Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 1

TECHNICAL BULLETIN November 2014

Peri-Operative Use of Key Points ® Injectable Rimadyl • Since inflammation is a driving factor in the develop ment of surgical pain, the anti-inflammatory (carprofen) properties of Rimadyl® (carprofen) make this drug an important component of a post-operative pain management protocol. • Preemptive pain management, followed by appro- priate intra-operative and post-operative analgesia, Sharon L. Campbell, DVM, MS, DACVIM can circumvent central sensitization and prevent Randi Brannan, DVM, FAVD, DAVDC the onset of chronic, intractable pain. Dennis Caywood, DVM, MS, DACVS, CCRT • Rimadyl is the only NSAID developed in the US Dennis J. Chmiel Jr., DVM, MBA specifically for canine use and is available as oral David Martin, DVM, DACVAA caplet, chewable tablet, and sterile injectable (SC) Paul Q Mitchell, DVM, DAVDC formulations. All formulations have the same indications: – relief of pain and inflammation associated with osteoarthritis; Zoetis Inc. – control of post-operative pain associated 100 Campus Drive with soft tissue and orthopedic procedures. Florham Park, NJ 07932 • Rimadyl is the only injectable NSAID approved by the FDA for controlling post-operative pain in the dog that is supported by greater than 10 years of research. • Rimadyl Injectable can be administered at 4.4 mg/kg (2.0 mg/lb) SC before surgery as part of a balanced, multimodal anesthesia/analgesia protocol, providing 24 hours of analgesia. After surgery, patients can be easily transitioned to oral Rimadyl since no wash-out period is required between use of the injectable and oral Rimadyl. • Clinical and pharmacokinetic studies support the benefits of administering Rimadyl Injectable pre- operatively to control post-operative pain in dogs, as dogs that received Rimadyl prior to surgery had better immediate post-operative analgesia than dogs that received Rimadyl after surgery. • The mechanism of action that allows NSAIDs to provide effective analgesia may also be responsible for adverse reactions in some patients. Although adverse events associated with Rimadyl Injectable are rare, patient selection is essential to ensure favorable outcomes. In stable canine patients, the benefits of administering Rimadyl Injectable pre- operatively outweigh the risks and will provide up to 24 hours of analgesia. Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 2

INTRODUCTION AND RATIONALE Although extensive studies have not been conducted to evaluate consecutive use of The effects of non-steroidal anti-inflammatory different NSAIDs, a wash-out period is drugs (NSAIDs) are exerted through the recommended when changing from one inhibition of cyclooxygenase (COX) enzymes NSAID to another.2 By using Rimadyl and the subsequent synthesis of prosta - Injectable pre-operatively, followed by oral glandins. As key components of inflammation, Rimadyl post-operatively, continuous and prostaglandins contribute to the generation of uninterrupted analgesia can be provided pain by synergistically interacting with other throughout surgery and recovery, including inflammatory mediators. Thus, the analgesic the convalescent period after the patient is effects of NSAIDs are mediated through released from the hospital. inhibition of COX enzymes and prostaglandin synthesis. With proper patient selection, preparation, and monitoring, the anti-inflammatory and analgesic Rimadyl® (carprofen) was the first NSAID benefits associated with pre-operative adminis- developed in the US specifically for use in the tration of an NSAID such as Rimadyl Injectable dog. The original oral tablet formulation was can outweigh potential risks. Evidence evalu- approved by the FDA in 1996, followed by ating the use of approval of the highly palatable chewable tablet Rimadyl Injectable in 1999. Rimadyl Injectable sterile solution was for control of post- approved in 2003 and is labeled for subcuta- operative pain, Since inflammation is a driving neous (SC) injection. Both formulations can be including a review of administered as a single daily dose of 4.4 relevant pharma- factor in the development of surgical mg/kg body weight (2.0 mg/lb) or divided into cology, efficacy, and pain, the anti-inflammatory twice-daily doses at 2.2 mg/kg (1.0 mg/lb).1 safety data, is properties of Rimadyl make this Both formulations have the same indications summarized in this for use: Bulletin to help drug an important component of a 1. Relief of pain and inflammation associated practitioners make post-operative pain-management with osteoarthritis informed decisions on protocol. 2. Control of post-operative pain associated when to include with soft tissue and orthopedic procedures Rimadyl Injectable as part of a multimodal Rimadyl is the first injectable NSAID, and anesthetic/analgesic protocol. First, however, carprofen is the only injectable NSAID that is the role of COX enzymes in pain and inflam- FDA approved for controlling post-operative matory responses is briefly reviewed. pain in the dog, and is backed by over 10 years of research. Since inflammation is a driving COX ENZYMES AND EARLY NSAIDs factor in the development of surgical pain, the anti-inflammatory properties of Rimadyl make By inhibiting COX enzymes, NSAIDs are anti- this drug an important component of a post- inflammatory, analgesic, and antipyretic. The operative pain-management protocol: two primary COX enzymes are identified as COX-1 and COX-2, and differences between • Rimadyl Injectable can be administered SC these enzymes are summarized below. before surgery as part of a balanced, multimodal anesthesia/analgesia protocol. COX-1: The injectable Rimadyl formulation provides an alternative to use of an oral pre- • Is constitutively expressed (i.e., is detect - operative NSAID, especially when the able at relatively constant levels during animal is sedated or unresponsive, normal physiological conditions) and intractable, or at risk of emesis (e.g., due to responsible for maintaining normal an anesthetic drug), or for other situations homeostasis in a number of organ systems where oral medications are not an option. including: 3 • After surgery, patients can be easily – gastrointestinal (GI) tract integrity; transitioned to oral Rimadyl since no wash- – renal sodium and water absorption;4 out period is required between use of the – platelet aggregation.5 injectable and oral Rimadyl formulations.

