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The RIMADYL Rewards Program: Program Overview • The program begins at initial diagnosis of osteoarthritis, when the veterinarian provides the dog owner RIMADYL® (carprofen) for trial use as well as a coupon for a $10 rebate off their first purchase - exclusively at the veterinary hospital. • A s owners continue to take care of their dogs with RIMADYL, the #1 pain medication prescribed by veterinarians,1 they’ll accumulate Reward Points based on the amount of RIMADYL purchased. • These Reward Points translate into dollar amounts on a debit card they can spend exclusively at your veterinary hospital to help pay for diagnostic tests, annual exams, additional RIMADYL, or any other hospital expense. • Includes reminders to dog owners to continue treatment and return to hospital. • Addresses all components of compliance from recommendation to acceptance and follow through. RIMADYL REWARDS PROGRAM: We take care of the program administration so you can take care of your patients! The RIMADYL® (carprofen) Rewards Program provides incentives and multiple opportunities to educate and encourage dog owners to continue their use of RIMADYL as prescribed, and to return to the hospital for follow-through over the long term. 3400 Suite 1750 3060 Peachtree Peachtree Road Road,NE, Suite 2000 Atlanta, Atlanta, GA GA 30326 30305 RIMADYL Kim Novick 81 Kirkwood Dr. 2ND Address line here Newtown, PA 18940-1791 Coupon Check enclosed! INITIATE: Recommendation > Receive > Rebate BAR CODE AREA October 2, 2008 Dear Kim Novick: We’re so excited that you’ve joined the RimaDog™ Community — if we had tails we’d b wagging them. Please find the enclosed RIMADYL® (carprofen) coupon check that you Recommendation Receive Rebate What to do now: • Veterinarian diagnoses dog with osteoarthritis and recommends RIMADYL • Dog owner accepts veterinarian’s recommendation • Veterinarian provides dog owner with RIMADYL sample and coupon for $10 rebate • Dog owner registers at rimadog.com • Dog owner receives letter 16 million tail-waggers can’t be wrong encouraging them to return to hospital along with One final$10 trick rebate check made payable to hospital requested. Be sure to visit the RimaDog Community regularly for other perks and incen — Take the enclosed coupon check to the veterinary clinic listed on the check — Receive an instant $10 savings toward your next RIMADYL purchase — Turn your dog into a RimaDog with proper use of RIMADYL — Continue talking to your veterinarian and checking back with the RimaDog Community at Rimadyl.com for additional promotions and community benefits 1 We’re happy that you and your veterinarian decided to help get your pooch back to Rim 1 form with RIMADYL — the number one NSAID for pain relief . Be sure to continue usin RIMADYL exactly as your doctor prescribes and take comfort in the fact that RIMADYL helped over 16 million dogs manage pain. Redeem the enclosed coupon check at your veterinarian’s clinic and you will automatic receive an additional $5 savings towards your next RIMADYL purchase! Sincerely, The RIMADYL Team 1. Market Dynamics Inc. (MDI), 2006 All brands are the property of Pfizer Inc., its affiliates, and/or its licensors. © 2009 Pfizer Inc. All rights reserved. 1750 2000 Suite Suite NE, Road, ree Road Peacht 30305 3400 , GA 30326 3060 Atlanta YL RIMAD Coupon Checked! enclos BAR RIM0907126 1750 Suite 2000 Suite Road NE, Peachtree Road, 3400 3060 Peachtree GA 30326 30305 Atlanta, Atlanta, GA k Novic Kim ood Dr. here 81 Kirkw ss line -1791 Addre A 2ND wn, PA 18940 E ARE Newto COD Kim Novick Dr. to ns Kirkwood 81 RIMADYL 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, in 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, here reaso 2ND Caplet/Chewable Tablets atAddress line Coupon More Stay PA 18940-1791 Check anddyl.cNewtown, om For oral use in dogs only alternative analgesia should Sit be considered. The use of another NSAID is not recommended. Sterile AREA Injectable Solution 50 mg/mL and we Due to the palatable nature of Rimadyl chewable tablets, store out of reach of dogs in a secured location. For subcutaneous use in dogs only Severe adverse reactions may occur if ofen), g enclosed! BAR CODE large quantities of tablets are ingested. If you suspect your dog has consumed Rimadyl chewable tablets ® (carpr above the labeled dose, please call your Non-steroidal, anti-inflammatory drug excitin veterinarian for immediate assistance and notify Pfizer Animal Health (1-800-366-5288). DYL some INFORMATION FOR DOG OWNERS: RIMA made Rimadyl, like other drugs of its class, is not free from adverse reactions. Owners should be advised of CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. with the potential for adverse reactions and be informed of the clinical signs associated with drug intolerance. Adverse reactions may include decreased to a $10 m and pain DESCRIPTION: Rimadyl (carprofen) is a non-steroidal anti-inflammatory drug (NSAID) of the propionic appetite, vomiting, diarrhea, dark acid class that includes ibuprofen, or tarry stools, increased water consumption, increased urination, pale gums due to anemia, yellowing g you naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substituted carbazole, 6-chloro-α-methyl-9H-carbazole-2-acetic of gums, skin or white of the eye due to dog’s progra jaundice, lethargy, incoordination, seizure, or behavioral changes. acid. The empirical formula is C15H12ClNO2 and the molecular weight 273.72. The chemical structure of carprofen DYL treatin is shown above. Carprofen is a white, ge your Serious adverse reactions associated with this drug class can occur without warning and in rare situations crystalline compound. It is freely soluble in ethanol, but practically insoluble in water at 25°C. RIMA s Rimadyl result in death (see Adverse mana rt, we’re Reactions). Owners should be advised to discontinue Rimadyl therapy and contact their veterinarian 2008 Injectable is a sterile solution containing carprofen. Each mL of Rimadyl Injectable contains 50.0 mg carprofen, immediately if signs of intolerance are k: help ped the to 30.0 mg arginine, 88.5 mg observed. October 2, glycocholic acid, 169.0 mg lecithin, 10.0 mg benzyl alcohol, 6.17 mg sodium hydroxide, with additional Novic promotion