Rimadyl Unleashed

U N LE ASHEDRelief: UnleashedCanine osteoarthritis is a chronic, progressive, inflammatory diseaseLeft unchecked, the cycle of inflammation and pain can lead to chronic pain (wind-up) and ongoing joint damage, both of which become progressively more difficult to treat as they worsen.17

NSAIDs are a cornerstone of osteoarthritis managementFor improved activity and quality of life, medical treatment of osteoarthritis should include the triad of weight control, exercise, and pharmacological management of inflammation and pain.5 NSAIDs break the progressive cycle of inflammation and pain by acting in both the joint and the dorsal horn.11 For most dogs, the benefits of using NSAIDs outweigh the risks.4,21

RIMADYL offers pain relief dogs can feel, for improved activity you can seeRIMADYL reduces inflammation and pain in dogs with osteoarthritis so they can stay active.3,4 Administration is simple because dogs enjoy the palatability of RIMADYL chewable tablets and dosing is once daily.22,24 With more than 90 evidence-based articles, RIMADYL has established safety and efficacy and allows veterinarians to confidently prescribe the #1 NSAID.26*

Ongoing control of inflammation and pain for chronic osteoarthritisRecent journal articles demonstrate that long-term use of NSAIDs (Innes et al), and specifically RIMADYL (Autefage et al), has clinical benefits, with a low risk of adverse events.4,21

A daily dose of pain relief

RELIEF.


References

*Clinical studies conducted in companion animals.

All trademarks are the property of Zoetis, Inc. or its subsidiaries, affiliates and licensees. ©2013 Zoetis Inc. All rights reserved. RIM0111002

Synovium

Synovial fluid

Cartilage

Capsule

Subchondral boneCruciate ligament destruction

Thickened capsule

Thickened subchondral bone

Fibrillated/destroyed cartilage

Osteophyte

Narrowed joint space

Inflamed synovium

Reduced viscosity of synovial fluid

OsteoarthritisNormal

Osteoarthritis involves all components of the joint

Overview of osteoarthritis

Osteoarthritis affects as many as 20% of dogs in the US and is one of the most common sources of canine pain.1,2

Osteoarthritis (OA) inflammation and pain: A progressive cycle of deterioration

• Involves the entire joint

• Ongoing inflammation

• Progressive degradation

• Chronic pain

• Decreased activity

• An overall negative impact on the patient

2

NSAIDs* and other pharmacologics

Exercise Weight Control

Most veterinarians believe that osteoarthritis is under-diagnosed and under-treated.7

Break the cycle of osteoarthritis with a comprehensive approach

Goals of osteoarthritis therapy are to decrease inflammation and pain, resulting in:

• Increased activity 3,4

• Preserved muscle mass and strength

• Regained function

Medical treatment of osteoarthritis should include the triad of weight control, exercise, and pharmacological management of inflammation and pain for an improved quality of life.5

If properly treated, the progression of osteoarthritis can be slowed.6

* Non-Steroidal Anti-Inflammatory Drug (NSAID).

Overview of OA

3

Perception of joint pain

Pro-inflammatory mediatorsProstaglandins•Cytokines•

Synoviocytes release pro-inflammatory mediators

Stimulates neurogenic inflammation

Causes further damage to cartilage leading to further release of MMPs & degradation products

Thickening of subchondral bone

Osteophyte

Damaged cartilage releases degradation products

Trauma

Progression to severe osteoarthritis

Damaged chondrocytes release MMPs

Inflammatory and pain cycle of osteoarthritis

4

Mechanism of disease8-10

In osteoarthritis, the initial damage to the cartilage causes the release of cartilage degradation products, and injury to the chondrocytes result in release of matrix metalloproteinases (MMPs). MMPs are catabolic enzymes that cause additional damage to the cartilage.

MMPs and cartilage degradation products stimulate synoviocytes to release pro-inflammatory mediators, such as cytokines and prostaglandins.