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Zoetis NSAID Technical Bulletin

COX-2: Results of these assays have been variable and the clinical relevance has not been established. • Is an inducible enzyme (i.e., only present Therefore, in vitro assays evaluating COX during pathological conditions such as inhibition by an NSAID are not reliably predictive inflammation) which is up-regulated after of efficacy or safety. Rather, the efficacy and arachidonic acid is released as a result of safety of an NSAID can only be determined by cell injury and initiates a cascade of events robust clinical studies.16 that results in synthesis of pro-inflammatory prostaglandins such as prostaglandin E2 Studies that have investigated the efficacy (PGE ) and prostacyclin (PGI ). 2 2 and safety of canine NSAIDs, combined with • Is constitutively expressed in the kidney their clinical history, have demonstrated that and, through PGE2 production, regulates all approved veterinary NSAIDs are safe and sodium and water absorption. effective when used according to label • Is up-regulated during renal ischemia, recommendations. Clear-cut distinctions in the performance of these NSAIDs have not been leading to synthesis of PGE2 and PGI2, both potent vasodilators that maintain renal observed in the general population of dogs, but individual patients may better tolerate one blood flow of the proximal renal artery to 17 preserve glomerular filtration rate in NSAID over another. Maximizing the benefits hypovolemic or hypotensive patients.6-8 and minimizing the risks of any NSAID used in an anesthesia protocol should involve appro- • May play a role in renal development priate patient selection, assessing the level of (COX-2-deficient mice have been shown analgesia required, supporting the patient to develop severe renal dysplasia).9 during surgery to maintain vital organ function, • Plays a cytoprotective role in the GI tract. monitoring the patient’s response, and Although not involved in maintaining GI accordingly adjusting the patient’s environment. homeostasis in the normal healthy GI tract, COX-2 enzymes are up-regulated in gastric ‘PAIN’ OVERVIEW inflammation and play an important role in healing gastric ulcerations.10 As potent anti-inflammatory drugs, NSAIDs are routinely used in human and veterinary When the first NSAIDs such as aspirin and medicine to control post-operative pain. The indomethacin were developed, the roles of the following graphics and discussion summarizes two COX enzymes were unknown. These key concepts that need to be considered for drugs indiscriminately inhibited both COX-1 managing the pain of a surgical patient. An and COX-2 enzymes, and although effective as overview of the pain pathway (Figure 1), the analgesics, the drugs had significant adverse- various types of pain, and the role that event profiles which limited their use. As it inflammation plays in initiating surgical pain became clear that COX-1 was constitutive and (Figure 2) is helpful to better understand the COX-2 was primarily involved in inflammation, analgesic effects of NSAIDs. newer COX-1-sparing NSAIDs were developed. The goal was to selectively inhibit the inflam- Pain Pathway matory activity of COX-2 enzymes while The pain pathway (Figure 1) has four distinct preserving the ‘housekeeping’ or homeostatic stages, starting with transduction and ending activities of COX-1 enzymes in an effort to with perception. Drug therapies have been minimize adverse effects. developed to interfere with pain transmission at each of these stages. NSAID effects occur at However, as the cytoprotective effects of the transduction and modulation. COX-2 enzymes were discovered, the need to balance COX-2 inhibition became apparent. Responses to Pain The currently available FDA-approved veterinary NSAIDs selectively inhibit COX-2 to a greater Pain is an unpleasant sensory and emotional extent than COX-1 in varying degrees. In vitro experience associated with actual or potential studies have been conducted to determine the tissue damage. Several responses to pain difference in COX-2 and COX-1 enzyme ensue once a peripheral pain signal has been inhibition of these drugs, in an effort to predict initiated. their clinical efficacy and safety profiles.11-15

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Figure 1 – The classical ‘pain pathway’ involves 4 major steps: transduction, transmission, modulation, and perception, with physiologic changes occurring at each of these steps.18 1. Transduction: The first step in the pain pathway starts when a sufficiently intense noxious stimulus (mechanical, thermal, or chemical) causes initiation of an action potential by high-threshold myelinated Aδ and unmyelin - ated C primary afferent nerve fibers. Transduction is the process where a non-electrical stimulus is transduced into an electrical potential at the nociceptors (free endings) of these sensory neurons. 2. Transmission: Once the action potential is initiated, the signal is transmitted along the primary sensory nerve to the dorsal horn of the spinal cord. 3. Modulation: Within the dorsal horn, the primary sensory neurons synapse with secondary neurons, where the pain signal is modulated and can be enhanced or diminished. 4. Perception: After the primary sensory neurons synapse with second-order neurons of specific ascending spinal tracts within the dorsal horn, the pain signal is projected to different areas within the brain, including the cerebral cortex, where it is perceived as pain.

