(Carprofen) Is a Non-Steroidal Anti-Inflammatory Drug (NSAID) of the Propionic Acid Class That Includes Ibuprofen, Reporting

Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Studies with the Injectable

Observation* Rimadyl (n=168) Placebo (n=163) Vomiting 10.1 9.2 Caplets/Chewable Tablets Diarrhea/soft stool 2.4 3.7 For oral use in dogs only Dermatitis 0.6 1.2 Dysrhythmia 0.6 0.6 Sterile Injectable Solution 50 mg/mL Swelling 0 1.2 Dehiscence 1.2 0 For subcutaneous use in dogs only WBC increase 13.7 6.7 Non-steroidal, anti-inflammatory drug * A single dog may have experienced more than one occurrence of an event. Post-Approval Experience: CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Although not all adverse reactions are reported, the following adverse reactions are based on voluntary post-approval adverse drug experience DESCRIPTION:Rimadyl (carprofen) is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class that includes ibuprofen, reporting. The categories of adverse reactions are listed by body system. naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substituted carbazole, 6-chloro-α-methyl-9H-carbazole-2-acetic acid. Gastrointestinal:Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis. The empirical formula is C15H12ClNO2 and the molecular weight 273.72. The chemical structure of carprofen is shown above. Carprofen is a white, Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, crystalline compound. It is freely soluble in ethanol, but practically insoluble in water at 25°C. bilirubinuria, hypoalbuminemia. Approximately one-fourth of hepatic reports were in Labrador Retrievers. 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 Neurologic:Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation. glycocholic acid, 169.0 mg lecithin, 10.0 mg benzyl alcohol, 6.17 mg sodium hydroxide, with additional sodium hydroxide and hydrochloric acid as Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities needed to adjust pH, and water for injection. including acute tubular necrosis, renal tubular acidosis, glucosuria. Behavioral: Sedation, lethargy, hyperactivity, restlessness, aggressiveness. CLINICAL PHARMACOLOGY:Carprofen is a non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic Hematologic:Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis. activity approximately equipotent to indomethacin in animal models.1 Dermatologic:Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis. The mechanism of action of carprofen, like that of other NSAIDs, is believed to be associated with the inhibition of cyclooxygenase activity. Two In rare situations, injection site reactions including necrosis, abscess and seroma formation, and granulomas have been reported with the unique cyclooxygenases have been described in mammals.2 The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for injectable formulation. Immunologic or hypersensitivity:Facial swelling, hives, erythema. 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 In rare situations, death has been associated with some of the adverse reactions listed above. To report a suspected adverse reaction call 1-800-366-5288. 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 DOSAGE AND ADMINISTRATION: Always provide Client Information Sheet with prescription. Carefully consider the potential benefits and risk been shown to inhibit the release of several prostaglandins in two inflammatory cell systems: rat polymorphonuclear leukocytes (PMN) and human of Rimadyl and other treatment options before deciding to use Rimadyl. Use the lowest effective dose for the shortest duration consistent with rheumatoid synovial cells, indicating inhibition of acute (PMN system) and chronic (synovial cell system) inflammatory reactions.1 individual response. The recommended dosage for oral administration to dogs is 2 mg/lb (4.4 mg/kg) of body weight daily. The total daily dose 5–9 may be administered as 2 mg/lb of body weight once daily or divided and administered as 1 mg/lb (2.2 mg/kg) twice daily. For the control of Several studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune responses. Data also indicate postoperative pain, administer approximately 2 hours before the procedure. Rimadyl tablets are scored and dosage should be calculated in half- 1 that carprofen inhibits the production of osteoclast-activating factor (OAF), PGE1, and PGE2 by its inhibitory effect in prostaglandin biosynthesis. 