In canine osteoarthritis, inflammation not only causes pain, but also contributes to irreversible joint damage.11

Pathophysiology of osteoarthritis

5

Prostaglandins and other pro-inflammatory mediators initiate and maintain 2 cycles:

Inflammatory cycle2,9,11-13

• Pro-inflammatory mediators cause further damage to the cartilage, resulting in the release of MMPs and cartilage degradation products

• The inflammatory cycle is perpetuated when MMPs and cartilage degradation products stimulate additional release of pro-inflammatory mediators

• If left untreated, inflammation eventually causes irreversible damage to cartilage, subchondral bone, synovium, and joint capsule

Pain cycle14

• Inflammation causes the initial pain through stimulation of joint nociceptors

• As more overt biochemical changes occur in the joint, mechano-receptors are engaged and contribute to pain

• Pain can contribute to the disease process of osteoarthritis through neurogenic inflammation15,16

Persistent, uncontrolled pain leads to chronic peripheral and central hypersensitization, also known as wind-up pain

Components of wind-up pain• Amplification

• Allodynia

• Lower activation threshold

• Activation of wide dynamic range neurons (WDR)

Pathophysiology of OA

Consequences of wind-up pain• Difficult to treat

• Often only managed, not eliminated

• Reoccurs without additional trauma

Trauma

NSAIDs NSAIDs

NSAIDs

NSAIDs

Prostaglandins

Perception of joint pain

Diagnosis and treatment of chronic pain is challenging

DiagnosisAlthough pain is the hallmark clinical sign of osteoarthritis, it can be subtle and often goes unnoticed. Some challenges of diagnosing chronic pain:

• Dog owners often do not mention it as a problem

– Might not recognize subtle signs – Attribute subtle changes to “old age” or “slowing down”

• Because dogs mask pain, the degree of pain may not be appreciated during physical examination

TreatmentSince wind-up is more difficult to treat, one treatment modality may not control the multiple receptors that have been activated in chronic pain.17 This adds to the complexity of treating chronic osteoarthritis.

Optimal management of osteoarthritis should focus on early and continuous treatment.

NSAIDs: A cornerstone of osteoarthritis management5,11

An important goal of osteoarthritis treatment is to break the progressive cycle of inflammation and pain.

Prostaglandins contribute to inflammation, pain, and loss of function of the affected joint. By selectively blocking the release of prostaglandins, NSAIDs decrease inflammation and provide analgesia in the joint. NSAID activity also provides pain relief in the dorsal horn.

6

Treatment of osteoarthritis

Assessing the benefits and risks of NSAID use18,19

For the majority of patients, the benefits of using NSAIDs will outweigh the risks. However, the risk-benefit analysis of using NSAIDs should be determined on a patient-to-patient basis. There are 2 major categories of adverse events (AEs):

The most common AEs seen with NSAIDs are inducible and include gastrointestinal irritation.20

Idiosyncratic reactions occur infrequently (≤1 in 10,000) and are more likely to appear in the first 5 to 90 days of treatment.18

Though individual patient response may vary, the benefits of treating with an NSAID most often outweigh the risks for the majority of dogs.4,21

Inducible • Reactions are dose related

• Reactions are attributable to the mechanism of action of the drug

• Predictable

Idiosyncratic• Not dose related

• Not attributable to the mechanism of action of the drug

• Unpredictable and rare

Clinical considerations when prescribing NSAIDs • Review history of previous medications and

medical conditions

• Perform a thorough physical exam

• Screen the patient for any underlying conditions

• Inform the owner of potential risks and benefits

• Distribute client information sheets

• Use the lowest label dose that achieves an effective response

• Monitor individual response to determine appropriate duration of treatment

7

Treatment of OA

Weight (lbs)

OnceDaily

Dosage100 mg

91-120

100 mg

61-90

100 mg

41-60

75 mg

31-40

100 mg

21-30

75 mg

16-2011-15

25 mg

5-10

1/2 Tab 1 Tab 1/2 Tab 1/2 Tab 1 Tab 1 Tab 1 1/2 Tabs 2 Tabs

25 mg

RIMADYL: Inflammation and pain relief unleashed

Effective treatment22

• Indicated for the relief of inflammation and pain associated with osteoarthritis in dogs

• Reduces pain in dogs with osteoarthritis so they can stay active3,4

• Also indicated for the control of postoperative pain associated with soft-tissue orthopedic surgeries in dogs

Effective dosing

• The FDA-approved safe and effective dose of RIMADYL is 2 mg/lb (4.4 mg/kg) once daily

• Once-daily dosing improves compliance among pet owners23

• More dosing options than any other NSAID

• Dogs enjoy the palatability of RIMADYL chewable tablets22,24

In a study conducted by the American Animal Hospital Association (AAHA), dog owners reported that chewable tablets were the easiest formulation to administer.25

88

RIMADYL® (carprofen)

An established efficacy and safety record

• RIMADYL has been used to safely treat more than 16 million dogs26

• With more than 90 evidence-based articles published in peer-reviewed journals, RIMADYL has established safety and efficacy and allows veterinarians to confidently prescribe the #1 NSAID26*

A trusted partner

• Zoetis, Inc. is fully committed to veterinarians and dedicated to continuing to build a diverse and innovative portfolio of first-in-class prescription medicines, such as RIMADYL

• RIMADYL was the first NSAID approved for canine use and has been a trusted NSAID to veterinarians since 1997

Important Safety InformationAs 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.