A. Withdrawal reflex: The peripheral sensory Pathological Pain neuron synapses with interneurons within the spinal cord, which synapse with Pain can be categorized as either: efferent motor neurons in the ventral horn 1) physiological pain, also known as nociceptive to stimulate flexor muscles and initiate a pain (see below); or 2) pathological pain, which withdrawal reflex. The withdrawal reflex includes: occurs simultaneously with projection of the • inflammatory pain (due to tissue damage); pain signal to the brain. This explains the • chronic pain or maladaptive pain; unconscious withdrawal response that occurs concurrently with the acknowledge - • neuropathic pain (due to nerve damage; ment of the pain sensation.19 see below).21 B. Neurogenic inflammation: As illustrated in Figure 3, neurogenic inflammation involves PHYSIOLOGICAL PAIN: Physiological pain is the immediate response to a noxious a positive feedback mechanism whereby stimulus and is mediated through high-threshold pain receptors located on thinly the peripheral sensory neuron releases myelinated Aδ and unmyelinated C nerve fibers. neurotransmitters in a retrograde manner, •Aδ nociceptors are responsible for ‘first pain’ which is typically sharp, localized, back to the area of inflammation, and and transient. stimulate release of prostaglandins and • C nociceptors conduct pain more slowly and project to larger receptive fields other inflammatory mediators. Neuro genic than Aδ nociceptors. Pain associated with C-fiber activation is characterized as inflammation can become part of a ‘second pain’ which has a slow onset, is dull or throbbing, and poorly localized. progressive cycle of inflammation and Physiological pain is unpleasant, causing the individual to immediately withdraw tissue damage that maintains the release of from the painful stimulus. Physiological pain is a protective mechanism that signals inflammatory mediators and contributes to individuals to avoid or reduce exposure to the inciting cause and allows an individual peripheral and central sensitization.20 to adapt and interact safely with their environment. C. Descending pathway modulation: Once the pain signal reaches the brain, descending NEUROPATHIC PAIN: This type of pain is a result of nerve damage which causes pathways can be inhibitory (providing ectopic generation of action potentials. Limb amputation, crushing injuries, and analgesia) or excitatory (exacerbating pain), endocrinopathies (e.g., diabetes mellitus, hepatic neuritis) are conditions associated further modulating the sensation of pain. with neuropathic pain. Similar to chronic inflammatory pain, neuropathic pain is also a maladaptation of the nervous system resulting in central sensitization and manifests as hyperalgesia and allodynia. 4 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 5

Figure 2 – Overview of the role of inflammation in iniating surgical pain. Tissue damage that occurs after trauma results in a dramatic change of the chemical environment of the Aδ and C nociceptors. The damaged cells, as well as inflammatory cells (mast cells, macrophages, and lymphocytes), release a number of inflammatory mediators, including prostaglandins, bradykinin, histamine, serotonin (5 HT), ATP, and nerve growth factor (NGF), creating an acidic environment known as the ‘sensitizing soup.’ Inflammatory mediators result in heat, swelling, redness, and pain, which are the hallmarks of inflammation. Some of the inflammatory mediators act directly on the nociceptor to initiate a pain signal, while others sensitize these high-threshold nociceptors, lowering the action potential threshold, resulting in peripheral sensitization. Once peripheral sensitization is established, the typically high-threshold nociceptors not only respond to lower threshold stimuli, but also amplify response to those stimuli. Peripheral sensiti- zation establishes a zone of primary hyperalgesia in the area of inflammation. The peripherally sensitized nociceptors, specifically C-fibers, increase the rate of action potentials, resulting in a supranormal release of neurotransmitters such as 1) glutamate, which activates N-methyl-D-aspartate (NMDA) and α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors; 2) Substance P, which activates Neurokinin-1 (NK-1) receptors; and 3) calcitonin gene-related peptide (CGRP), which activates CGRP receptors. The increased release of neurotransmitters sensitizes the dorsal horn neurons, resulting in central sensitization. Just as with peripheral sensitization, the neurons in the dorsal spinal cord become sensitized to pain signals. Central sensitization involves an alteration of synaptic receptor density, threshold, and activation. Changes associated with central sensitization lead to allodynia and secondary hyperalgesia. Pain associated with central sensitization persists even after the primary pain stimulus resolves. 5 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 6

Figure 3 – Neurogenic inflammation due to retrograde release of neurotransmitters such as substance P and CGRP back to the area of inflammation, resulting in vasodilation, leakage of proteins, fluid, and inflammatory cells, which further contribute to the inflammatory response.

