Rimadyl - do we expect too
much from this NSAID?

RIMADYL (carprofen) is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. It is restricted to use by, or on the order of, a licensed veterinarian.

Carprofen is a white, crystalline compound with an empirical formula of C15/H12/NO2/Cl and a molecular weight of 273.72. It is freely soluble in ethanol, but practically insoluble in water at 25degC.

Clinical pharmacology
Carprofen is non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and anti-pyretic activity approximately equipotent to indomethocin in animal models. As with other NSAIDs, the exact mode of action of carprofen has not been established; however, inhibition of prostaglandin synthesis accounts for at least part of its mode of action. Carprofen is a reversible inhibitor of cyclo-oxygenase and a moderately potent inhibitor of phospholipase A2. Carprofen has also been shown to inhibit the release of several prostaglandins in two inflammatory cell systems: rat polymorphonuclear leukocytes (PMN) and human rheumatoid synovial cells, indicating inhibition of acute (PMN system) and chronic (synovial cell system) inflammatory reactions.

In rats, carprofen has been shown to be a much weaker blocker of arachidonic acid-induced diarrhoea than indomethocin. This decreased effect of carprofen on prostaglandin synthesis in the gastrointestinal tract may explain its relatively low ulcerogenic activity compared to other drugs in its class.

Several studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune responses. Data also indicate that carprofen inhibits the production of osteoclast-activating factor PGE1, and PGE2 by its inhibitory effects on prostaglandin biosynthesis.

Based upon comparison with data obtained from intravenous administration, carprofen is rapidly and nearly completely absorbed (more than 90% bioavailable) when administered orally. Peak blood plasma concentrations are achieved in 1-3 hours after oral administration of 1, 5, and 25 mg/kg to dogs. The mean terminal half-life of carprofen is approximately 8 hours (range 4.5-9.8 hours) after single oral doses varying from 1-35 mg/kg of body weight. After a 100 mg single intravenous bolus dose, the mean elimination half-life was approximately 11.7 hours in the dog. Rimadyl is more than 99% bound to plasma protein and exhibits a very small volume of distribution.

Carprofen is eliminated in the dog primarily by biotransformation in the liver followed by rapid excretion of the resulting meta bolites (the ester glucuronide of carprofen and the ether glucuronides of 2 phenolic metabolites, 7-hydroxy carprofen and 8-hydroxy carprofen) in the faeces (70-80%) and urine (10-20%). Some enterohepatic circulation of the drug is observed.

Indication: Rimadyl is indicated for the relief of pain and inflammation associated with osteoarthritis in dogs.

Administration: The recommended dosage for oral administration to dogs is 1mg/lb of body weight twice daily. Rimadyl caplets and chewable tablets are scored and dosage should be calculated in half-tablet increments. Tablets can be halved by placing the tablet on a hard surface and pressing down on both sides of the score. Rimadyl chewable tablets are palatable and willingly consumed by most dogs when offered by the owner. Therefore, they may be fed by hand or placed on food. Care should be taken to ensure that the dog consumes the complete dose.

Palatability: A controlled palatability study was conducted which demonstrated that Rimadyl chewable tablets were readily accepted and consumed on first offering by a majority of dogs.

Safety
Laboratory studies and clinical field trials have demonstrated that Rimadyl is well tolerated in dogs after oral administration. In target animal safety studies, Rimadyl was administered to dogs at one, three, and five times the recommended dose for 42 consecutive days with no significant adverse reactions.

Serum albumin for a single female dog receiving five times the recommended dose decreased to 2.1 g/dL after two weeks of treatment, returned to the pre-treatment value (2.6 g/dL) after four weeks of treatment, and was 2.3 g/dL at the final six-week evaluation.

Over the six-week treatment period, black or bloody stools were observed in one dog (one incident) treated with the recommended dose and in one dog (two incidents) treated with three times the recommended dose.

Redness of the colonic mucosa was observed in one male that received three times the recommended dose. Two of eight dogs receiving 10 times the recommended dose (10 mg/lb twice daily) for 14 days exhibited hypoalbuminemia. The mean albumin level in the dogs receiving this dose was lower (2.38 g/dL) than each of two placebo control groups (2.88 and 2.93 g/dL, respectively). Three incidents of black or bloody stools were observed in one dog. Five of eight dogs exhibited reddened areas of duodenal mucosa on gross pathologic examination.

Histologic examination of these areas revealed no evidence of ulceration, but did show minimal congestion of the lamina propria in two of the five dogs.

In separate safety studies lasting 13 and 52 weeks, respectively, dogs were administered up to 11.4 mg/lb/day (5.7 times the recommended total daily dose) of carprofen. In both studies, the drug was well tolerated clinically by all of the animals. No gross or histologic changes were seen in any of the treated animals. In both studies, dogs receiving the highest doses had average increases in serum L-alanine aminotransferase (ALT) of approximately 20 IU. In the 52-week study, minor dermatologic changes occurred in dogs in each of the treatment groups but not in the control dogs. The changes were described as slight redness or rash and were diagnosed as non-specific dermatitis. The possibility exists that these mild lesions were treatment related, but no dose relationship was observed.

Clinical field studies were conducted with 297 dogs of different breeds at the recommended dose for 14 days. The drug was clinically well tolerated and the incidence of clinical adverse reactions for Rimadyl-treated animals was no higher than placebo-treated animals (placebo contained inactive ingredients found in Rimadyl). Mean post-treatment serum ALT values were 11 IU greater and 9 IU less than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. Differences were not statistically significant.