99

RIMADYL

® (carprofen)

RIMADYL is the only NSAID FDA approved for use in dogs as young as 6 weeks old.†† 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.

10

Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis”21

• Long-term was defined as 28 to 120 days of continuous treatment

• Published studies were evaluated based on the strength of scientific evidence

– Only 15 peer-reviewed articles met the evaluation criteria

• Of these 15 articles, 10 included carprofen

• Safety, efficacy, progressive decrease in pain, progressive tolerance over time, altered disease progression, and an increase (or decrease) in adverse events were evaluated

* Not all products evaluated in these studies are approved by the FDA for use in companion animals. Zoetis, Inc. does not recommend use of any product in an extra label manner.

† RIMADYL is approved in the USA for use in dogs for the relief of pain and inflammation associated with osteoarthritis and control of postoperative pain associated with soft tissue and orthopedic surgeries at the dose of 4.4 mg/kg (2 mg/lb) body weight. In some of these studies, carprofen was used at the lower European dose of 4.0 mg/kg body weight.

Papers reviewed to evaluate the safety and efficacy of long-term NSAID use for the treatment of canine osteoarthritis*†

Carprofen

Firocoxib and carprofen

Firocoxib

Carprofen and etodolac and meloxicam

Carprofen and meloxicam

Carprofen

Meloxicam and carprofen

Carprofen

Firocoxib and etodolac

Carprofen

Aspirin and carprofen and etodolac

Deracoxib and aspirin

Meloxicam

Carprofen

Licofelone

NSAID

YES

YES

YES

YES

YES

YES

YES

YES

FUNCTIONAL EFFICACY STUDIED

84 days

30 days

29 days

90 days

60 days

2 months

60 days

120 days

30 days

28 days

28 days

28 days

28 days

28 days

28 days

TREATMENT PERIOD

805

218

6

36

71

22

62

110

149

6

24

24

40

6

16

NUMBER OF DOgS

750

202

6

29

68

22

62

97

128

6

24

24

38

6

13

NUMBER OF DOgS COMPLETINg STUDY

Mansa and others (2007)

Pollmeier and others (2006)

Ryan and others (2006)

Luna and others (2007)

Moreau and others (2003)

Raekallio and others (2006)

Sauvé and others (2003)

Autefage and gosselin (2007)

Hanson and others (2006)

Lipscomb and others (2002)

Reimer and others (1999)

Sennello and Leib (2006)

Doig and others (2000)

Pelletier and others (2000)

Moreau and others (2007)

REFERENCESAFETY STUDIED

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

YES

Long-term NSAID use : Systematic review

“

Results

• Of the 15 articles reviewed, 7 compared efficacy over time

– 6 showed progressive improvement

– 1 showed no difference

• There was no significant correlation between study length and experimental (adverse) event rate

“...the current evidence suggests that there is a clinical benefit of longer-term NSAID use for dogs with chronic osteoarthritis and that this is associated with a low risk of serious adverse events.”

— Innes et al. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec. 2010.


11

Innes et al

VAS

Sco

re (

mm

)

Day of study

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0

Day 0 Day 5 Day 30 Day 60 Day 90 Day 120

Overall severity of the condition

Lameness

Limitation ofjoint movements

Pain on movement

12

Long-term RIMADYL use : Clinical study

Efficacy and safety of long-term oral administration of carprofen in the treatment of osteoarthritis in dogs”4

• 110 dogs with chronic signs of osteoarthritis were administered RIMADYL once daily for 120 days*

Results

Veterinary investigators• The percentage of dogs showing a positive treatment effect increased from 12% on Day 5 to

74% on Day 120

• Mean Visual Analog Scale (VAS) scores for the 4 clinical parameters assessed by the veterinary investigators significantly decreased throughout the study (P≤0.05)

Improvement in signs increased steadily over time

* RIMADYL is approved in the USA for use in dogs for the relief of pain and inflammation associated with osteoarthritis and control of postoperative pain associated with soft tissue and orthopedic surgeries at the dose of 4.4 mg/kg (2 mg/lb) body weight. In some of these studies, carprofen was used at the lower European dose of 4.0 mg/kg body weight.

