active ingredient either 20 mg or 50 mg carprofen." (B266)

Note: preparations contain racemic mixture R and S enantiomers in 50:50 mix. (B340.10.w10, J289.27S1.w1)

Cattle:

• 1.4 mg/kg as a single dose, by subcutaneous or intravenous injection. (UK)(B340.10.w10)
• 1.4 mg/kg (Eire)(B201.10.w10)
• 1.4 mg/kg (1 mL of 5% w/v solution per 35 kg) subcutaneously or intravenously, administered once. (B266)

Experimental data:

• In cows with experimentally induced Escherichia coli endotoxin mastitis, treatment with a single dose of carprofen (0.7 mg/kg intravenously), given two hours after endotoxin administration, when the affected quarter was clearly swollen and body temperature was raised, significantly reduced clinical signs of mastitis including swelling of the quarter (p<0.01), rectal temperature (p<0.001), heart rate (P<0.01) and general depression (P<0.01). (J289.14.w2)
• In calves of eight to 10 weeks old, administration of carprofen at 0.7 mg/kg intravenously attenuated the temperature rise which occurred in response to injection of carrageenin or dextran, although the effects were not statistically significant at most sampling times; skin swelling due to these substances was attenuated by carprofen but the effect was not statistically significant. Carprofen also reduced ex vivo serum thromboxane B₂ synthesis but the effect was slight and was not significant at most sampling times. (J35.152.w3)
• In calves of 16 to17 weeks old, administration of carprofen at 0.7 mg/kg intravenously did not inhibit synthesis of prostaglandin PGE₂ in exudate in a tissue cage; 12-hydroxyeicosatetraenoic acid concentrations were reduced, indicting partial inhibition of 12-lipoxygenase, but this effect was generally not statistically significant. (J35.152.w4)
• Administration of carprofen to post-partum cows at 0.7 mg/kg intravenously daily for five days was considered to be well tolerated by all the cows. The drug significantly (P<0.05) reduced plasma levels of 15-keto-13,14-dihydro-prostaglandin F2 alpha (the primary metabolite of the prostaglandin PGF2α); levels were 28-47% of pre-treatment values, compared with levels of 64-101% of pre-treatment values in control cows. This effect was seen from immediately after administration of carprofen and was at its maximum at three to six hours after injection: 60-80% inhibition at this time after the first injection and 40-85% inhibition at this time after the fifth daily injection. It was considered that the data showed that a single dose of 0.7 mg/kg carprofen intravenously effectively suppresses release of PGF2αs in the post-partum cow. (J171.131.w2)

Sheep:

• 4 mg/kg subcutaneously for prolonged post-operative analgesia. (B217.69.w69)
• 1 mg/kg intravenously once pre-operatively before caesarean section. (Note: not licensed for use in sheep in the UK).[2000](J15.22.w2)
• 1.5-2.0 mg/kg by subcutaneous or intravenous injection once daily. (B322.5.w5)

Experimental data:

• Carprofen administered at 0.7 mg/kg 30 minutes prior to the application of a tourniquet in adult male neutered Suffolk-cross sheep attenuated the development of mechanical hyperalgesia seen after application of the tourniquet; thresholds to noxious mechanical stimulation were not significantly different from control values in sheep given carprofen, whereas they were significantly reduced at 10, 15 and 20 minutes after application of a tourniquet without any analgesic. (J21.57.w1)
• Carprofen at 0.7 mg/kg maintained plasma levels at or higher than 1.5 µg/mL (the level required to produce analgesia in the horse) for up to 48 hours. (J21.53.w2)
• At a dosage of 4 mg/kg racemic carprofen or 2 mg/kg S(+) carprofen in sheep, the maximum inhibitory effect on serum thromboxane (TXB₂) was greater than 99% and that on exudate prostaglandin (PGE₂) was greater than 95%. The S(+) carprofen concentrations producing 50% of the maximum inhibitory effects were, following injection of the racemate, 9.39+/- 2.24 (mean +/- SD) µg/mL for TXB₂ inhibition in serum and 1.76 +/- 1.08 µg/mL for inhibition of exudate PGE₂; following injection of the S(+) enantiomer alone the values were 13.29 +/- 7.67 µg/mL and 2.11 +/- 0.79 respectively. (J289.26.w2)
• Following intravenous administration of 4 mg/kg racemic carprofen or 2 mg/kg S(+) carprofen in sheep, serum thromboxane 2 (TXB₂) and exudate prostaglandin PGE₂ generation was significantly inhibited for 32 hours, with a 50 to 98% reversible inhibitory effect. Administration of R(-) carprofen at 2 mg/kg intravenously significantly attenuated serum TXB₂ generation but did not affect exudate PGE₂ production. (J13.63.w1)