Inflammatory pain — Peripheral sensitization is clinically manifested as primary hyperalgesia, an exaggerated and Inflammatory pain occurs after tissue trauma prolonged pain response initiated by the sensiti- (such as surgery) and is a result of cell damage zation of the Aδ, C, and silent nociceptors that causes a release of ions and inflammatory located in the area directly affected by tissue mediators (such as prostaglandins, see Figure damage and inflammation. 2) which sensitize Aδ and C nociceptors. Sensitized nociceptors have a decreased Several inflammatory mediators are involved in de polari za tion threshold so that these typically the development of peripheral sensitization, high-threshold nociceptors respond to low- including those summarized in Figure 2. threshold stimuli. This heightened or hyper - Though these inflammatory mediators can act sensitive response to pain stimuli is called independently, they more often work together to peripheral sensitization (Figure 2).22 Peripheral create a ‘sensitizing soup’ that leads to sensitization also involves activation of ‘silent peripheral sensitization.24-27 nociceptors’, normally inactive C-fiber noci - ceptors that become activated by inflammatory Peripheral sensitization is reversible, with pain mediators. Once activated, the silent noci - signaling returning to a normal state after the ceptors respond to mechanical and thermal injury resolves. Similar to physiological pain, stimuli, contributing to peripheral hypersensiti- peripheral sensitization can be a protective and zation. Therefore, peripheral sensitization results reparative response to tissue damage, initiating in a hyperactivity to pain both through lowered behavioral changes that allow an individual to activation thresholds and recruitment of silent rest and protect the injured area, in order to nociceptors.23 prevent further injury and facilitate healing.22

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Zoetis NSAID Technical Bulletin

Central sensitization — a specific injury, and will resolve when the injury heals. In contrast, chronic pain represents a Central sensitization occurs when repetitive maladaptation to pain and persists after the firing of sensitized C-fibers causes a constant initial injury resolves. It is a continuation of release of excitatory neurotransmitters within central sensitization with a drastic alteration in the dorsal horn (Figure 2). Constant bombard - pain processing within the dorsal horn of the ment and release of neurotransmitters such as spinal cord. The net effect of chronic pain is that Substance P, calcitonin gene-related peptide pain is no longer associated with the original (CGRP), and glutamate leads to an increase in injury but is now a disease itself, arising sponta- the sensitivity of the dorsal horn neurons.27 neously and resistant to treatment. These neurotransmitters bind to specific receptors in the dorsal horn, including neuro - kinin-1 receptors, CGRP receptors, N-methyl- COX ENZYMES, PROSTAGLANDINS, D-aspartate (NMDA), and α-amino-3-hydroxy- AND SENSITIZATION 5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and contribute to the exaggerated As mentioned earlier, prostaglandins are among response to pain.27 Central sensi tization is not the inflammatory mediators contributing to the only a result of an increase in excitatory development of peripheral and central sensiti- stimulus but can also result from a decreased zation associated with inflammatory and response to inhibitory neurotransmitters.27 chronic pathological pain. Peripherally, in response to tissue damage, COX-2 enzymes Clinical manifestations of central sensitization are up-regulated, resulting in the synthesis of include secondary hyperalgesia and allodynia. prostaglandins that contribute to the ‘sensitizing Secondary hyperalgesia involves a pain soup’ which leads to peripheral sensitization of sensation that appears to originate outside the the nociceptors. Prostaglandins facilitate the area of the damaged tissue and is due to Aδ development of peripheral sensitization and nerve fiber activation. Allodynia occurs when a primary hyperalgesia by lowering the C and light tactile touch results in painful response Aδ nociceptor action potential thresholds. due to Aβ sensory nerve fiber activation. Prostaglandins can also activate silent C Although both secondary hyperalgesia and nociceptors, thus increasing the number of allodynia appear to originate from the periphery, nociceptors involved in pain and further these phenomena are actually generated contributing to primary hyperalgesia.32,33 CENTRAL centrally due to the modification and dynamic Clinical evidence that COX-2 enzymes and SENSITIZATION: changes in processing of input in Aδ fibers and prostaglandins contribute to post-operative Aβ sensory nerve fibers within the dorsal pain was demonstrated in a study involving “Central sensitization horn.25-30 human patients undergoing surgery.34 In this introduces another study, an increase in COX-2-derived dimension, one Central sensitization occurs concurrently with prostaglandin levels in the peripheral nervous where the CNS can peripheral sensitization and is also a protective system was correlated with an increased change, distort, or mechanism which is reversible, typically intensity of post-operative pain. 31 amplify pain, resolving after the injury heals. However, when Centrally, COX-1 and COX-2 enzymes are increasing its degree, trauma is severe or when pain is allowed to persist or is under-treated, the continued trans- constitutively expressed in the dorsal root duration, and spatial mission of pain signals to the dorsal horn of the ganglia and spinal cord.35 Depolarization of extent in a manner spinal cord can cause continued changes to the dorsal horn neurons leads to up-regulation of that no longer dorsal horn neurons, leading to chronic pain or COX-2 and an increase in PGE2 production. directly reflects the maladapative pain. PGE2 both facilitates release of neurotrans- specific qualities of mitters from the primary afferent sensory peripheral noxious Acute vs Chronic Pain — neuron and decreases the depolarization stimuli, but rather the threshold of the dorsal horn neurons, creating a Pain has also been classified as acute or cycle that perpetuates central sensitization. particular functional chronic. Often, an arbitrary time interval has states of circuits in Additionally, circulating inflammatory cytokines been used to describe the difference between α α the CNS.” such as tumor necrosis factor- (TNF- ) and acute and chronic pain. However, a more interleukin 1β (IL-1β) can also lead to up- — CJ Woolf 27 accurate description is based on the underlying regulation of COX-2 in the CNS.36-38 pathophysiology. Acute pain is associated with