Evolution over time of the 4 clinical parameters scored by investigators

Adapted from Autefage et al.

“

Revue Méd. Vét., 2007, 158, 03, 119-127

Efficacy and safety of the long-term oral admi-nistration of carprofen in the treatment of osteo-arthritis in dogsA. AUTEFAGE1 and J. GOSSELLIN2*

1 Professor, Head of the Department of Surgery, National Veterinary School of Toulouse, 23 Chemin des Capelles, F-31076 Toulouse Cedex 3, France.2 Veterinary Medicine Research and Development, Pfizer Ltd., Ramsgate Road, Sandwich Kent, CT13 9NJ, United Kingdom.

* Corresponding author: E-mail : [email protected]

SUMMARY

The aim of this study conducted in France was to confirm the efficacy andsafety of the oral administration of carprofen (Rimadyl®) at 4 mg/kg once aday during four months in the treatment of clinically chronic osteoarthritis indogs. One hundred and ten dogs with chronic clinical signs of osteoarthritiswere enrolled. The overall severity of the osteoarthritis condition and the cli-nical signs of osteoarthritis were assessed using visual analogue scales(VAS) on days 0, 5, 30, 60, 90 and 120. During the same visits, owners wereasked to perform their own efficacy assessment through the grading of sevenparameters using categorical scales. Hematological analyses were perfor-med on days 0 and 120. Clinical blood chemistry evaluations were perfor-med on days 0, 5, 60 and 120. The percentage of dogs showing a positivetreatment effect increased from 12% on day 5 to 74% on day 120. The meanVAS scores significantly decreased throughout the study (P ≤ 0.05). Gastro-intestinal undesirable effects likely to be related to carprofen but with noharmful consequences were observed in 5% of treated dogs. No detrimentaleffects of the treatment on haematological, renal and hepatic parameterswere observed. These results show that carprofen at 4 mg/kg once daily canbe safely used over a 4 month period in the treatment of osteoarthritis in dogsand provides a steadily increasing improvement of the clinical signs.

Key-Words : osteoarthritis, carprofen, efficacy, safety,dog

RÉSUMÉ

Efficacité et innocuité de l’administration orale de carprofène à longterme dans le traitement de l’arthrose chez les chiens.

L'objectif de cette étude menée en France était de confirmer l'efficacité etla sécurité d'emploi du carprofène (Rimadyl®) administré par voie orale à laposologie de 4 mg/kg une fois par jour et pendant quatre mois dans le traite-ment de l'arthrose accompagnée de signes cliniques chroniques chez leschiens. Cent dix chiens présentant des signes cliniques chroniques d'arthroseont été inclus dans cette étude. La sévérité globale de l'arthrose ainsi que lessignes cliniques d'arthrose ont été évalués en utilisant une échelle analogiquevisuelle (EAV) aux jours 0, 5, 30, 60, 90 et 120. Aux mêmes visites, les pro-priétaires ont procédé à leur propre évaluation de l'efficacité en quantifiantsept paramètres sur des échelles qualitatives. Des analyses hématologiquesont été réalisées aux jours 0 et 120. Des analyses biochimiques sanguinesont été réalisées aux jours 0, 5, 60 et 120. Le pourcentage de chiens montrantun effet positif du traitement a augmenté de 12% au jour 5 à 74% au jour120. Les scores moyens d'EAV ont diminué de manière significative durantl'étude (P ≤ 0.05). Des effets indésirables gastro-intestinaux probablementliés au carprofène mais sans conséquences dommageables ont été observéschez 5% des chiens traités. Aucun effet préjudiciable du traitement n'a étéobservé sur les paramètres hématologiques, rénaux et hépatiques. Ces résul-tats montrent que le carprofène administré quotidiennement à la posologie de4 mg/kg peut être utilisé sans risque sur une période de quatre mois dans letraitement de l'arthrose chez les chiens tout en améliorant progressivementles signes cliniques.