needed reasons ued suppo sodium hydroxide and hydrochloric revam acid as ued to you. More The vast majority of patients with drug-related adverse reactions have recovered when the signs are recognized, to adjust pH, and water for injection. Kim the drug is withdrawn, and veterinary contin contin s like We’ve care, if at tails we’d be appropriate, is initiated. Owners should be advised of the importance of periodic follow up for all dogs during Product Dear DYL. had CLINICAL PHARMACOLOGY: Carprofen is a non-narcotic, administration of any NSAID. your non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic your tail — if we owner you’ve RIMA wag WARNINGS: Keep out of reach of children. Not for human use. Consult a physician in cases of accidental activity approximately equipotent to indomethacin for you! in animal models. value ingestion by humans. For use in dogs Community glad Kim Novick: only. Do not use in cats. that you ase of news ted dog Dearing The mechanism of action of carprofen, like that of other NSAIDs, check se we RimaDog™ includ is believed to be associated with the inhibition of cyclooxygenase activity. Two We’re coupon purch All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. good ct joined theh tipsunique cyclooxygenases have been described in mammals. The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for ® (carprofen) Appropriate laboratory tests to establish for dedica is in dogs hematological and serum biochemical baseline data prior to, and periodically during, administration of normal gastrointestinal rs, becau your next incentives. that you’ve and renal function. The inducible cyclooxygenase, some COX-2, generates prostaglandins involved in inflammation. Inhibition , produ and any NSAID should be considered. Owners healt RIMADYL ically perks should be advised to observe for signs of potential drug toxicity (see Information for Dog Owners, Adverse of COX-1 is thought to be associated with gastrointestinal starte s have and renal toxicity while inhibition of COX-2 provides anti-inflammatory activity. The arthrit other Reactions, Animal Safety and PostWe’re so excited onials forversus theieenclosed Approval Experience). specificity of a particular NSAID for COX-2 COX-1 may vary from species to species. In an in vitro study using canine cell cultures, regularly toward Dogg es. For testim the them.r Please find ped specif ation about carprofen demonstrated selective inhibition of COX-2 versus COX-1. Clinical relevance of these data ADVERSE REACTIONS: During investigational studies for the caplet formulation with twice daily administration Community has not been shown. Carprofen has also good chang have of 1 mg/lb, no clinically significant been shown to inhibit the release of several prostaglandins in two inflammatory cell systems: rat polymorphonuclear owner develo adverse reactions were reported. Some clinical signs were observed during field studies (n=297) which leukocytes (PMN) and human were similar for carprofen caplet- and inform even wagging tips, visit the RimaDog rheumatoid synovial cells, indicating inhibition of acute (PMN system) and chronic (synovial cell system) to registe n check unity placebo-treated dogs. Incidences of the following were observed in both groups: vomiting (4%), diarrhea inflammatory reactions. (4%), changes in appetite (3%), lethargy Be sure to s studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune latest health (1.4%), behavioral changes (1%), and constipation (0.3%). The product vehicle served as control. coupo Several comm er, you’ll so be sure requested. responses. Data also indicate onial es the that carprofen inhibits the production of osteoclast-activating factor (OAF), PGE1, and PGE2 by its inhibitory canine There were no serious adverse events reported during clinical field studies with once daily administration effect in prostaglandin biosynthesis. d a new a memb of 2 mg/lb. The following categories of DYL, testim provid ines, abnormal health Based upon comparison with data obtained from intravenous administration, observations r were reported. The product vehicle served as control. check carprofen is rapidly and nearly completely absorbed (more than 90% create you’re unity bioavailable) when administered orally. Peak blood plasma of RIMA Owne concentrations are achieved in 1–3 hours after oral administration of 1, 5, and 25 mg/ also listed on the nt guidel clinic promotionsPercentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study (2 mg/lb once daily) kg to dogs. The mean terminal Comm half-life of carprofen is approximately 8 hours (range 4.5–9.8 hours) after single oral doses varying from its. Once purchases 1–35 mg/kg geme We’ve Product veterinary of body weight. After a 100 mg single intravenous bolus dose, the mean elimination half-life was approximately og™ Observation 11.7 hours in the dog. Rimadyl is Rimadyl (n=129) mana Placebo (n=132) more than 99% bound to plasma protein and exhibits check to the er benef purchase a very small volume of distribution. RimaD future Inappetence 1.6 RIMADYL The 1.5 Comparison of anext single 25 mg s on dose in Beagle dogs after subcutaneous and oral administration demonstrated that the dorsoscapular enclosed coupon and pain nal memb Vomiting your results subcutaneous 3.1 3.8 administration mingwithin in a slower rate of drug input (as reflected by mean peak observed concentrations) but comparable total — Take the saving Diarrhea/Soft stool r care drug absorption 3.1 savings 4.5 a 12 hour dosing interval (as reflected by area under the curve from hours zero to 12 postdose). Upcotoward Behavior change prope s use ofin theRIMADYL 0.8 and additio additional 0.8 and other instant $10 Carprofen is eliminated Dermatitis tips dog primarily by biotransformation in the liver followed by rapid excretion of the resulting metabolites 0.8 st tions proper 0.8 Receive an (the ester —ry, DYL withevent glucuronide of carprofen and the ether glucuronides ofRimaDog PU/PD 2 phenolic metabolites, 7-hydroxy carprofen and 8-hydroxy carprofen) in the feces 0.8 Doggie health – promo RimaDog is, surge (70–80%) and urine (10–20%). Some enterohepatic SAP increase to reque . circulation of the drug is observed. 