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RATIONALE FOR for controlling acute PERI-OPERATIVE NSAIDs post-operative pain The intent of preventive analgesia is to and preventing Although general anesthetic drugs render a the development provide sufficient pain control to patient unconscious, these drugs do not of chronic post- prevent development of peripheral and interfere with the pathways and processes operative pain.43 central sensitization. involved with the development of central sensi- Since inflammatory tization. Therefore, the use of analgesic drugs mediators play a pre-, intra-, and post-operatively are necessary critical role in the to adequately address surgical pain. Local development of pain by sensitizing nociceptors anesthetics and systemic analgesics are often and sensitizing dorsal horn neurons,45 peri- used for multimodal analgesia. NSAIDs interfere operative administration of NSAIDs is routinely with both peripheral and central sensitization practiced in both human and veterinary and provide prolonged analgesia during the medicine. post-operative period39,40 by inhibiting COX-2 enzymes and prostaglandin production at the The following sections describe evidence to surgical site and in the dorsal horn.41 Clinical support use of Rimadyl for treatment of surgical studies confirm that NSAID effects on post- pain, including an overview of Rimadyl operative pain are mediated, at least partially, pharmacology, efficacy, and safety. by interfering with the development of periph - eral and central sensitization.42 Notably, both RIMADYL PHARMACOLOGY pre-operative or post-operative administration of Rimadyl has been demonstrated to help Carprofen, the active ingredient of Rimadyl, is a reduce peripheral and central sensitization.40 NSAID of the propionic acid class that includes ibuprofen, naproxen, and ketoprofen. Rimadyl is eliminated primarily by biotransformation in the liver followed by rapid excretion of the resulting NSAIDs interfere with both peripheral metabolites in the feces (70-80%) and urine and central sensitization and provide (10-20%).1 Rimadyl also undergoes entero- prolonged analgesia during the post- hepatic recirculation to some extent. Since elimination involves both hepatic and renal operative period. components, caution is warranted when using Rimadyl in dogs with hepatic or renal dysfunction. Preventive Analgesia Strategy Preemptive analgesia is the concept of adminis- tering pain medication in advance of a painful µ stimulus in an attempt to block sensitization of Carprofen plasma concentration ( g/mL) nociceptors throughout the peri-operative 25 43 Pre-operative administration ()n=12 period. Preventive analgesia, however, Post-operative administration ()n=9 broadens the conversation from pre-incisional 20 analgesia to include any analgesic that is administered during the entire peri-operative 15 period. The intent of preventive analgesia is to provide sufficient pain control to prevent development of peripheral and central sensiti- 10 zation. Key concepts of preventive analgesia include initiating analgesia early, ensuring that 5 the degree of analgesia is appropriate to address the severity of pain, and continuing 0 analgesia until pain and inflammation has 0 5 10 15 20 25 subsided.44 Anesthesia Time (hours) and surgery Research in human patients has shown that preventive analgesia is the preferred approach Figure 4 – Mean (±SEM) plasma carprofen concentrations over time following pre-operative or post-operative administration of Rimadyl Injectable (4.0 mg/kg SC) in dogs undergoing ovariohysterectomy.40 8 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 9

Zoetis NSAID Technical Bulletin

Table 1 – Carprofen pharmacokinetic outcomes following pre-operative or post-operative administration of Rimadyl Injectable (4.0 mg/kg SC) in dogs undergoing ovariohysterectomy.40

Tmax Cmax t ½ ß AUClast AUMClast MRTlast (hours) (µg/mL) (hours) (µg•hr/mL) (µg•hr2/mL) (hours)

