Companion Animal Product & Promotions Guide

(carprofen) Caplets/Chewable Tablets For oral use in dogs only Sterile Injectable Solution 50 mg/mL For subcutaneous use in dogs only Non-steroidal, anti-inflammatory drug CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION: Rimadyl (carprofen) is a non-steroidal anti-inflamma tory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substi tuted carbazole, 6-chloro-α-methyl-9H-carbazole-2-acetic acid. The empirical formula is C 15 H 12 ClNO 2 and the molecular weight 273.72. The chemical structure of carprofen is shown above. Carprofen is a white, crystalline compound. It is freely soluble in ethanol, but practically insoluble in water at 25°C. Rimadyl Injectable is a sterile solution containing carprofen. Each mL of Rimadyl Injectable contains 50.0 mg carprofen, 30.0 mg arginine, 88.5 mg glycocholic acid, 169.0 mg lecithin, 10.0 mg benzyl alcohol, 6.17 mg sodium hydroxide, with additional sodium hydroxide and hydrochloric acid as needed to adjust pH, and water for injection. CLINICAL PHARMACOLOGY: Carprofen is a non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic activity approximately equipotent to indomethacin in animal models. 1 The mechanism of action of carprofen, like that of other NSAIDs, is believed to be associated with the inhibition of cyclooxygenase activity. Two unique cyclooxygenases have been described in mammals. 2 The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for normal gastrointestinal and renal function. The inducible cyclooxygenase, COX-2, generates prostaglandins involved in inflammation. Inhibition of COX-1 is thought to be associated with gastrointestinal and renal toxicity while inhibition of COX-2 provides anti-inflammatory activity. The specificity of a particular NSAID for COX-2 versus COX-1 may vary from species to species. 3 In an in vitro study using canine cell cultures, carprofen demonstrated selective inhibition of COX-2 versus COX-1. 4 Clinical relevance of these data has not been shown. 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. 1 Several studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune responses. 5 –9 Data also indicate that carprofen inhibits the production of osteoclast-activating factor (OAF), PGE 1 , and PGE 2 by its inhibitory effects on prostaglandin biosynthesis. 1 Based upon comparison with data obtained from intravenous administration, carprofen is rapidly and nearly completely absorbed (more than 90% bioavailable) when administered orally. 10 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. Comparison of a single 25 mg dose in Beagle dogs after subcutaneous and oral administration demonstrated that the dorsoscapular subcutaneous administration results in a slower rate of drug input (as reflected by mean peak observed concentrations) but comparable total drug absorption within a 12 hour dosing interval (as reflected by area under the curve from hours zero to 12 postdose). Carprofen is eliminated in the dog primarily by biotransformation in the liver followed by rapid excretion of the resulting metabolites (the ester glucuronide of carprofen and the ether glucuronides of 2 phenolic metabolites, 7-hydroxy carprofen and 8-hydroxy carprofen) in the feces (70–80%) and urine (10–20%). Some enterohepatic circulation of the drug is observed. INDICATIONS: Rimadyl is indicated for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated with soft tissue and orthopedic surgeries in dogs. CONTRAINDICATIONS: Rimadyl should not be used in dogs exhibiting previous hypersensitivity to carprofen. 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 hematolo gical 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 (see Information for Dog Owners, Adverse Reactions, Animal Safety and Post-Approval Experience). PRECAUTIONS: As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Effects may result from decreased prostaglandin production and inhibition of the enzyme cyclooxygenase which is responsible for the formation of prosta glandins from arachidonic acid. 11–14 When NSAIDs inhibit prosta glandins that cause inflammation they may also inhibit those prosta glandins which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically sig nificant disease in patients with underlying or pre-existing disease more often than in healthy patients. 12,14 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. 11–14 The use of parenteral fluids during surgery should be considered to reduce the potential risk of renal complications when using NSAIDs perioperatively. Carprofen is an NSAID, and as with others in that class, adverse reactions may occur with its use. The most frequently reported effects have been gastrointestinal 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. Concurrent administration of potentially nephrotoxic drugs should be approached cautiously, with appropriate monitoring. Concomitant use of Rimadyl with other anti-inflammatory drugs, such as other NSAIDs or corticosteroids, should be avoided because of the potential increase of adverse reactions, including gastrointestinal ulcerations and/or perforations. Sensitivity to drug-associated adverse reactions varies with the individual patient. Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Rimadyl treatment was not associated with renal toxicity or gastrointestinal ulceration in well-controlled safety studies of up to 10 times the dose in healthy dogs. As with any parenterally injected product, good hygienic procedures should be used when administering Rimadyl Injectable. 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 animals less than 6 weeks of age, pregnant dogs, dogs used for breeding purposes, or in lactating bitches has not been established. Safety has not been established for IV or IM administration. Studies to determine the activity of Rimadyl when administered concomitantly with other protein-bound or similarly metabolized drugs have not been conducted. Drug compatibility should be monitored closely in patients requiring additional therapy. Such drugs commonly used include cardiac, anticonvulsant and behavioral medications. It has been suggested that treatment with carprofen may reduce the level of inhalant anesthetics needed. 15 It is suggested to use different sites for additional injections. If additional pain medication is warranted after administration of the total daily dose of Rimadyl, alternative analgesia should be considered. The use of another NSAID is not recommended. Consider appropriate washout times when switching from one NSAID to another or when switching from corticosteroids use to NSAID use. 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 labeled dose, please call your veterinarian for immediate assistance and notify Zoetis at 1-888-963-8471. 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, diarrhea, dark or tarry stools, increased water consumption, increased urination, pale gums due to anemia, yellowing of gums, skin or white of the eye due to jaundice, lethargy, incoordination, seizure, or behavioral changes. Serious adverse reactions associated with this drug class can occur without warning and in rare situations result in death (see Adverse Reactions). Owners should be advised to 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. ADVERSE REACTIONS: During investigational studies for the caplet formulation with twice daily administration of 1 mg/lb, no clinically significant adverse reactions were reported. Some clinical signs were observed during field studies (n=297) which were similar for carprofen caplet- and placebo-treated dogs. Incidences of the following were observed in both groups: vomiting (4%), diarrhea (4%), changes in appetite (3%), lethargy (1.4%), behavioral changes (1%), and constipation (0.3%). The product vehicle served as control. There were no serious adverse events reported during clinical field studies with once daily administration of 2 mg/lb. The following categories of abnormal health observations were reported. The product vehicle served as control. Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study (2 mg/lb once daily) Observation Rimadyl (n=129) Placebo (n=132) Inappetence 1.6 1.5 Vomiting 3.1 3.8 Diarrhea/Soft stool 3.1 4.5 Behavior change 0.8 0.8 Dermatitis 0.8 0.8 PU/PD 0.8 — SAP increase 7.8 8.3 ALT increase 5.4 4.5 AST increase 2.3 0.8 BUN increase 3.1 1.5 Bilirubinuria 16.3 12.1 Ketonuria 14.7 9.1 Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical judgment is necessary to determine clinical relevance. During investigational studies of surgical pain for the caplet formulation, no clinically significant adverse reactions were reported. The product vehicle served as control. Percentage of Dogs with Abnormal Health Observations Reported in Surgical Pain Field Studies with Caplets (2 mg/lb once daily) Observation* Rimadyl (n=148) Placebo (n=149) Vomiting 10.1 13.4 Diarrhea/Soft stool 6.1 6.0 Ocular disease 2.7 0 Inappetence 1.4 0 Dermatitis/Skin lesion 2.0 1.3 Dysrhythmia 0.7 0 Apnea 1.4 0 Oral/Periodontal disease 1.4 0 Pyrexia 0.7 1.3 Urinary tract disease 1.4 1.3 Wound drainage 1.4 0 * A single dog may have experienced more than one occurrence of an event. During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed in some dogs. These signs included vomiting and soft stools. There were no serious adverse events reported during clinical field studies for the injectable formulation. The following categories of abnormal health observations were reported. Saline served as control. Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study with the Injectable Observation* Rimadyl (n=168) Placebo (n=163) Vomiting 10.1 9.2 Diarrhea/soft stool 2.4 3.7 Dermatitis 0.6 1.2 Dysrhythmia 0.6 0.6 Swelling 0 1.2 Dehiscence 1.2 0 WBC increase 13.7 6.7 * A single dog may have experienced more than one occurrence of an event. 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 decreas ing order of frequency by body system. Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis. Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, bilirubinuria, hypoalbuminemia. Approximately one-fourth 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. Behavioral: 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. In rare situations, injection site reactions including necrosis, abscess and seroma formation, and granulomas have been reported with the injectable formulation. Immunologic or hypersensitivity: Facial swelling, hives, erythema. In rare situations, death has been associated with some of the adverse reactions listed above. To report a suspected adverse reaction call 1-888-963-8471. ® Cl N H O OH CH 3

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