7.8 back with the 8.3 RimaDog and But RIMA dog into a ALT increase tunity benefits checking 5.4 INDICATIONS: Rimadyl is indicated for the relief of pain and inflammation ly, arthrit nality. 4.5 associated with osteoarthritis and for the control of postoperative pain — Turn your yl.com AST increase oppor 2.3 associated with soft tissue and orthopedic and community surgeries in dogs. 0.8 unate BUN increase and regain g to your veterinarian DOSAGE 3.1 promotions 1.5 its perso at Rimad AND ADMINISTRATION: Always provide Client Information Sheet with prescription. The recommended talking Bilirubinuria dosage for oral administration 16.3 12.1 ge pain s it. Unfort even for additional Continuerevivin to dogs is!2 mg/lb (4.4 mg/kg) of body weight daily. The total daily dose may be administered as 2 mg/lb today Ketonuria of body 14.7 s and 9.1 mana — toward administered as 1 mg/lb (2.2 mg/kg) twice daily. For the control of postoperative pain, administer approximately weight once daily or divided and at Rimadyl.com 2 hours before the procedure. 1 dogs ess, and mean Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical Rimadyl tablets are scored and dosage should be calculated in half-tablet increments. Tablets can be Owner testimonial judgement is necessary to determine clinical halved by placing the tablet on a hard And more first stepCommunity relevance. surface and pressing down on both sides of the score. Rimadyl chewable tablets are palatable and willingly his tail consumed by most dogs when offered joy, happin 16 million take the to toRimaDog by the owner. Therefore, they may be fed by hand or placed on food. Care should wags During investigational studies of surgical pain for the caplet formulation, no clinically significant adverse be taken back ensure that the dog consumes the complete dose. reactions were reported. The product dog’s over who vehicle served as control. your topooch The recommended dosage for subcutaneous administration get dogs is 2 mg/lb (4.4 mg/kg) of body weight daily. The total daily dose may you’ll 1 your be administered as either 2to a dog mg/lbhelp of body weight once daily or divided and administered asusing Percentage of Dogs with Abnormal Health Observations Reported in Surgical Pain Field Studies with decided away Caplets (2 mg/lb once daily) has helpedCommunity, postoperative to continue 1 mg/lb (2.2 mg/kg) twice daily. For control of pain, administer approximately12 hours before og is the procedure. take . Be sure DYL your veterinarian relief og has PALATABILITY: A controlled Observation* palatability study was conducted which demonstrated that Rimadyl chewable Rimadyl (n=148) pain A RimaD pain can Placebo (n=149) RIMA Upcoming that you and consumed on firstfor offering by a majority of dogs. that RIMADYL tablets were readily accepted and NSAID Vomiting oneEFFECTIVENESS: 10.1 We’re happy s of In fact the RimaD 13.4 in the fact Diarrhea/Soft stool Confirmation ofcomfort the effectiveness of Rimadyl for the relief of pain and inflammation associated with osteoarthritis, and 6.1 — the number cause 6.0 for the l pain. events control of postoperative joining Ocular disease pain associated with soft tissue and orthopedic surgeries, was demonstrated in 7 placebo-controlled, and take 2.7 masked studies RimaDog 0 og. examining the anti-inflammatory and analgesic effectiveness of Rimadyl caplets in various breeds of prescribes contro Inappetence form with RIMADYL 1.4 les. By dogs. 0 your doctor Dermatitis/Skin lesion RimaD helps 2.0 Separate placebo-controlled, masked, multicenter field studies confirmed the anti-inflammatory and analgesic lifesty 1.3 exactly as effectiveness of Rimadyl caplets Dysrhythmia your pain. 0.7 when dosed at 2 mg/lb once daily or when divided and administered at 1 mg/lb twice daily. In these 2 0 RIMADYL active field studies, dogs diagnosed with Apnea within 1.4 osteoarthritis showed statistically significant overall improvement based on lameness evaluations by 07126 dogs manage when 0 their the veterinarian and owner observations Oral/Periodontal disease 1.4 spirit administered Rimadyl at labeled doses. 0 . RIM09 over 16 million Pyrexia 0.7 helped 1.3 active Based upon the blood level comparison between subcutaneous and oral administration, Rimadyl effectiveness reserved Urinary tract disease for osteoarthritis after the 1.4 rights 1.3 dorsoscapular subcutaneous and oral administration should be similar, although there may be a slight Wound more! drainage And delay in the onset of relief after automatically 1.4 Inc. All 0 subcutaneous injection. and you will Pfizer clinic * A single dog may have experienced more than one occurrence of an event. Separate placebo-controlled, masked, multicenter field studies confirmed the effectiveness of Rimadyl caplets for the control of postoperative pain . © 2009 when at 2 veterinarian’s mg/lb once daily in various breeds of dogs. In these studies, dogs presented for ovariohysterectomy, During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed your rely, at dosed cruciate repair and aural in some dogs. These signs included checksurgeries its licensors purchase! were administered Rimadyl preoperatively and vomiting and soft stools. for a maximum of 3 days (soft tissue) or 4 days (orthopedic) postoperatively. In general, Since your significant RIMADYL and/or YL Team dogs administered Rimadyl 2006 hstatistically showed reduction in pain scores compared to controls. enclosed coupon There were no serious adverse events reported during clinical field studies for the injectable formulation. your next The following categories of abnormal throug ANIMAL SAFETY STUDIES: towards Redeem the Laboratory studies in unanesthetized dogs and clinical field studies have demonstrated that Rimadyl its affiliates, health observations were reported. The product vehicle served as control. is ea, well The RIMAD ics Inc. (MDI), savings Inc., tolerated in dogs after oral administration. iption Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Studies with the diarrh additional $5 of Pfizer Dynam Injectable 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 receive an g and, by prescr ngdailyand recommended total dose) for 42 consecutive days with no significant adverse reactions. Serum albumin for a single female 1. Market are the property Observation* receiving 5 Rimadyl (n=168) warnin Placebo (n=163) lt returned to the pre-treatment value (2.6 g/dL) after 4 weeks ofdog mg/lbvomiti twice daily decreased to 2.1 tg/dL ble only loss, after 2 weeks of treatment, treatment, and Vomiting was 2.3 g/dL at the final All brands 10.1 6-week evaluation. Over the consu withou 6-week treatment period, black or bloody stools were observed in 1 dog (1 incident) treated availa 9.2 ite with Diarrhea/soft stool and treated 1 mg/lb twice daily and in 1 dog (2yincidents) 2.4 with 3 mg/lb twice daily. Redness of the colonic mucosa was observed in 1 male that occur 3.7 ation Dermatitis received 3 mg/lb twice daily. e appet 0.6 may 1.2 medic Sincerely, Dysrhythmia yl10therap 0.6 includ 0.6 Two of 8 dogs receiving mg/lb orally twice daily (10 times the recommended total daily dose) for 14 days exhibited hypoalbuminemia. atory effects albumin Swelling The mean may RIM0907126 0 Team Rimad 1.2 level in the dogs receiving this dose was lower (2.38 g/dL) than each side of 2 placebo control groups (2.88 and 2.93 g/dL, respectively). Three Dehiscence flamm The RIMADYL rights reserved. 1.2 ance All of tinue 0 incidents of black or bloody stool were observed in 1Inc. dog. Five 8 dogs exhibited reddened areas of duodenal mucosa on gross pathologic Pfizer WBC increase these 13.7 © 2009 6.7 Histologic exam of these al anti-in areas revealed no evidence of ulceration, but did show minimal congestion of the lamina propria in 2 of discon 5examination. yl intoler Some of Inc. (MDI), 2006 the and/or its licensors. dogs. teroid * A single dog may have experienced more than one occurrence of an event. ation. its affiliates, s. Dynamics ofoccur, Rimad 1. Market In separate safety studies lasting 13 and 52 weeks, respectively, dogs were administered orally up to signs Pfizer Inc.,inform total a non-s signs of Post-Approval Experience: 11.4 mg/lb/day (5.7 times the recommended are the property daily dose of 2 mg/lb) of carprofen. In both studies, the drug was well tolerated clinically by all of the or kidney yl is , Although not all adverse reactions are reported, the following adverse reactions are based on voluntary animals. No gross or histologic All brands 662 post-approval adverse drug experience liver changes were seen in any of the treated animals. In both studies, . If these prescribing ations Rimad reporting. The categories of adverse reactions are listed by body system. 00084 dogs receiving the highest doses had average increases in serum L-alanine aminotransferase (ALT) of approximately 20 IU. full Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal medic ation: ive tract, even death ulceration, gastrointestinal bleeding, In the 52-week study, minor dermatologic changes occurred in dogs in each of the treatment groups pancreatitis. -class but not in the control dogs. The changes were digest n of the Inform on or described as slight redness or rash and were diagnosed as66-21 Hepatic: Inappetence, vomiting, jaundice,your acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, non-specific dermatitis. The possibility exists that these mild lesions were treatment NSAID ing the related, but no dose relationship was observed. bilirubinuria, hypoalbuminemia. through alizati Safety Approximately one-fourth of hepatic reports were in Labrador Retrievers. rs” sectio 530 other Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation. tant involv hospit by prescription Clinical field studies were conducted with 549 dogs of different breeds at the recommended oral doses Owne only for 14 days (297 dogs were included Urinary: Hematuria, polyuria, polydipsia, in urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities Impor ng in As with a study evaluating 1 mg/lb twice daily and 252 dogs were included in a separate study evaluating 2 mg/lb effects available and diarrhea, once daily). In both studies the drug including for Dog acute tubular necrosis, renal tubular acidosis, glucosuria. was clinically well tolerated and the incidence of clinical adverse reactions for Rimadyl-treated vomiting arian. tory medication animals was no higher than placebo-treated te side loss, s, resulti Behavioral: Sedation, lethargy, hyperactivity, restlessness, ation and, aggressiveness. animals (placebo contained inactive ingredients found in Rimadyl). For animals receiving 1 mg/lb twice appetite veterin daily, the mean anti-inflamma post-treatment indica serum Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis. include ALT values were 11 IU greater and 9 IU less than pre-treatment without warning may values for dogs receiving Rimadyl and placebo, be seriou rtant Inform respectively. Differences were not Dermatologic: occur non-steroidal Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, could a animals statistically significant. is For may receiving 2 mg/lb once daily, the mean post-treatment intolerance ventral ecchymosis. serum ALT values were 4.5 IU greater and 0.9 IU effects In rare situations, injection site reactionsand consult Rimadyl including necrosis, abscess and seroma formation, and granulomas have been reported with the than pre-treatment values for dogs receiving Rimadyl and placebo, which side less ons may the “Impo of Rimadyl respectively. In the latter study, 3 Rimadyl-treated dogs developed a 3-fold or injectable formulation. therapy signs of these 2008 greater increase in (ALT) and/or (AST) during the ZERO course of therapy. One placebo-treated situati dog hadSome Rimadyl a greater than 2-fold increase in ALT. None of Safety Information: Immunologic See or hypersensitivity: Facial swelling, hives, erythema. ZERO medications, these animals showed clinical signs associated with laboratory or kidneys. value changes. Changes in the clinical laboratory values (hematology and Important ber 2, NSAID-class PERIOD in rare clinical In rare situations, death has been associated with some of the adverse reactions listed above. liver arian. chemistry) were not considered clinically significant. occur, discontinue tract, ZERO The 1 mg/lb twice daily course of therapy was repeated as signs needed at 2-week intervals in 244 Octo To report a suspected adverse reaction call 1-800-366-5288. ONE digestive dogs, some for as long as As with other 5 years. veterin the DOLLAR 2000 death. If these involving STORAGE: Store tablets at controlled