Pre-operative

median 3.00 11.03 16.34 115.07 952.88 8.28

maximum 5.00 22.08 59.57 247.34 2162.64 9.00

minimum 2.00 7.30 6.08 75.96 602.68 6.77

Post-operative

median 4.00 20.60 22.23 175.01 1414.73 8.11

maximum 8.00 30.22 33.24 416.49 3812.30 9.43

minimum 1.00 7.60 11.22 65.33 406.60 6.22

Statistical significance (pre vs post) * * *

* P < 0.05, Mann-Whitney statistical test

Pharmacokinetics of Rimadyl Injectable with conditions under which the drug is used in clinical practice. ‘Pharmacokinetics’ describes the absorption, metabolism, distribution, and elimination of a A study conducted under ‘real-world’ clinical drug (i.e., what the body does to a drug), and conditions evaluated the pharmacokinetics of provides information for determining the dose Rimadyl Injectable when administered to and dosing schedule of a drug. While drug anesthetized dogs undergoing ovariohyster - efficacy typically depends upon the achieve - ectomy.40 Rimadyl Injectable was administered ment of therapeutic concentrations in targeted SC at 4 mg/kg* body weight, either prior to tissues or organs, plasma concentrations are surgery or just after extubation. In addition, a often used to represent tissue concentrations control group of dogs received placebo treat- and are noninvasive and easier to collect. ments, to allow assessment of Rimadyl In some cases, however, plasma pharmacoki- analgesic efficacy. Pharmacokinetic results netics may not accurately predict tissue summarized in Table 1 and Figure 4 reveal that concentrations (e.g., highly protein-bound the median time to maximum plasma concen- drugs). Furthermore, when using pharmacoki- tration (T ; can predict onset of activity) and netics to predict clinical outcome, these studies max the median drug half-life (t ; can predict should be conducted in a manner consistent 1/2

*The approved label dose for Rimadyl is 4.4 mg/kg/day in the US. Studies using a dose of 4.0 mg/kg reflect the approved label dose in Europe. 9 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 10

Mean DIVAS pain score *P £ 0.05 **P £ 0.01 60 ** * * * No analgesics ()n=20 50 Pre-operative carprofen (0)n=1 Post-operative carprofen (8)n= 40

30

20

10

0 ex + 20 p ex 2 p ex 4 p ex 8 p ex 12 p ex 20 Assessment times

Figure 5 – Mean (±SEM) pain scores (dynamic interactive visual analog scale, or ‘DIVAS’) for dogs undergoing ovariohysterectomy that received either pre-operative or post-operative administration of Rimadyl Injectable (4.0 mg/kg SC).40

duration of effect) were similar for pre-operative operative Rimadyl Injectable, a greater degree (Tmax 3.0 h; t1/2 16.43 h) and post-operative of analgesia was achieved with pre-operative (Tmax 4.0 h; t1/2 22.23 h) Rimadyl administration. administration. One reason for improved These pharmacokinetic parameters correlate analgesia with pre-operative Rimadyl adminis- with outcomes of clinical studies which found tration could simply be due to timing. Since the that the analgesic effects were detected within Rimadyl onset of activity is approximately 2 to 4 2 hours after administration, and the duration of hours, the fact that pre-operative administration analgesia to last up to 24 hours.40,46-50 provided better post-operative analgesia is not surprising. This pharmacokinetic study using anesthetized dogs also compared the analgesic efficacy of However, several other pharmacokinetic factors pre-operative vs post-operative administration could also help explain why pre-operative of Rimadyl Injectable. Results summarized in administration of Figure 5 indicate that pre-operative Rimadyl Rimadyl Injectable administration provided: provided better post- operative analgesia. Rimadyl tissue concentration may be • significantly better analgesia at 2 hours The researchers post-operatively compared to post- increased at the surgical site due to: suggest that the lower operative Rimadyl administration; 1) the effects of anesthetic drugs on median carprofen • significantly better analgesia at 2, 4, and 8 plasma concentration drug distribution; hours post-operatively compared to the observed after pre- 2) the effects of inflammation on control group. operative Rimadyl protein concentration at the administration may be In contrast, post-operative Rimadyl adminis- a reflection of higher surgical site; tration only provided significantly better tissue concentration, 3) the high protein-binding capacity analgesia at 2 hours post-operatively vs the likely related to vasodi- of Rimadyl. control group. lation caused by the anesthetic agents used It is interesting that even though peak plasma in the study (acepro- concentrations (Cmax) and the total drug mazine, thiopental, and halothane). Intra- exposure (area under the curve, or AUC) were operative vasodilation can increase the volume significantly greater for dogs that received post- of distribution, which increases tissue exposure

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to Rimadyl and, therefore, increases tissue 40 concentration. Limiting increased tissue By inhibiting prostaglandin synthesis concentration of Rimadyl to the surgical site would be desirable since this is the target for early in the inflammatory response, both the anti-inflammatory and analgesic pre-operative administration of an effects. Because Rimadyl is highly protein NSAID can preemptively decrease the bound (>99%), limited passage from the plasma to tissues occurs, with the exception inflammation and pain associated with of inflammatory exudates.51,52 Since the inflam- surgery. matory response generated by surgical trauma causes plasma proteins to infiltrate and concentrate at the surgical site, Rimadyl preemptively decrease the inflammation and concentration may also be increased at the pain associated with surgery.31 Together, these surgical site due to binding to these proteins. various factors help explain the differences in Therefore, an increase in Rimadyl tissue pharmacokinetics and analgesic effects concentration at the surgical site could be the associated with pre-operative vs post-operative result of: 1) the effects of anesthetic drugs on administration of Rimadyl Injectable, and lend drug distribution; 2) the effects of inflammation strong support for the administration of Rimadyl on protein concentration at the surgical site; Injectable before surgery. and 3) the high protein-binding capacity of Rimadyl; and may further explain why pre- Bioequivalence of Oral and SC Rimadyl operative administration can provide better post-operative analgesia. Another pharmacokinetics study investigated the bioequivalence of the oral and injectable A final consideration is the fact that up- Rimadyl formulations after administration of a regulation of COX-2 enzymes and release of single dose of approximately 2.2 mg/kg (1 prostaglandins occurs 2 to 8 hours after tissue mg/lb) in awake laboratory dogs.53 Pharmaco- injury.31 Pre-operative Rimadyl administration kinetic values generated in the study (Table 2) could allow therapeutic drug concentrations at differ from those reported in the previous the surgical site to coincide with COX-2 study40 because a lower dose was evaluated enzymes up-regulation and prostaglandin (2.2 mg/kg vs 4.0 mg/kg) and the study was production. By inhibiting prostaglandin conducted in awake dogs (outcomes free of synthesis early in the inflammatory response, any impacts of anesthesia and surgery on the pre-operative administration of an NSAID can pharmacokinetics of pre-operative Rimadyl