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 Based upon comparison with data obtained from intravenous administration, carprofen is rapidly and nearly completely absorbed (more than 90% 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 bioavailable) when administered orally.10 Peak blood plasma concentrations are achieved in 1–3 hours after oral administration of 1, 5, and 25 mg/ should be taken to ensure that the dog consumes the complete dose. 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 The recommended dosage for subcutaneous administration to dogs is 2 mg/lb (4.4 mg/kg) of body weight daily. The total daily dose may be 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 administered as either 2 mg/lb of body weight once daily or divided and administered as 1 mg/lb (2.2 mg/kg) twice Fordaily. control ofpostoperative more than 99% bound to plasma protein and exhibits a very small volume of distribution. pain, administer approximately 2 hours before the procedure. Comparison of a single 25 mg dose in Beagle dogs after subcutaneous and oral administration demonstrated that the dorsoscapular subcutaneous PALATABILITY: A controlled palatability study was conducted which demonstrated that Rimadyl chewable tablets were readily accepted and administration results in a slower rate of drug input (as reflected by mean peak observed concentrations) but comparable total drug absorption consumed on first offering by a majority of dogs. within a 12 hour dosing interval (as reflected by area under the curve from hours zero to 12 postdose). EFFECTIVENESS:Confirmation of the effectiveness of Rimadyl for the relief of pain and inflammation associated with osteoarthritis, and for the Carprofen is eliminated in the dog primarily by biotransformation in the liver followed by rapid excretion of the resulting metabolites (the ester control of postoperative pain associated with soft tissue and orthopedic surgeries, was demonstrated in 7 placebo-controlled, masked studies glucuronide of carprofen and the ether glucuronides of 2 phenolic metabolites, 7-hydroxy carprofen and 8-hydroxy carprofen) in the feces examining the anti-inflammatory and analgesic effectiveness of Rimadyl caplets in various breeds of dogs. (70–80%) and urine (10–20%). Some enterohepatic circulation of the drug is observed. Separate placebo-controlled, masked, multicenter field studies confirmed the anti-inflammatory and analgesic effectiveness of Rimadyl caplets INDICATIONS: Rimadyl is indicated for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain when dosed at 2 mg/lb once daily or when divided and administered at 1 mg/lb twice daily. In these 2 field studies, dogs diagnosed with associated with soft tissue and orthopedic surgeries in dogs. osteoarthritis showed statistically significant overall improvement based on lameness evaluations by the veterinarian and owner observations CONTRAINDICATIONS: Rimadyl should not be used in dogs exhibiting previous hypersensitivity to carprofen. when administered Rimadyl at labeled doses. 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 Based upon the blood level comparison between subcutaneous and oral administration, Rimadyl effectiveness for osteoarthritis after only. Do not use in cats. dorsoscapular subcutaneous and oral administration should be similar, although there may be a slight delay in the onset of relief after subcutaneous injection. 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 Separate placebo-controlled, masked, multicenter field studies confirmed the effectiveness of Rimadyl caplets for the control of postoperative pain should be advised to observe for signs of potential drug toxicity (see Information for Dog Owners, Adverse Reactions, Animal Safety and Post- when dosed at 2 mg/lb once daily in various breeds of dogs. In these studies, dogs presented for ovariohysterectomy, cruciate repair and aural Approval Experience). surgeries were administered Rimadyl preoperatively and for a maximum of 3 days (soft tissue) or 4 days (orthopedic) postoperatively. In general, dogs administered Rimadyl showed statistically significant reduction in pain scores compared to controls. 