room temperature 15°–30°C (59°–86°F). Store injectable under refrigeration veterinarian. information. your Clinical or even field studies were conducted in 297 dogs of different nbreeds 2°–8°C (36°–46°F). Once effects l Health Suite undergoing orthopedic or soft-tissue surgery.prescribing broached, product may be stored at temperatures up to 25°C (77°F) for 28 days. full Dogs were administered 2 mg/lb of Rimadyl two hours prior to surgery then once daily, as needed for 2 days (soft tissueof hospitalizatio the indicate side Animaree Road, surgery) in or 3 days (orthopedic surgery). Rimadyl was could well tolerated HOW SUPPLIED: Rimadyl caplets and chewable tablets are scored, and contain 25 mg, 75 mg, or 100 mg when used in conjunction with a variety of anesthetic-related drugs. resulting which The type and severity of abnormal health observation in RimadylPfizer of carprofen per caplet or tablet. Each Owners” section and placebo-treated animals were approximately caplet size is packaged in bottles containing 30, 60, or 180 caplets, or blister paks containing 4 caplets. e Peacht Each chewable tablet size is packaged in for Dog may be serious, was vomiting and was observed at approximately bottles containing 7, 30, 60, or 180 tablets. Rimadyl 3060 , GA 30305 the same frequency in Rimadyl- and placebo-treated animals. Changes in clinicopathologic Injectable is supplied in 20-mL, amber, glass, sterile, multi-dose vials. 00084662 Information in rare situations indices of hematopoetic, renal, hepatic, and clotting function were not clinically significant. The mean post-treatment serum ALT REFERENCES: values were 7.3 IU Atlanta and 2.5 IU less than pre-treatment values for dogs receiving Rimadyl and placebo, See the “Important 2, 2009 respectively. The mean post-treatment AST values were 3.1 IU 1. Baruth H, et al: In Anti-Inflammatory and Anti-Rheumatic Drugs, Vol. II, Newer Anti-Inflammatory Drugs, ry2006 Rainsford KD, ed. CRC Press, Boca Raton, p. 33, 1986. 66-21 less for dogs receiving Rimadyl and 0.2 IU greater 1Market Dynamics for dogs receiving placebo. Inc. (MDI), 2. Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol 25:102, qual and few in number (see Adverse Reactions). The most frequent abnormal your veterinarian. pp. 9–21, 1996. Janua health observation ***** Clinical field studies on the use of Rimadyl Injectable 3. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase d bywere conducted on 331 dogs undergoing orthopedic or soft tissue surgery. Dogs were activity in human platelets and mononuclear cells by NSAIDs and COX530 administered 2 mg/lb of Rimadyl subcutaneously two hours prior to surgery and once daily thereafter, ital 2 inhibitors. Inflammation Research 44:253–257, 1995. as needed, for 2 days (soft tissue surgery) or cashe 3 days (orthopedic surgery).be 4. Ricketts AP, Lundy KM, Seibel SB: Evaluation of selective inhibition of canine cyclooxygenase 1 and Rimadyl was well tolerated when used in conjunction with a variety of anesthetic-related drugs. The ********** 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J type and severity al Hosp Health of abnormal health Vet Res 59:11, pp. 1441–1446, November 1998. observations in Rimadyl- and placebo-treated animals were approximately equal and few in number (see Adverse must Animal Reactions). 2000 The most frequent 5. Ceuppens JL, et al: Non-steroidal anti-inflammatory agents inhibit the synthesis of IgM rheumatoid Pfizer Anim abnormal health observation was vomiting and was observed at approximately the same frequency in Rimadylfactor in vitro. Lancet 1:528, 1982. 2,and2008 check Changes Road, Suite TS ***** placebotreated animals. 6. Ceuppens JL, et al: Endogenous prostaglandin E2 enhances polyclonal immunoglobulin production in clinicopathologic indices of hematopoetic, renal, hepatic, and clotting function October Peachtree by ionically inhibiting T suppressor cell activity. Cell Immunol 70:41, 1982. This were not clinically significant. The y Land 3060 CEN mean post-treatment serum ALT values were 8.4 IU and 7.0 IU less 7. Schleimer RP, et al: The effects of prostaglandin synthesis inhibition Rima er 2, Octob 2008 Rimadyl.com 1 2 3 4 1 5–9 1 What to do now: Your dog deserves RimaDog to be a 10 rs can’t be wrong 16 million tail-wagge Important Safety Information: Rimadyl is a non-steroidal anti-inflammatory medicatio veterinarian. As with other NSAID-class medications, signs of Rimadyl intolerance may One final trick which could indicate side effects involving the digestive tract, liver or kidneys. Some of . 00 $10 in rare situations may be serious, resulting in hospitalization or even death. If these sign your veterinarian. See the “Important Information for Dog Owners” section of the full pre $10 . 00 Happ ********** TEN ********** Fido AND 00 k Novic Kim od Dr -1791 18940 81 Kirkwo wn PA Newto than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. 30305 The mean post-treatment Atlanta, GA AST values were 1.5 IU and 0.7 IU greater for dogs receiving Rimadyl and placebo, respectively. CONTRAINDICATIONS: Rimadyl should not be used in dogs exhibiting previous hypersensitivity to carprofen. 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 prostaglandins from arachidonic acid.11–14 When NSAIDs inhibit prostaglandins that cause inflammation they may also inhibit those prostaglandins 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 Hospital been undiagnosedAnimal 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. Happy Land The use of parenteral fluids during surgery should be considered to reduce the ********* potential risk of renal complications when using NSAIDs perioperatively. 12,14 11–14 TEN AND 00 CENTS *********** 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. Since many NSAIDs possess the potential to induce gastrointestinal ulceration, concomitant use of Rimadyl with such as corticosteroids and NSAIDs, should be avoided or very closely monitored. Sensitivity to drug-associated other anti-inflammatory drugs, the individual patient. For example, Rimadyl treatment was not associated with renal toxicity or gastrointestinal adverse reactions varies with ulceration in well-controlled safety studies of up to ten times the dose in dogs. As with any parenterally injected product, good hygienic procedures should be used when administering Rimadyl Injectable. ******************** This check Kim Novick Dr 81 Kirkwood 18940-1791 Newtown PA on the immune response. Immunopharmacology 3:205, 1981. 