Table 2 – Carprofen pharmacokinetic outcomes (arithmetic means) following administration of Rimadyl oral or injectable (SC) formulations at 2.2 mg/kg in awake dogs.53

Pharmacokinetic parameters (±SD)

Tmax Cmax AUC t ½ Formulation (hours) (µg/mL) (µg•hr/mL) (hours)

Oral 1.05 (±0.76) 16.47 (±3.95) 71.7 (±17.4) 4.95 (±1.32)

Injectable 2.58 (±1.64) 8.08 (±1.46) 64.9 (±9.7) 7.07 (±2.25)

SD=standard deviation; AUC = area under the time concentration curve; Cmax = maximum plasma concentration; Tmax = time to maximum plasma concentration; t1/2 = plasma half-life.

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administration). In the bioequivalence study, ectomy experienced significantly better pain similar total drug exposure calculated as the control at 4, 8, and 12 hours after surgery and area under the curve (AUC) was generated by a at the first and second assessments on the day single dose of either formulation of Rimadyl, after surgery. Finally, the dogs that received although the peak plasma concentration (Cmax) Rimadyl for cruciate repair had significantly was lower and the Tmax was longer for the better pain control at all assessment periods injectable formulation. As seen in the previous through the third day post-surgery. study and several other clinical trials, Cmax and Tmax may not necessarily correlate with thera- Other published studies have also investigated peutic effect.40,46, 47,49,54 The researchers the efficacy of Rimadyl Injectable. As discussed concluded that AUC was the parameter most previously in the Pharmacology section, a 1998 relevant for assessing bio equivalence between study found that administration of Rimadyl the oral and injectable formulations. (4 mg/kg* SC) prior to surgery (ovariohysterec - tomy) provided significantly better pain control The similar AUC values generated by oral and than the same dose administered post- SC administration of Rimadyl indicated operatively.40 Furthermore, administration of bioequivalence and suggested that the two both pre-operative or post-operative Rimadyl formulations can be used interchangeably.46,53 treatment provided the best duration of This important finding confirmed that dogs analgesia and also reduced signs of peripheral treated pre-operatively with Rimadyl Injectable and central sensitization. More recently, a 2012 can experience continuity in analgesia when study found that Rimadyl was effective in subsequently treated with the oral Rimadyl controlling post-operative pain for dogs under- formulation. going tibial plateau leveling osteotomy (TPLO).55 The study compared dogs that received pre- EFFICACY OF RIMADYL INJECTABLE operative Rimadyl (4 mg/kg SC) vs those that received a placebo control. Both groups were Control of Post-Operative Pain and maintained on isoflurane and intra-operative Inflammation constant-rate infusion of sufentanyl. Although intra-operative requirements for sufentanyl did Multiple studies have demonstrated the effec- not differ between groups, Rimadyl-treated tiveness of Rimadyl Injectable for controlling dogs demonstrated superior cardiovascular pain and inflammation associated with canine stability (lower heart rate and mean arterial soft-tissue and orthopedic surgery. In 3 studies pressure), an observation thought to indicate conducted to receive FDA approval for control better intra-operative analgesia compared to of post-operative pain, Rimadyl Injectable was the controls. The Rimadyl Injectable group also administered SC at 4.4 mg/kg approximately 2 had lower post- hours prior to surgery, followed by 4.4 mg/kg operative pain scores SC once daily for 2 additional days for dogs starting at 30 minutes undergoing soft-tissue surgery (ovariohyster - after intubation Rimadyl Injectable contributed to ectomy and aural surgeries), or 3 additional (approximately 2 hours improved quality of recovery, post- days for orthopedic surgery (cruciate repair).46 after administration of operative comfort, and analgesia. Responses were compared to placebo controls Rimadyl) and at most which received pre- and post-operative saline time points evaluated. injections. Post-operative pain was evaluated at A significantly lower 4, 8, and 12 hours after surgery, and then twice incidence of dysphoria and lower dose daily until the end of the study. In all 3 studies, requirement for buprenorphine (the rescue drug) the Rimadyl-treated dogs experienced signifi- was also reported for dogs treated with Rimadyl cantly better pain control than dogs in the vs the control group. The researchers placebo group. The dogs that received Rimadyl concluded that preemptive administration of for aural surgeries had better pain control at 4, Rimadyl Injectable contributed to improved 8, and 12 hours post-surgery and at the first quality of recovery, post-operative comfort, and assessments on the day after surgery. Similarly, analgesia. dogs that received Rimadyl for ovariohyster -