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 enzymecyclooxygenase which is responsible for the formation of prosta- ANIMAL SAFETY STUDIES:Laboratory studies in unanesthetized dogs and clinical field studies have demonstrated that Rimadyl is well glandins from arachidonic acid. tolerated in dogs after oral administration. 11–14 When NSAIDs inhibit prostaglandins that cause inflammation they may also inhibit those prostaglandins In target animal safety studies, Rimadyl was administered orally to healthy Beagle dogs at 1, 3, and 5 mg/lb twice daily (1, 3 and 5 times the which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically significant disease in patients with recommended total daily dose) for 42 consecutive days with no significant adverse reactions. Serum albumin for a single female dog receiving 5 underlying or pre-existing disease more often than in healthy patients.12,14 NSAID therapy could unmask occult disease which has previously been mg/lb twice daily decreased to 2.1 g/dL after 2 weeks of treatment, returned to the pre-treatment value (2.6 g/dL) after 4 weeks of treatment, and undiagnosed due to the absence of apparent clinical signs. Patients with underlying renal disease for example, may experience exacerbation or was 2.3 g/dL at the final 6-week evaluation. Over the 6-week treatment period, black or bloody stools were observed in 1 dog (1 incident) treated decompensation of their renal disease while on NSAID therapy.11–14 The use of parenteral fluids during surgery should be considered to reduce the with 1 mg/lb twice daily and in 1 dog (2 incidents) treated with 3 mg/lb twice daily. Redness of the colonic mucosa was observed in 1 male that potential risk of renal complications when using NSAIDs perioperatively. received 3 mg/lb twice daily. 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 Two of 8 dogs receiving 10 mg/lb orally twice daily (10 times the recommended total daily dose) for 14 days exhibited hypoalbuminemia. The mean gastrointestinal signs. Events involving suspected renal, hematologic, neurologic, dermatologic, and hepatic effects have also been reported. albumin level in the dogs receiving this dose was lower (2.38 g/dL) than each of 2 placebo control groups (2.88 and 2.93 g/dL, respectively). Three Patients at greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/ incidents of black or bloody stool were observed in 1 dog. Five of 8 dogs exhibited reddened areas of duodenal mucosa on gross pathologic or hepatic dysfunction.Concurrent administration of potentially nephrotoxic drugs should be approached cautiously, with appropriate monitoring. examination. Histologic exam of these areas revealed no evidence of ulceration, but did show minimal congestion of the lamina propria in 2 of the Concomitant use of Rimadyl with other anti-inflammatory drugs, such as other NSAIDs or corticosteroids, should be avoided because of the potential 5 dogs. increase of adverse reactions, including gastrointestinal ulcerations and/or perforations. Sensitivity to drug-associated adverse reactions varies with In separate safety studies lasting 13 and 52 weeks, respectively, dogs were administered orally up to 11.4 mg/lb/day (5.7 times the recommended the individual patient. Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Rimadyl total daily dose of 2 mg/lb) of carprofen. In both studies, the drug was well tolerated clinically by all of the animals. No gross or histologic 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. changes were seen in any of the treated animals. In both studies, dogs receiving the highest doses had average increases in serum L-alanine As with any parenterally injected product, good hygienic procedures should be used when administering Rimadyl Injectable. aminotransferase (ALT) of approximately 20 IU. Rimadyl is not recommended for use in dogs with bleeding disorders (e.g., Von Willebrand’s disease), as safety has not been established in 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 dogs with these disorders.The safe use of Rimadyl in animals less than 6 weeks of age, in pregnant dogs, dogs used for breeding purposes, or described as slight redness or rash and were diagnosed as non-specific dermatitis. The possibility exists that these mild lesions were treatment in lactating bitches has not been established.Safety has not been established for IV or IM administration.Studies to determine the activity of related, but no dose relationship was observed. Rimadyl when administered