8. Leung KH, et al: Modulation of the development of cell mediated immunity: Possible roles of the products of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Int J Immunopharmacology 4:195, 1982. 9. Veit BC: Immunoregulatory activity of cultured-induced suppressor macrophages. ZERO Cell Immunol 72:14, 1982. PERIOD ZERO 10. Schmitt M, et al: Biopharmaceutical evaluation ZERO of carprofen following single intravenous, oral, and rectal doses in dogs. Biopharm Drug Dispos 11(7):585, 1990. DOLLAR ONE 11. Kore AM: Toxicology of nonsteriodal anti-inflammatory drugs. Veterinary Clinics of North America, Small Animal Practice 20, March 1990. 12. Binns SH: Pathogenesis and pathophysiology of ischemic injury in cases of acute renal failure. Compend for Cont Ed 16:1, January 1994. 13. Boothe DM: Prostaglandins: Physiology and clinical implications. Compend for Cont Ed 6:11, November 1984. 14. Rubin SI: Nonsteroidal anti-inflammatory drugs, prostaglandins, and the kidney. JAVMA 188:9, May 1986. 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. 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. NADA #141-053, NADA #141-111, NADA #141-199 Approved by FDA. 2, 2009 Injectable Manufactured by: Vericore Limited, Dundee, United Kingdom must be cashed by January Distributed by: Exton, PA 19341, USA Div. of Pfizer Inc NY, NY 10017 August 2006 Printed in USA Fido Pfizer Animal Health 3060 Peachtree Road, Suite 2000 Atlanta, GA 30305 Octobe Happy Land Animal Hospital 3 Key Components of Compliance: 2 • Recommendation • Acceptance • Follow-Through Important Safety Information: ******************** TEN AND 00 CENTS ******************** Fido Kim Novick 81 Kirkwood Dr Newtown PA 18940-1791 As with other NSAIDs, rare but serious side effects involving the digestive system, kidneys, or liver may occur. Regular monitoring is required for pets on medication. Pet owners should be advised to discontinue RIMADYL therapy if side effects occur and to contact their veterinarian. Refer to the full prescribing information for complete details. 1. VetInsight Analytics, September, 2010. 2. 2009 AAHA Compliance Follow-up Study. Here’s how it works CONTINUE: Return > Refill > Reward > Remind Return • Dog returns to the hospital for evaluation and dog owner purchases RIMADYL Remind Dog owner receives email reminders and may download a mobile app: • Reminders to return to hospital for follow-ups • Reminders to give their dog their doses • Refill prescriptions • Manage their Rewards AT&T Refill 12:34 PM • Dog owner submits proof of RIMADYL purchase at rimadog.com and begins accumulating Rewards Points • Dog owner continues to administer RIMADYL as instructed by veterinarian • Dog owner continues to upload RIMADYL proofs-of-purchase—mobile app available for uploading proofs-of-purchase • Reward Points translate to dollars earned • Each point is approximately 10 cents per point-visit rimadog.com for exact points value Reward • Dog owner accumulates a minimum of 200 points • Receives Debit Card (Rewards Card) with dollars earned • More purchases = more rewards loaded on card 3060 Peachtree Road, Suite 2000 Atlanta, GA 30305 Sample Pet Owner 1234 Any Street Apartment ABC Somewhere, USA 12345 A Rewards539094 Pro 0000000000 that Offsets thegram Your Dog’s Car Costs of e GOOD THRU 08/13 J. SMITH HAPPYLAND PET HOSPITAL Program Rule s The RIMADY L Rewards RIMADYL REWAR Program is with your a rewarding veterinarian DS PROGR • Limit one way to partner AM: to ensure your dog. (1) Reward the health It’s also a s Card per and well-be great way made after household. ing of long-term to help you September Offer valid care your offset the costs 1 30, 2011 or for purchas • Invoice dog needs. We’re glad you’re using RIMADYL® (carprofen), the #1 pain medication prescribed by veterinarians , for to help manage the is from date es required to the of registra inflammation and pain associated with your dog’s arthritic joints. To show our appreciation we’ve enclosed a $10 •reward good validate proof of tion. Invoice card What must include purchase. does healthy the followin rewards mean? towards your next purchase of RIMADYL. • Purchas g information: your Reward e of RIMADY It means that s points towards L chewable you can use • Dog’s name tablets or caplets clinic includin ANY expens g diagnostics e at your veterina • Customer’s and annual ry name exams. Dear Valued Customer Introducing healthy rewards for you and your dog! • Veterinary clinic name or authoriz DOLLA The RIMADYL Rewards Program is uniquely EARN designed to benefit your dog’s health while helping you provide long term care. • MG and RS WITH ed home delivery sizes of bottle YOUR LOVIN As you continu company name purchased As you continue to care for your dog with RIMADYL, you’ll ebe to accumulate reward points that translate into dollar amounts. G CARE. • Receipts to eligible (i.e., 25mg, care for your will not be medica 30 tablets) dog earned dollars. See the enclosed brochure for tionyour As you continue to earn points, we continue to reload Rewards Card with prescri unauthorizedmore accepted from online bed by veterina with RIMADYL, the #1 pharmacies reward home delivery pain rians, information on the exciting RIMADYL Rewards Program sign your dog up at www.rimadog.com. pointsand or • Invoice may you’ll accumu companies. based on the amoun be sent via late These reward t of RIMADY mail, fax, or • All proofs points transla L you purchas by uploadi of purchas spend exclusi te into dollar ng a photo e must be e. amounts you purchase. online. vely at your submitted veterinary within 1 (one) can diagnostic clinic to offset tests, annual • Minimum year of of 200 points the cost for exams, addition The RimaDog™ Community is your officialother online companion, thealwell being of dogs everywhere. That’s why we’re per clinic expense. helping ensure of initial RIMADY proof of purchas dog must be approve L or any friends. Together, thrilled to have the support of members like you who only want the best for their furry, four-legged we’re reviving thee submis d within 1 the first (one) year sion for Reward time. After spirit inside every RimaDog! that, points s Card to be valid proof will be loaded loaded of purchas to the card e provided. • Purchases with each for multiple Sincerely, dogs cannot point require be combin ments. Maximu ed to meet • Rebate amount m 3,360 points minimum per dog per The RIMADYL Team must be redeem year. Rewards Card ed within 1 load or by Pfizer Animal Health (one) year card expirati of last in that time on date. Dollars are forfeited . not redeem • Users ed monitor or any P.S. You can use your RIMADYL Rewards Card to offset the costs for diagnostic testing, annual exams, additionalcan RIMADYL balance inquirie and track progress of proof of other expense exclusively at your veterinary clinic. s and more purchase approva by logging on www.ri madog.com. in to their MY ls, ACCOUNT profile 1. VetInsight Analytics, September, 2010. Limit up to 5 dogs per household. Program IMPORTANT SAFETY INFORMATION: RIMADYL is a non-steroidal anti-inflammatory medication available only by canprescription change at through any time without your veterinarian. As with other NSAID-class medications, signs of RIMADYL intolerance may include appetite loss, vomiting and notice. U.S. Residents diarrhea, which could indicate side effects involving the digestive tract, liver or kidneys. Some of these side effects may occur without Only. warning and, in rare situations may be serious, resulting in hospitalization or even death. If these signs occur, discontinue RIMADYL RIMADYL is a registered therapy and consult your veterinarian. See the “Important Information for Dog Owners” section of the full prescribing information. RIM091101 trademark Your RimaDog Community This card is issued by FNB Bank. Services are provided by FirstView Financial, LLC. Your Card funds are FDIC insured. All brands are the property of Pfizer, Inc., its affiliates, and/or its licensors. © 2011 Pfizer Inc. All Rights Reserved. RIM0511009A 9 of Pfizer Inc. © 2011 Pfizer Inc. All rights reserved. FVIBB02 RIMADYL Rew ard s Program: Healthy Rew ard and Your Dog s for You www.rimadog. com Pet owners receive the above items Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Studies with the Injectable Observation* Vomiting Diarrhea/soft stool Dermatitis Dysrhythmia Swelling Dehiscence WBC increase 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 Rimadyl (n=129) 1.6 3.1 3.1 0.8 0.8 0.8 7.8 5.4 2.3 3.1 16.3 14.7 Placebo (n=132) 1.5 3.8 4.5 0.8 0.8 – 8.3 4.5 0.8 1.5 12.1 9.1 Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical judgement 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* Vomiting Diarrhea/Soft stool Ocular disease Inappetence Dermatitis/Skin lesion Dysrhythmia Apnea Oral/Periodontal disease Pyrexia Urinary tract disease Wound drainage Rimadyl (n=148) 10.1 6.1 2.7 1.4 2.0 0.7 1.4 1.4 0.7 1.4 1.4 Placebo (n=149) 13.4 6.0 0 0 1.3 0 0 0 1.3 1.3 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. The product vehicle served as control. 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 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 1-800-366-5288. DOSAGE AND ADMINISTRATION: Always provide Client Information Sheet with prescription. Carefully consider the potential benefits and risk of Rimadyl and other treatment options before deciding to use Rimadyl. Use the lowest effective dose for the shortest duration consistent with 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 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 postoperative pain, administer approximately 2 hours before the procedure. Rimadyl tablets are scored and dosage should be calculated in halftablet 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. 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 administered as either 2 mg/lb of body weight once daily or divided and administered as 1 mg/lb (2.2 mg/kg) twice daily. For control of postoperative pain, administer approximately 2 hours before the procedure. 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. EFFECTIVENESS: Confirmation of the effectiveness of Rimadyl for the relief of pain and inflammation associated with osteoarthritis, and for the control of postoperative pain associated with soft tissue and orthopedic surgeries, was demonstrated in 7 placebo-controlled, masked studies examining the anti-inflammatory and analgesic effectiveness of Rimadyl caplets in various breeds of dogs. Separate placebo-controlled, masked, multicenter field studies confirmed the anti-inflammatory and analgesic effectiveness of Rimadyl caplets 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 osteoarthritis showed statistically significant overall improvement based on lameness evaluations by the veterinarian and owner observations when administered Rimadyl at labeled doses. Based upon the blood level comparison between subcutaneous and oral administration, Rimadyl effectiveness for osteoarthritis after dorsoscapular subcutaneous and oral administration should be similar, although there may be a slight delay in the onset of relief after subcutaneous injection. Separate placebo-controlled, masked, multicenter field studies confirmed the effectiveness of Rimadyl caplets for the control of postoperative pain when dosed at 2 mg/lb once daily in various breeds of dogs. In these studies, dogs presented for ovariohysterectomy, cruciate repair and aural 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. ANIMAL SAFETY STUDIES: Laboratory studies in unanesthetized dogs and clinical field studies have demonstrated that Rimadyl is well tolerated in dogs after oral administration. 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 recommended total daily dose) for 42 consecutive days with no significant adverse reactions. Serum albumin for a single female dog receiving 5 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 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 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 received 3 mg/lb twice daily. 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 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 incidents of black or bloody stool were observed in 1 dog. Five of 8 dogs exhibited reddened areas of duodenal mucosa on gross pathologic examination. Histologic exam of these areas revealed no evidence of ulceration, but did show minimal congestion of the lamina propria in 2 of the 5 dogs. 