Mots-Clés : arthrose, carprofène, efficacité, sécuritéd’emploi, chien

IntroductionOsteoarthritis is a common concern for owners of old dogs

but it has also been estimated that some forms of osteo-arthritis affect more than 20% of dogs which are more thanone year old [5]. Osteoarthritis is a slowly progressive degen-erative disease of synovial joints characterized by pain,disability, destruction of cartilage, and bony remodelling [6].As it is a chronic disease that cannot be cured, it requireslong-term care. The current trend is to promote the contin-uous use of non steroidal anti-inflammatory drugs (NSAIDs)over long periods because of their ability to reduce joint painand decrease synovitis [6]. However several NSAIDs used inveterinary medicine have been involved in gastro-intestinal,renal and haematological adverse effects as well as in carti-lage destruction in cases of prolonged administration [4].

Carprofen (Rimadyl®; Pfizer) is a member of the group ofNSAIDs. It is a carboxylic acid belonging to the subclass ofarylpropionic acids which exerts its anti-inflammatory andanalgesic effects primarily by inhibiting the cyclooxygenaseenzyme and blocking the production of prostaglandins [3].Carprofen is approved for the long-term treatment of osteo-arthritis in dogs in most European countries.

The safety margin of carprofen was found to be relativelywide compared with other NSAIDs in toxicological studies[4]. In addition, daily administrations of carprofen at 4 mg/kgdid not have any deleterious effect on the cartilage structurein several in vitro and in vivo studies. Instead, the latterstudies showed a potential beneficial effect [1, 11, 2]. At ther-apeutic concentrations in dogs, carprofen increases thesynthesis of proteoglycans in the osteoarthitic cartilage [1,11, 2]. In experimentally induced osteoarthritis in dogs,

MARS07.book Page 119 Lundi, 26. mars 2007 11:00 11

13

Pet owners• Owners also observed a continuous and steady improvement of the following 6 parameters

• The improvements observed by owners were comparable to what was observed by the veterinary investigators

Other clinical observations• Gastrointestinal undesirable effects likely to be related to carprofen, but with no harmful

consequences, were observed in 5% of the treated dogs

• No detrimental effects of the treatment of hematological, renal, and hepatic parameters were observed


– Going up and down stairs

– Walking

– Standing up or lying down

– Playing or doing physical exercise

– Running

– Jumping

“...the long-term administration of carprofen provides a steadily increasing improvement of clinical signs of osteoarthritis in dogs and does not result in an increase of the incidence of suspected adverse reactions.”

— Autefage et al. Efficacy and safety of the long-term oral administration of carprofen in the treatment of osteoarthritis in dogs. Revue Med Vet. 2007.

Autefage et al

1. Gaynor, J et al. (Eds) 2003. The Essential Guide to Pain Management: A complete Resource for Veterinary Pain Management. Zoetis, Inc., New York.

2. Johnston SA. Osteoarthritis: joint anatomy, physiology and pathobiology. Vet Clin N Am Small Anim Pract. 1997;27:699-723.

3. Brown DC et al. Use of activity monitor to detect response to treatment in dogs with osteoarthritis. JAVMA. 2010;237:66-70.

4. Autefage A, Gossellin J. Efficacy and safety of long-term oral administration of carprofen in the treatment of osteoarthritis in dogs. Revue Med Vet. 2007;158(3):119-127.

5. Johnston SA, Budsberg SC. Non-steroidal anti-inflammatory drugs and corticosteroids for the management of canine osteoarthritis. Vet Clin North Am Small Anim Pract. 1997;27:841-862.

6. Litman D. Maximizing success in osteoarthritis care: benefits of a comprehensive management approach. Int J Rheum. 2008;5:1-37.

7. Proprietary Market Research, Zoetis, Inc.

8. Pelletier JP et al. Etiopathogenesis of osteoarthritis. In: A Textbook of Rheumatology. Koopman W (ed). 14th ed, 2195-2245. Lippincott, Williams and Wilkins; Baltimore, 2000.

9. Clegg PD et al. Characterisation of equine matrix metalloproteinases 2 and 9 and identification of the cellular source of these enzymes in joints. Equine Vet J. 1997;29:335-342.

10. Martel-Pelletier et al. Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci. 1990;4: D694-D703.

11. Camu F, Shi l, Vanlersberghe C. The role of COX-2 inhibitors in pain modulation. Drugs. 2003;63(Suppl 1):1-7.

12. Kammerman et al. Tumor necrosis factor-∂ in canine arthritis: Immunolocalization of TNF∂, stromelysin and TNF receptors in canine arthritic cartilage. Osteoarthritis Cartilage. 1996;4:23-34.