concomitantly with other protein-bound or similarly metabolized drugs have not been conducted. Drug compatibility Clinical field studies were conducted with 549 dogs of different breeds at the recommended oral doses for 14 days (297 dogs were included in should be monitored closely in patients requiring additional therapy. Such drugs commonly used include cardiac, anticonvulsant and behavioral a study evaluating 1 mg/lb twice daily and 252 dogs were included in a separate study evaluating 2 mg/lb once daily). In both studies the drug medications. It has been suggested that treatment with carprofen may reduce the level of inhalant anesthetics needed. 15 It is suggested to use was clinically well tolerated and the incidence of clinical adverse reactions for Rimadyl-treated animals was no higher than placebo-treated different sites for additional injections.If additional pain medication is warranted after administration of the total daily dose of Rimadyl, alternative animals (placebo contained inactive ingredients found in Rimadyl). For animals receiving 1 mg/lb twice daily, the mean post-treatment serum analgesia should be considered. The use of another NSAID is not recommended. 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. For animals receiving 2 mg/lb once daily, the mean post-treatment serum ALT values were 4.5 IU greater and 0.9 IU less 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 than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. In the latter study, 3 Rimadyl-treated dogs developed a 3-fold or large quantities of tablets are ingested. If you suspect your dog has consumed Rimadyl chewable tablets above the labeled dose, please call your greater increase in (ALT) and/or (AST) during the course of therapy. One placebo-treated dog had a greater than 2-fold increase in ALT. None of veterinarian for immediate assistance and notify Pfizer Animal Health (1-800-366-5288). these animals showed clinical signs associated with laboratory value changes. Changes in the clinical laboratory values (hematology and clinical INFORMATIONFOR DOG OWNERS: chemistry) were not considered clinically significant. The 1 mg/lb twice daily course of therapy was repeated as needed at 2-week intervals in 244 Rimadyl, like other drugs of its class, is not free from adverse reactions. Owners should be advised of the potential for adverse reactions and dogs, some for as long as 5 years. be informed of the clinical signs associated with drug intolerance. Adverse reactions may include decreased appetite, vomiting, diarrhea, dark Clinical field studies were conducted in 297 dogs of different breeds undergoing orthopedic or soft-tissue surgery. Dogs were administered or tarry stools, increased water consumption, increased urination, pale gums due to anemia, yellowing of gums, skin or white of the eye due to 2 mg/lb of Rimadyl 2 hours prior to surgery then once daily, as needed for 2 days (soft tissue surgery) or 3 days (orthopedic surgery). Rimadyl was jaundice, lethargy, incoordination, seizure, or behavioral changes. well tolerated when used in conjunction with a variety of anesthetic-related drugs. The type and severity of abnormal health observation in Rimadyl- Serious adverse reactions associated with this drug class can occur without warning and in rare situations result in death (see Adverse Reactions). and placebo-treated animals were approximately equal and few in number (see Adverse Reactions). The most frequent abnormal health observation Owners should be advised to discontinue Rimadyl therapy and contact their veterinarian immediately if signs of intolerance are observed. was vomiting and was observed at approximately the same frequency in Rimadyl- and placebo-treated animals. Changes in clinicopathologic indices of hematopoetic, renal, hepatic, and clotting function were not clinically significant. The mean post-treatment serum ALT values were 7.3 IU and 2.5 The vast majority of patients with drug-related adverse reactions have recovered when the signs are recognized, the drug is withdrawn, and veterinary IU less than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. The mean post-treatment values AST were 3.1 IU less for care, if appropriate, is initiated. Owners should be advised of the importance of periodic follow up for all dogs during administration of any .NSAID dogs receiving Rimadyl and 0.2 