Erinaceus europaeus - West European Hedgehog:

• 4 mg/kg by subcutaneous injection, once daily for three days. (J15.21.w1)
• 5-10 mg/kg once daily or twice daily, subcutaneous or oral. For analgesia and reducing inflammation; use generally restricted to three days of treatment. (B284.6.w6)
• 5mg/kg subcutaneously once daily. (D93)
• 4 mg/kg subcutaneously at 24-36 hour intervals. (D107)

Bears (Ursidae - Bears (Family)):

• For analgesia: 3.2 mg/kg subcutaneously as soon as the bear has been anaesthetised (for Cholecystectomy in Bears) and post-operatively 4.4 mg/kg orally once daily. (V.w89, V.w90)
• Has been used long-term by Animals Asia Foundation in some bears with severe arthritis, at 4.4 mg/kg orally daily, with apparent minimal untoward effect on the liver (no significant rise in liver enzymes after a year of daily treatment). (V.w90)

Lagomorphs - Oryctolagus cuniculus domesticus - Domestic rabbit:

• 1.5 mg/kg orally twice daily. (B373.Guide.w41)
• 2.0 - 4.0 mg/kg subcutaneously once daily. (B373.Guide.w41)
• 2.0 - 4.0 mg/kg subcutaneously once daily. (B600.4.w4, B601.15.w15)
• 1.5 mg/kg orally twice daily. (Mix tablets with jam, fruit juice or syrup). (B600.4.w4)
• 1.0 - 2.0 mg/kg orally every 12 hours. (B602.41.w41)
• 2.0 - 4.0 mg/kg orally or subcutaneously every 24 hours. (B603.5.w5)
• 1.5 mg/kg orally or 1 - 2 mg/kg subcutaneously or intravenously, every 24 hours. (B546)
• 1.0 - 2.2 mg/kg orally every 12 hours. (B548.w8)
• 1.5 mg/kg orally every 12 hours. (B548.w8)
• 2.2 mg/kg orally every 12 hours. (B548.w8)
• 2.0 - 4.0 mg/kg subcutaneously every 24 hours. (B548.w8)
• 4.0 mg/kg subcutaneously or intramuscularly every 24 hours. (B548.w8)

Ferrets - Mustela putorius furo - Ferret:

• 1 mg/kg orally every 12 - 24 hours. (B602.41.w41)
• (B626.App.w22)
• (B631.21.w21)

Great Apes

• Adult Pan troglodytes - Chimpanzee: 2 mg/kg orally twice daily. (W768.Jun2012.w1)
• Primates: 2 - 4 mg/kg orally twice daily. (D425.3.15.w3o)

• Monitor if on long-term treatment. (B201.10.w10)
• Prior to administration, particularly in geriatric dogs, those with chronic pre-existing disease and those in which prolonged treatment is likely, baseline data should be established (physical examination, haematology, biochemistry, urinalysis). (B263)
• Liver enzyme levels should be reassessed after one week of treatment, discontinuing therapy if these are raised from baselines, and for individuals on prolonged therapy, at intervals. (B263)
• Clinical efficacy should be monitored. (B263)
• Monitor for signs of adverse effects e.g. inappetance, diarrhoea, vomiting, melaena, polyuria/polydipsia, anaemia, jaundice, lethargy, behavioural changes, ataxia, seizures. (B263)