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 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 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 549 dogs of different breeds at the recommended oral doses for 14 days (297 dogs were included in 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 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). For animals receiving 1 mg/lb twice daily, the 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. 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 than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. In the latter study, 3 Rimadyl-treated dogs developed a 3-fold or 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 these animals showed clinical signs associated with laboratory value changes. Changes in the clinical laboratory values (hematology and clinical 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 dogs, some for as long as 5 years. Clinical field studies were conducted in 297 dogs of different breeds undergoing orthopedic or soft-tissue surgery. Dogs were administered 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 well tolerated when used in conjunction with a variety of anesthetic-related drugs. The type and severity of abnormal health observation in Rimadyland placebo-treated animals were approximately equal and few in number (see Adverse Reactions). The most frequent abnormal health observation 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 IU less than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. The mean post-treatment AST values were 3.1 IU less for dogs receiving Rimadyl and 0.2 IU greater for dogs receiving placebo. Clinical field studies on the use of Rimadyl Injectable were conducted on 331 dogs undergoing orthopedic or soft tissue surgery. Dogs were 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 days (orthopedic surgery). Rimadyl was well tolerated when used in conjunction with a variety of anesthetic-related drugs. The type and severity of abnormal health observations in Rimadyl- and placebo-treated animals were approximately equal and few in number (see Adverse Reactions). The TAKE TIME most frequent abnormal health observation 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 posttreatment 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. 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 to 25°C (77°F) for 28 days. HOW SUPPLIED: Rimadyl caplets and chewable tablets are scored, and contain 25OBSERVE mg, 75 mg,LABEL or 100 mg of carprofen per caplet or tablet. Each DIRECTIONS 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 bottles containing 7, 30, 60, or 180 tablets. Rimadyl Injectable is supplied in 20-mL, amber, glass, sterile, multi-dose vials. REFERENCES: 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. 2. Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol 25:102, pp. 9–21, 1996. 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 COX2 inhibitors. Inflammation Research 44:253–257, 1995. 4. Ricketts AP, Lundy KM, Seibel SB: Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs. Am J Vet Res 59:11, pp. 1441–1446, November 1998. 5. Ceuppens JL, et al: Non-steroidal anti-inflammatory agents inhibit the synthesis of IgM rheumatoid factor in vitro. Lancet 1:528, 1982. 6. Ceuppens JL, et al: Endogenous prostaglandin E2 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. 8. Leung KH, et al: Modulation of the development of cell mediated immunity: Possible roles of the products of cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism. Int J Immunopharmacology 4:195, 1982. 9. Veit BC: Immunoregulatory activity of cultured-induced suppressor macrophages. Cell Immunol 72:14, 1982. 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. 11. Kore AM: Toxicology of nonsteriodal anti-inflammatory drugs. Veterinary Clinics of North America, Small Animal Practice 20, March 1990. 12. Binns SH: Pathogenesis and pathophysiology of ischemic injury in cases of acute renal failure. Compend for Cont Ed 16:1, January 1994. 13. Boothe DM: Prostaglandins: Physiology and clinical implications. Compend for Cont Ed 6:11, November 1984. 14. Rubin SI: Nonsteroidal anti-inflammatory drugs, prostaglandins, and the kidney. JAVMA 188:9, May 1986. 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. TAKE TIME —OBSERVE LABEL DIRECTIONS 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. NADA #141-053, NADA #141-111, NADA #141-199 Approved by FDA. Injectable Manufactured by: Vericore Limited, Dundee, United Kingdom Made in India Distributed by: TAKE TIME Div. of Pfizer Inc NY, NY 10017 All trademarks are the property of Zoetis, Inc. or its subsidiaries, affiliates and licensees. ©2013 Zoetis Inc. All rights reserved. RIM1011021 Placebo (n=163) 9.2 3.7 1.2 0.6 1.2 0 6.7 * A single dog may have experienced more than one occurrence of an event. 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-inflammatory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substituted carbazole, 6-chloro-α-methyl-9H-carbazole-2-acetic acid. The empirical formula is C15H12ClNO2 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), PGE1, and PGE2 by its inhibitory effect in 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 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 (see Information for Dog Owners, Adverse Reactions, Animal Safety and PostApproval 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 prostaglandins from arachidonic acid.11–14 When NSAIDs inhibit prostaglandins that cause inflammation they may also inhibit those prostaglandins 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.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, in 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. 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 Pfizer Animal Health (1-800-366-5288). 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, 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 Inappetence Vomiting Diarrhea/Soft stool Behavior change Dermatitis PU/PD SAP increase ALT increase AST increase BUN increase Bilirubinuria Ketonuria Rimadyl (n=168) 10.1 2.4 0.6 0.6 0 1.2 13.7 OBSERVE LABEL DIRECTIONS December 2007 Printed in USA