IU greater for dogs receiving placebo. ADVERSE REACTIONS: During investigational studies for the caplet formulation with twice daily administration of 1 mg/lb, no clinically significant Clinical field studies on the use of Rimadyl Injectable were conducted on 331 dogs undergoing orthopedic or soft tissue surgery. Dogs were adverse reactions were reported. Some clinical signs were observed during field studies (n=297) which were similar for carprofen caplet- and administered 2 mg/lb of Rimadyl subcutaneously 2 hours prior to surgery and once daily thereafter, as needed, for 2 days (soft tissue surgery) or 3 placebo-treated dogs. Incidences of the following were observed in both groups: vomiting (4%), diarrhea (4%), changes in appetite (3%), lethargy days (orthopedic surgery). Rimadyl was well tolerated when used in conjunction with a variety of anesthetic-related drugs. The type and severity of (1.4%), behavioral changes (1%), and constipation (0.3%). The product vehicle served as control. abnormal health observations in Rimadyl- and placebo-treated animals were approximately equal and few in number (see Adverse Reactions). The There were no serious adverse events reported during clinical field studies with once daily administration of 2 mg/lb. The following categories of most frequent abnormal health observation was vomiting and was observed at approximately the same frequency in Rimadyl- and placebo-treated abnormal health observations were reported. The product vehicle served as control. animals. Changes in clinicopathologic indices of hematopoetic, renal, hepatic, and clotting function were not clinically significant. The mean post- Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study (2 mg/lb once daily) treatment serum ALT values were 8.4 IU and 7.0 IU less than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. The mean post-treatment AST values were 1.5 IU and 0.7 IU greater for dogs receiving Rimadyl and placebo, respectively. TAKE TIME Observation Rimadyl (n=129) Placebo (n=132) STORAGE: Store tablets at controlled room temperature 15°–30°C (59°–86°F).Store injectable under refrigeration 2°–8°C (36°–46°F). Once broached, product may be stored at temperatures up 25°Cto (77°F) for 28 days. Inappetence 1.6 1.5 Vomiting 3.1 3.8 HOW SUPPLIED:Rimadyl caplets and chewable tablets are scored, and contain 25 mg, 75 mg, or 100 mg of carprofen per caplet or tablet. Each Diarrhea/Soft stool 3.1 4.5 caplet size is packaged in bottles containing 30, 60, or 180 caplets, or blister paks containing 4 caplets. Each chewable tablet size is packaged in Behavior change 0.8 0.8 bottles containing 7, 30, 60, or 180 tablets. Rimadyl Injectable is supplied in 20-mL, amber, glass, sterile, multi-dose vials. Dermatitis 0.8 0.8 REFERENCES: OBSERVE LABEL PU/PD 0.8 SAP increase 7.8 8.3– DIRECTIONS ALT increase 5.4 4.5 AST increase 2.3 0.8 BUN increase 3.1 1.5 1. Baruth H, et al: In Anti-Inflammatory and Anti-Rheumatic Drugs, Vol. II, Newer Anti-Inflammatory Drugs, Rainsford KD, ed. CRC Press, Boca Raton, p. 33, 1986. Bilirubinuria 16.3 12.1 2. Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs.Scand J Rheumatol25:102, pp. 9–21, 1996. Ketonuria 14.7 9.1 3. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and COX- Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical judgement is necessary to determine clinical relevance. 2 inhibitors. Inflammation Research 44:253–257, 1995. 4. Ricketts AP, Lundy KM, Seibel SB: Evaluation of selective inhibition of canine cyclooxygenaseand 1 2 by carprofen and other nonste roi dal anti-inflammatory drugs.Am J During investigational studies of surgical pain for the caplet formulation, no clinically significant adverse reactions were reported. The product Vet Res 59:11, pp. 1441–1446, November 1998. vehicle served as control. 5. Ceuppens JL,et al: Non-steroidal anti-inflammatory agents inhibit the synthesis of IgM rheumatoid factorin vitro . Lancet 1:528, 1982. Percentage of Dogs with Abnormal Health Observations Reported in Surgical Pain Field Studies with Caplets (2 mg/lb once daily) 6. Ceuppens JL,et al: Endogenous prostaglandin2 E enhances polyclonal immunoglobulin production by ionically inhibiting T suppressor cell activity.Cell Immunol 70:41, 1982. 7. Schleimer RP,et al: The effects of prostaglandin synthesis inhibition on the immune response.Immunopharmacology 3:205, 1981.