• "Slaughter 21 days; should not be used in cattle producing milk for human consumption." Data for Rimadyl Injection (Pfizer, Eire) and Zenecarp Solution (Cypharm, Eire) following subcutaneous or intravenous injection. (B201.10.w10)

UK: 

• "Cattle must not be slaughtered for human consumption during treatment or within 21 days of treatment with Rimadyl Large Animal Solution". (B266)
• "Not for use in cattle producing milk for human consumption." (B266)

• Contraindicated in individuals with a history of hypersensitivity to this drug or to other propionic-class NSAIDs. (B201.10.w10, B263)
• Contraindicated in dogs with bleeding disorders such as Von Willebrand's disease. (B263)
• Use with caution in individuals with pre-existing chronic disease such as inflammatory bowel disease, renal insufficiency or hepatic insufficiency. (B263)
• Contraindicated in individuals with cardiac, renal or hepatic disease. (B201.10.w10)
• Contraindicated in individuals in which there is a possibility of gastro-intestinal ulceration or bleeding. (B201.10.w10)
• Contraindicated as a treatment concurrent with (or within 24 hours of) other NSAIDs. (B201.10.w10)
• Horses: Contraindicated in racehorses prior to racing. (B201.10.w10)
• Contraindicated in pregnant animals. (B340.10.w10); contraindicated in pregnant horses. (B201.10.w10)
• Use with caution in pregnancy (may not have been fully evaluated for safety). (B201.10.w10)
• Use with caution in animals less than six weeks old, aged animals, individuals with dehydration, hypovolaemia or hypotension. (B340.10.w10, B201.10.w10)
• Avoid using concurrently with, or within 24 hours of, use of other NSAIDs. (B340.10.w10, B201.10.w10)
• Avoid using concurrently with potentially nephrotoxic drugs. (B340.10.w10, B201.10.w10)
• Not recommended for concomitant administration with aspirin (see drug interactions above). (B263)
• Rabbits: Use with care in hypotensive individuals. (B600.4.w4)

• Adverse effects are uncommon. (B263)
• Mild gastro-intestinal effects are the most likely side-effects. (B263)
• With prolonged use, possibility of gastro-intestinal lesions, inappetance, vomiting, diarrhoea. (B201.10.w10)
• Serious effects which have been reported include hepatocellular damage and/or renal disease, haematological effects and gastro-intestinal effects. (B263)
• Side effects (toxicity) may be more likely to occur in elderly dogs or those with chronic diseases such as inflammatory bowel disease, renal insufficiency or hepatic insufficiency. (B263)
• One third of cases of reported hepatic syndrome were in Labrador Retrievers, although this was not proven to be statistically significant. (B263)
• Use with care in very young (less than six weeks old) or old animals. (B201.10.w10)
• Avoid using in individuals with dehydration, hypovolaemia or hypotension. (B201.10.w10)
• Avoid using concurrently with potentially nephrotoxic drugs. (B201.10.w10)

• May be significant variations between individuals in responses to either acute or chronic overdose. (B263)

• Dogs: little adverse reaction reported following studies with repeated doses of up to ten times recommended dose. Effects seen included hypoalbuminaemia, melaena, slight ALT increase. (B263)

• Note: has been used long-term by Animals Asia Foundation in some bears with severe arthritis with apparent minimal untoward effect on the liver (no significant rise in liver enzymes after a year of daily treatment at 4.4 mg/kg orally. (V.w90)

• In rats: little evidence of teratogenicity following administration to rats at 2 mg/kg, 6mg/kg or 20 mg/kg. Slightly prolonged gestation and a small increase in fetal deaths was observed with the highest dose. (J289.27S1.w1)

--

--

--