13. Oegema TR et al. Role of acute trauma in development of osteoarthritis. Agents Actions. 1993;40:220-223.

14. Johnston S. Overview of pain in the lame patient. Vet Clin North Am Small Anim Pract. 2001;31:39-53.

15. Konttinen YT et al. Pain fibers in osteoarthritis: a review. Semin Arthritis Rheum. 1989;18(4 Suppl 2):35-40.

16. Konttinen YT et al. Peripheral and spinal neural mechanisms in arthritis, with particular reference to treatment of inflammation and pain. Arthritis Rheum. 1994;37:965-982.

17. Muir WW. Choosing and administering the right analgesia therapy. In: Veterinary Pain Management. Eds: Gaynor JS, Muir WW. Mosby 2002.

18. Lee WM. Drug-induced hepatotoxicity. NEJM. 2003;349:474-485.

19. Park BK et al. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol. 1992;34: 377-395.

20. Wolf MM et al. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. NEJM. 1999;340:1888-1899.

21. Innes JF, Clayton J, Lascelles BD. Review of the safety and efficacy of long-term NSAID use in the treatment of canine osteoarthritis. Vet Rec. 2010;166:226-230.

22. RIMADYL Freedom of Information, S/NADA 141-111, August 21, 2002.

23. American Animal Hospital Association. Compliance: Taking Quality Care to the Next Level, A Report of the 2009 AAHA Compliance Follow-Up Study. AAHA Press, Lakewood, CO. 2009.

24. Data on file, Study Report No. 1760R-60-06-759, Zoetis, Inc.

25. American Animal Hospital Association. 2009 AAHA Compliance Follow-Up Study. Module II, Slide 41. Unpublished.

26. VetInsite Analytics, September 2010.

References

References

U N LE ASHEDRelief: UnleashedCanine osteoarthritis is a chronic, progressive, inflammatory diseaseLeft unchecked, the cycle of inflammation and pain can lead to chronic pain (wind-up) and ongoing joint damage, both of which become progressively more difficult to treat as they worsen.17

NSAIDs are a cornerstone of osteoarthritis managementFor improved activity and quality of life, medical treatment of osteoarthritis should include the triad of weight control, exercise, and pharmacological management of inflammation and pain.5 NSAIDs break the progressive cycle of inflammation and pain by acting in both the joint and the dorsal horn.11 For most dogs, the benefits of using NSAIDs outweigh the risks.4,21

RIMADYL offers pain relief dogs can feel, for improved activity you can seeRIMADYL reduces inflammation and pain in dogs with osteoarthritis so they can stay active.3,4 Administration is simple because dogs enjoy the palatability of RIMADYL chewable tablets and dosing is once daily.22,24 With more than 90 evidence-based articles, RIMADYL has established safety and efficacy and allows veterinarians to confidently prescribe the #1 NSAID.26*

Ongoing control of inflammation and pain for chronic osteoarthritisRecent journal articles demonstrate that long-term use of NSAIDs (Innes et al), and specifically RIMADYL (Autefage et al), has clinical benefits, with a low risk of adverse events.4,21


RELIEF.


References


All trademarks are the property of Zoetis, Inc. or its subsidiaries, affiliates and licensees. ©2013 Zoetis Inc. All rights reserved. RIM0111002

Caplets/Chewable TabletsFor oral use in dogs only

CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian.DESCRIPTION: Rimadyl (carprofen) is a non-steroidal anti-inflamma tory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Carprofen is the nonproprietary designation for a substi tuted carbazole, 6-chloro- -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 hematolo gical and serum biochemical baseline data prior to, and periodically during, administration of any NSAID should be considered. Owners should be advised to observe for signs of potential drug toxicity (see Information for Dog Owners, Adverse Reactions, Animal Safety and Post-Approval Experience).PRECAUTIONS: As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Effects may result from decreased prostaglandin production and inhibition of the enzyme cyclooxygenase which is responsible for the formation of prosta-glandins from arachidonic acid.11–14 When NSAIDs inhibit prosta glandins that cause inflammation they may also inhibit those prosta glandins which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically 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 Rimadyl (n=129) Placebo (n=132) Inappetence 1.6 1.5 Vomiting 3.1 3.8 Diarrhea/Soft stool 3.1 4.5 Behavior change 0.8 0.8 Dermatitis 0.8 0.8 PU/PD 0.8 SAP increase 7.8 8.3 ALT increase 5.4 4.5 AST increase 2.3 0.8 BUN increase 3.1 1.5 Bilirubinuria 16.3 12.1 Ketonuria 14.7 9.1

Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical 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* Rimadyl (n=148) Placebo (n=149)Vomiting 10.1 13.4 Diarrhea/Soft stool 6.1 6.0 Ocular disease 2.7 0 Inappetence 1.4 0 Dermatitis/Skin lesion 2.0 1.3 Dysrhythmia 0.7 0 Apnea 1.4 0 Oral/Periodontal disease 1.4 0 Pyrexia 0.7 1.3 Urinary tract disease 1.4 1.3 Wound drainage 1.4 0

* A single dog may have experienced more than one occurrence of an event.During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed in some dogs. These signs included vomiting and soft stools.There were no serious adverse events reported during clinical field studies for the injectable formulation. The following categories of abnormal health observations were reported. The product vehicle served as control.

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 Diarrhea/soft stool 2.4 3.7 Dermatitis 0.6 1.2 Dysrhythmia 0.6 0.6 Swelling 0 1.2 Dehiscence 1.2 0 WBC increase 13.7 6.7

* A single dog may have experienced more than one occurrence of an event.

Post-Approval Experience: Although not all adverse reactions are reported, the following adverse reactions are based on voluntary post-approval adverse drug experience reporting. The categories of adverse reactions are listed 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 half-tablet increments. Tablets can be halved by placing the tablet on a hard surface and pressing down on both sides of the score. Rimadyl chewable tablets are palatable and willingly consumed by most dogs when offered by the owner. Therefore, they may be fed by hand or placed on food. Care should be taken to ensure that the dog consumes the complete dose.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 admini stration, 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 Rimadyl- and 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 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 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 25 mg, 75 mg, or 100 mg of carprofen per caplet or tablet. Each 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 COX- 2 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 nonste roi dal 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 Immuno pharma cology 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. Veter inary 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.

December 2007 Printed in USA

OBSERVE LABEL DIRECTIONS

TAKE TIME

Sterile Injectable Solution 50 mg/mLFor subcutaneous use in dogs onlyNon-steroidal, anti-inflammatory drug

–

Injectable Manufactured by: Vericore Limited, Dundee, United KingdomMade in India

NY, NY 10017

Distributed by:Zoetis Inc.333 Portage St.Kalamazoo, MI 49007

Manufactured by:Zoetis LLCLincoln, NE, USA

Revised: April 2013Printed in USA.

Modulation of the development of cell mediated immunity: Possible roles of the products of cyclooxygenase and lipoxygenase pat Modulation of the development of cell mediated immunity: Possible roles of the products of cyclooxygenase and lipoxygenase pathways of arachidonic hways of arachidonic

72:14, 1982. 72:14, 1982. Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs. Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs. Biopharm Drug DisposBiopharm Drug Dispos 11(7):585, 1990. 11(7):585, 1990.Biopharm Drug DisposBiopharm Drug Dispos 11(7):585, 1990.Biopharm Drug DisposBiopharm Drug Dispos

Veter inary Clinics of North America, Small Animal PracticeVeter inary Clinics of North America, Small Animal Practice 20, March 1990. 20, March 1990.Veter inary Clinics of North America, Small Animal PracticeVeter inary Clinics of North America, Small Animal Practice 20, March 1990.Veter inary Clinics of North America, Small Animal PracticeVeter inary Clinics of North America, Small Animal PracticeCompend for Cont EdCompend for Cont Ed 16:1, January 1994. 16:1, January 1994.Compend for Cont EdCompend for Cont Ed 16:1, January 1994.Compend for Cont EdCompend for Cont Ed

6:11, November 1984. 6:11, November 1984. 188:9, May 1986. 188:9, May 1986.

Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. JAVMAJAVMA 217:1025–1028, 2000. 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 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. at 1-800-366-5288.

Revised: April 2013Revised: April 2013Printed in USA.Printed in USA.Printed in USA.Printed in USA.

217:1025–1028, 2000. 217:1025–1028, 2000.

at 1-800-366-5288. at 1-800-366-5288.

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Rimadyl Unleashed