Observation* Rimadyl (n=148) Placebo (n=149) 8. Leung KH, et al: Modulation of the development of cell mediated immunity: Possible roles of the products of cyclooxygenaseTAKE TIME and— lipoxygenaseOBSERVE pathways LABEL of arachidonic DIRECTIONS acid metabolism.Int J Immunopharma cology 4:195, 1982. Vomiting 10.1 13.4 9. Veit BC: Immunoregulatory activity of cultured-induced suppressor macrophages.Cell Immunol 72:14, 1982. Diarrhea/Soft stool 6.1 6.0 10. Schmitt M, et al: Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs.Biopharm Drug Dispos 11(7):585, 1990. Ocular disease 2.7 0 11. Kore AM: Toxicology of nonsteriodal anti-inflammatory drugs.Veter inary Clinics of North America, Small Animal Practice 20, March 1990. Inappetence 1.4 0 12. Binns SH: Pathogenesis and pathophysiology of ischemic injury in cases of acute renal failure.Compend for Cont Ed 16:1, January 1994. Dermatitis/Skin lesion 2.0 1.3 13. Boothe DM: Prostaglandins: Physiology and clinical implications.Compend for Cont Ed 6:11, November 1984. Dysrhythmia 0.7 0 14. Rubin SI: Nonsteroidal anti-inflammatory drugs, prostaglandins, and the kidney.JAVMA 188:9, May 1986. Apnea 1.4 0 15. Ko CH, Lange DN, Mandsager RE,et al: Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.JAVMA 217:1025–1028, 2000. Oral/Periodontal disease 1.4 0 Pyrexia 0.7 1.3 For a copy of the Material Safety Data Sheet (MSDS) call 1-800-733-5500. To report adverse reactions call Pfizer Animal Health at 1-800-366-5288. Urinary tract disease 1.4 1.3 NADA #141-053, NADA #141-111,NADA #141-199Approved by FDA. Wound drainage 1.4 0 Injectable Manufactured by: Vericore Limited, Dundee, United Kingdom * A single dog may have experienced more than one occurrence of an event. Made in India During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed in some dogs. These signs included Distributed by: TAKE OBSERVE LABEL vomiting and soft stools. TIME DIRECTIONS There were no serious adverse events reported during clinical field studies for the injectable formulation. The following categories of abnormal Div. of Pfizer Inc December 2007 health observations were reported. The product vehicle served as control. NY, NY 10017 Printed in USA

All trademarks are the property of their respective owners. ©2009 Pfizer Inc. All rights reserved. RIM0110002 1 Market Dynamics Inc (MDI), 2008 T How RIMADYL co A label-to-label comparison in black and white. O m par TH E R N es es

S † AID ® (carprofen) S .

Incidence of Special FDA-Approved Clinical US Usage Dosing Age Nsaid Class Dose* Vomiting– Administration Blood Work Indications Pharmacology Record Flexibility restrictions Labeling Clinical Field Study Instructions

• Relief of pain and inflammation associated • 2 mg/lb (4.4 mg/kg) of body • OA: 3.1% (4 of 129) vs 3.8% (5 of • In an in vitro study using canine cell • For control of postoperative pain, • #1 in US, in US • Once a day or twice a day • 6 weeks** • Appropriate laboratory tests • As a class, cyclooxygenase inhibitory NSAIDs may be with osteoarthritis in dogs weight once daily or divided 132) in placebo group cultures, carprofen demonstrated administer approximately 2 hours prior market since 19971 to establish hematological and associated with gastrointestinal, renal, and hepatic toxicity • 25 mg, 75 mg, 100 mg chewable and administered as 1 mg/lb selective inhibition of COX-2 vs COX-1. to procedure serum biochemical baseline data • Control of postoperative pain associated • Orthopedic: 10.1% (17 of 168) vs • 16 million dogs tablets or caplets • Concomitant use of RIMADYL with other anti-inflammatory (2.2 mg/kg) twice daily 1 prior to, and periodically during, with soft tissue surgery in dogs 9.2% (15 of 163) in placebo group • Clinical relevance of these data has not treated orally in US drugs, such as other NSAIDs and corticosteroids, should • Injectable solution administration of any NSAID • Control of postoperative pain associated been shown be avoided because of the potential increase of adverse • Soft Tissue: 10.1% (15 of 148) vs should be considered reactions, including gastrointestinal ulcerations and/or with orthopedic surgery in dogs (orally or subcutaneously) 13.4% (20 of 149) in placebo group perforations