Changes in clinical laboratory values (hematology and clinical chemistry) were not considered clinically significant nor reported as adverse reactions. The recommended course of therapy was repeated as needed at 2-week intervals in 244 of the dogs, some for as long as five years.

Contraindications:
Rimadyl should not be used in dogs exhibiting previous hypersensitivity to carprofen.

Precautions
As a class, cyclo-oxygenase inhibitory NSAIDs may be associated with gastro-intestinal and renal toxicity. Effects may result from decreased prostaglandin production and inhibition of the enzyme cyclo-oxygenase which is responsible for the formation of prosta-glandins from arachidonic acid. When NSAIDs inhibit prostaglandins that cause inflammation they may also inhibit those prosta-glandins which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically significant disease in patients with underlying or pre-existing disease more often than in healthy patients.

NSAID therapy could unmask occult disease which has previously been undiagnosed due to the absence of apparent clinical signs. Patients with underlying renal disease for example, may experience exacerbation or decompensation of their renal disease while on NSAID therapy.

Carprofen is a NSAID and as with others in that class, adverse reactions may occur with its use. The most frequently reported effects have been gastro-intestinal signs. Events involving suspected renal, hematologic, neurologic, dermatologic, and hepatic effects have also been reported. Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic dysfunction.

Since many NSAIDs possess the potential to induce gastrointestinal ulceration, concomitant use of Rimadyl with other anti-inflammatory drugs, such as corticosteroids and NSAIDs, should be avoided or very closely monitored. Sensitivity to drug-associated adverse reactions varies with the individual patient.

For example, Rimadyl treatment was not associated with renal toxicity or gastro-intestinal ulceration in well-controlled safety studies of up to 10 times the dose in dogs.

Rimadyl is not recommended for use in dogs with bleeding disorders (e.g., Von Willebrand's disease), as safety has not been established in dogs with these disorders. The safe use of Rimadyl in pregnant dogs, dogs used for breeding purposes, or in lactating bitches has not been established. Studies to determine the activity of Rimadyl when administered concomitantly with other protein-bound drugs have not been conducted. Drug compatibility should be monitored closely in patients requiring additional therapy.

Due to the palatable nature of Rimadyl chewable tablets, store out of reach of dogs in a secured location. Severe adverse reactions may occur if large quantities of tablets are ingested. If you suspect your dog has consumed Rimadyl chewable tablets above the labelled dose, please call your veterinarian for immediate assistance and notify Pfizer Animal Health (US1-800-366-5288).

Information for dog owners
Rimadyl, like other drugs of its class, is not free from adverse reactions. Owners should be advised of the potential for adverse reactions and be informed of the clinical signs associated with drug intolerance. Adverse reactions may include decreased appetite, vomiting, diarrhoea, dark or tarry stools, increased water consumption, increased urination, pale gums due to anaemia, yellowing of gums, skin or white of the eye due to jaundice, lethargy, inco-ordination, seizure, or behavioural changes.

Serious adverse reactions associated with this drug class can occur without warning and in rare situations result in death. Owners should discontinue Rimadyl therapy and contact their veterinarian immediately if signs of intolerance are observed.

The vast majority of patients with drug-related adverse reactions have recovered when the signs are recognized, the drug is withdrawn, and veterinary care, if appropriate, is initiated.

Owners should be advised of the importance of periodic follow-up for all dogs during administration of any NSAID.

Warnings: Keep out of reach of children. Not for human use. Consult a physician in cases of accidental ingestion by humans. For use in dogs only. Do not use in cats.

All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to, and periodically during administration of any NSAID should be considered. Owners should be advised to observe for signs of potential drug toxicity.

Adverse reactions
During investigational studies for the caplet formulation, no clinically significant adverse reactions were reported. Some clinical signs were observed during field studies which were similar for carprofen caplet and placebo-treated dogs. Incidences of the following were observed in both groups: vomiting (4%), diarrhoea (4%), changes in appetite (3%), lethargy (1.4%), behavioural changes (1%), and constipation (0.3%). The product vehicle served as control. During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed in some dogs. These signs included vomiting and soft stools.

Post-approval experience: Although not all adverse reactions are reported, the following adverse reactions are based on voluntary post-approval adverse drug experience reporting. The categories of adverse reactions are listed in decreasing order of frequency by body system.

Gastrointestinal: Vomiting, diarrhoea, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis.

Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, hyper-bilirubinuria, hypoalbuminemia. Approximately quarter of hepatic reports were in Labrador retrievers.

Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation.

Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities including acute tubular necrosis, renal tubular acidosis, glucosuria.

Behavioural: Sedation, lethargy, hyperactivity, restlessness, aggressiveness.

Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis.

Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis.

Immunologic or hypersensitivity: Facial swelling, hives, erythema. In rare situations, death has been associated with some of the adverse reactions listed. Report any suspected adverse reaction to your vet. Store at controlled room temperature 15deg-30degC (59deg-86degF).

Rimadyl chewable tablets are scored, and contain 25 mg, 75 mg, or 100 mg of carprofen per tablet. Each tablet size is packaged in bottles containing 60 or 180 tablets. Rimadyl caplets are scored and contain 25mg, 75mg, or 100mg of carprofen per caplet. Each caplet size is packaged in bottles containing 100 or 250 caplets.

For a copy of the Material Safety Data Sheet (MSDS) or to report adverse reactions call Pfizer Animal Health at (US)1-800-366-5288. For countries outside the US, phone your nearest Pfizer branch. This information is provided for education only and must not replace discussions with your veterinarian.