• Control of pain and inflammation • Osteoarthritis Pain and Inflammation: • OA: 2.9% (3 of 105) vs 3.9% (4 of • Deracoxib inhibited COX-2 mediated PGE2 • Since Deramaxx tablet bioavailability is • In US market • Once a day • 4 months** • Appropriate laboratory tests • As a class, NSAIDs may be associated with gastrointestinal, associated with osteoarthritis in dogs 0.45 - 0.91 mg/lb/day (1 to 2 mg/kg/ 104) in placebo group production in LPS stimulated human whole blood greatest when taken with food, to establish hematological and renal, and hepatic toxicity since 2002 • 25 mg, 75 mg, 100 mg day) as a single daily dose, as needed • Deramaxx tablets do not inhibit COX-1 based on in postprandial administration is preferable serum biochemical baseline data • Control of postoperative pain and • Orthopedic: 10.5% (11 of 105) vs • Since NSAIDs possess the potential to produce vitro studies using cloned canine cyclooxygenase • Chewables only prior to, and periodically during, ® inflammation associated with orthopedic • Postoperative Orthopedic Pain and 5.9% (6 of 102) in placebo group gastrointestinal ulceration and/or perforation, Inflammation: 1.4 - 1.8 mg/lb/day (3 to administration of any NSAID is surgery in dogs ≥ 4 lbs (1.8 kg) • The clinical relevance of this in vitro data has not concomitant use of Deramaxx tablets with other DERAMAXX (deracoxib) 4 mg/kg/day) as a single daily dose, been shown recommended as needed, not to exceed 7 days of anti-inflammatory drugs, such as other NSAIDs and • Non-linear elimination kinetics are exhibited at corticosteroids, should be avoided administration doses above 8 mg/kg/day, at which competitive (orally) inhibition of constitutive COX-1 may occur

• Control of pain and inflammation • The recommended dosage of • OA: 3.9% (5 of 128) vs 6.6% (8 of 121) • Results from in vitro studies showed • Due to tablet sizes and scoring, dogs • In US market • Once a day • Use of this product at • Appropriate laboratory testing • As a class, cyclooxygenase inhibitory NSAIDs may be PREVICOX (firocoxib) for oral active control group firocoxib to be highly selective for the weighing less than 12.5 lb (5.7 kg) doses above the to establish hematological associated with renal, gastrointestinal, and hepatic toxicity associated with osteoarthritis in dogs since 2005 • 57 mg tablets, 227 mg tablets administration in dogs is 2.27 mg/lb COX-2 enzyme when canine blood was cannot be accurately dosed recommended 2.27 mg/lb and serum baseline data is • Control of postoperative pain and • Soft Tissue: 3.94% (5 of 127) vs • Since NSAIDs possess the potential to produce (5.0 mg/kg) body weight once daily exposed to drug concentrations • Chewables only (5 mg/kg) in puppies recommended prior to, and ® inflammation associated with soft tissue as needed for osteoarthritis and for 3 4.58% (6 of 131) control group gastrointestinal ulcerations, and/or gastrointestinal comparable to those observed following less than 7 months of age periodically during, administration (firocoxib) and orthopedic surgery in dogs days as needed for postoperative pain perforations, concomitant use with other anti-inflammatory PREVICOX • Orthopedic: 0.85% (1 of 118) a once daily 5 mg/kg oral dose in dogs. has been associated with of any NSAID and inflammation associated with soft drugs, such as NSAIDs or corticosteroids, should be vs 0% (0 of 108) control group serious adverse reactions, tissue and orthopedic surgery • However, the clinical significance of avoided including death (orally) these findings has not been established

• Control of pain and inflammation associated • Metacam (5 mg/mL) Solution for Injection • OA: 25.5% (40 of 157) vs 15.4% (23 • Some evidence of enhanced drug • Particular care should be given with • In US market • Once a day (dogs) • 6 months (dogs)** • Appropriate laboratory testing • As a class, cyclooxygenase inhibitory NSAIDS may with osteoarthritis in dogs should be administered initially as a single of 149) in placebo (Metacam Oral accumulation and terminal elimination regard to the accuracy of dosing since 2003 to establish hematological be associated with gastrointestinal, renal, and hepatic • 0.5 mg/mL and 1.5 mg/mL dose at 0.09 mg/lb (0.2 mg/kg) body weight Suspension); 28.4% (31 of 109) vs half-life prolongation when dogs are and serum biochemical baseline toxicity • To prevent accidental overdosing of Oral Suspension (dogs) intravenously (IV) or subcutaneously (SQ) 13.0% (15 of 115) placebo (Metacam dosed for 45 days or longer data is recommended prior to dogs under 10 lb, administer drops on • Since NSAIDs possess the potential to produce • Metacam Oral Suspension should be 5mg/mL Solution for Injection) • 5 mg/mL Solution for Injection and periodically during ® food only, never directly into the mouth gastrointestinal ulceration and/or perforations, administered initially at 0.09 mg/lb (0.2 mg/ (dogs) administration of any NSAID concomitant use with other anti-inflammatory drugs, METACAM (meloxicam) kg) body weight only on the first day of in dogs treatment such as NSAIDs or corticosteroids, should be avoided • For all treatments after day 1, Metacam Oral Suspension should be administered once daily at a dose of 0.045 mg/lb (0.1 mg/kg)

• Control of pain and inflammation associated • The recommended dose of etodolac is • OA: 4.3% vs 1.7% in placebo group • In vitro experiments have shown that • Due to tablet sizes and scoring, dogs • In US market • Once a day • 12 months** • Appropriate laboratory tests • As a class, cyclooxygenase inhibitory NSAIDs may be with osteoarthritis in dogs 10 to 15 mg/kg body weight (4.5 to 6.8 etodolac selectively inhibits COX-2 weighing less than 5 kg (11 lb) cannot since 1998 to establish hematological and associated with gastrointestinal, renal, and hepatic toxicity • 150 mg, 300 mg, 500 mg mg/lb) administered once daily activity. The clinical relevance of this be accurately dosed serum biochemical baseline data • Since NSAIDs possess the potential to produce ® data has not been shown • Oral tablets prior to, and periodically during, • 10 to 15 mg/kg body weight (4.5 to 6.8 gastrointestinal ulceration and/or gastrointestinal administration of any NSAID ETOGESIC (etodolac) mg/lb) administered once daily • Sterile Injectable Solution perforation, concomitant use of ETOGESIC with other should be considered anti-inflammatory drugs, such as NSAIDs or corticosteroids, (orally) should be avoided

• Control of pain and inflammation • Administer 10 mg/kg (4.5 mg/lb) or • OA: 2% (2 of 101) vs 4.8% (5 of 104) • The mechanism of action of tepoxalin, like • Place the rapidly-disintegrating tablet into • In US market • Once a day • 6 months** • Appropriate laboratory tests • As a class, cyclooxygenase inhibitory NSAIDs may be associated with osteoarthritis in dogs 20 mg/kg (9.1 mg/lb) on the initial active control group (7 day study); other NSAIDs, is believed to be associated dog’s mouth. Keep the mouth closed for a since 2003 should be conducted to associated with gastrointestinal and renal toxicity • 50 mg, 100 mg, 200 mg day of treatment, followed by a daily 19.6% (21 of 107; placebo data not with the inhibition of cyclooxygenase sufficient amount of time (~4 seconds) to establish hematological and • Since many NSAIDs possess the potential to induce maintenance dose of 10 mg/kg on label; 28 day study) activity. Additionally, tepoxalin has been ensure tablet dispersion • Rapidly disintegrating tablets serum biochemical baseline data ® gastric ulceration, concomitant use of Zubrin tablets shown to be an inhibitor of lipoxygenase before, and periodically during, (tepoxalin) • Should be administered either with food or with any other anti-inflammatory drugs, such as other ZUBRIN and is thus classified as a dual inhibitor of administration of any NSAID within 1 to 2 hours after feeding NSAIDs and corticosteroids, should be avoided or arachidonic acid metabolism • Due to tablet sizes, dogs weighing less than closely monitored 3 kg (6.6 lbs) cannot be accurately dosed

* The use of the lowest effective dose for the shortest

1 duration is recommended. The facts prove it. You can be confident prescribing the #1 canine pain reliever. ** The safe use of this product has not been evaluated From surgery to arthritis, RIMADYL provides safe pain relief throughout a dog’s life. in dogs younger than the age indicated. CONCLUSION: † Data sourced from individual FDA-approved product labels for dogs.