*The approved label dose for Rimadyl is 4.4 mg/kg/day in the US. Studies using a dose of 4.0 mg/kg reflect the approved label dose in Europe. 12 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 13

Zoetis NSAID Technical Bulletin

Rimadyl Injectable vs Opioids hours and 8 hours after surgery, dogs treated with Rimadyl or the Rimadyl+buprenorphine Multiple studies have evaluated the efficacy of combination demonstrated significantly less Rimadyl compared to opioids such as pethidine wound swelling than dogs treated with (meperidine), morphine, and buprenorphine. buprenorphine alone. Buprenorphine had a The first study compared the analgesic effect of dose-sparing effect on the induction agent, Rimadyl vs pethidine in dogs undergoing ortho- whereas Rimadyl did not. Although the pedic surgery.47 Dogs in the Rimadyl group Rimadyl+buprenorphine combination did not received a single pre-operative dose at 4 mg/kg provide additional analgesia in this study, the SC while dogs in the pethidine group received a dose-sparing effects of buprenorphine on 5.0 mg/kg SC dose both before and after the propofol induction, together with the analgesia procedure. Pain assessments were made at 1, and decreased wound swelling provided by 2, and 4 hours after surgery, later on the Rimadyl, supports the use of Rimadyl and evening of surgery, and the day after surgery. buprenorphine together as a multimodal peri- Mean pain scores were significantly lower for operative anesthesia/analgesia protocol. Rimadyl-treated dogs at each time period compared to dogs treated with pethidine.

In another study, dogs undergoing ovariohys- terectomy were treated pre-operatively with At 2 hours and 8 hours after surgery, either: 1) Rimadyl (4 mg/kg SC); 2) pethidine dogs treated with Rimadyl or the (5.0 mg/kg SC); or 3) a combination of Rimadyl and pethidine (4 mg/kg SC and 5.0 mg/kg SC, Rimadyl+buprenorphine combination respectively).49 Compared to dogs treated with demonstrated significantly less wound pethidine alone, dogs in the Rimadyl and swelling than dogs treated with Rimadyl+pethidine groups had lower pain buprenorphine alone. scores from 4 to 20 hours post-surgery (assessments ended at 20 hours post-surgery). Dogs in the pethidine group also required significantly more rescue analgesia than dogs A fourth study compared the post-operative treated with Rimadyl or with the Rimadyl+ analgesic effect of Rimadyl to that provided by pethidine combination. Although the short morphine.57 Dogs undergoing ovariohys- duration of action for pethidine (approximately 2 terectomy received either: 1) Rimadyl before hours) was likely the primary reason for the surgery (4 mg/kg SC); 2) morphine before increased pain scores in pethidine-treated surgery (0.4 mg/kg SC, followed by morphine dogs, the researchers reported that the every 4-6 hours post-operatively); or 3) both Rimadyl+pethidine group showed decreased Rimadyl and morphine (same dosages/ signs of central sensitization compared to the regimens). Dogs treated with Rimadyl experi- other groups, indicating a possible additive or enced post-operative analgesia equivalent to synergistic effect between Rimadyl and the morphine group and the Rimadyl+morphine pethidine. group at each time point (1, 2, 4, 6, and 20 The analgesic effect of Rimadyl (4 mg/kg SC) hours post-surgery). Failure to show synergy was compared to buprenorphine (0.02 mg/kg between the two drugs was unexpected. The IM) or the combination of both drugs adminis- authors recommended additional studies to tered pre-operatively to dogs undergoing ovari- evaluate the synergistic effects of the two ohysterectomy.56 Dogs treated with Rimadyl drugs. and Rimadyl+buprenorphine had superior pain Rimadyl has been shown to provide post- scores compared to the dogs treated with operative analgesia similar to morphine or buprenorphine alone. However, the combination superior to pethidine or buprenorphine when of the two drugs did not improve pain control vs administered pre-operatively to dogs under- Rimadyl alone. Investigators in this study also going ovariohysterectomy. However, NSAIDs evaluated the anti-inflammatory effects of (i.e., Rimadyl) can provide additional benefits in Rimadyl by assessing wound swelling. At 2 a surgical setting:

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• A single SC injection of Rimadyl delivers periodontal ligament, and alveolar bone. effective pain relief for up to 24 hours when Injectable Rimadyl is appropriate for most administered at a dose of 4.4 mg/kg (2.0 dental procedures in dogs, from comprehensive mg/lb). In contrast, most opioids are short- teeth cleaning to oral surgery. acting and necessitate multiple administra - tions or constant rate infusions to deliver Periodontitis is the most prevalent disease in continuous analgesia over a 24-hour companion animals.59 It is a condition caused period. by local infection from the bacteria in plaque, resulting in gingival inflammation and pain. • Rimadyl has been shown to provide anti- When ignored, periodontitis can lead to inflammatory effects, and decrease swelling destruction of the gingiva, periodontal ligament, at the surgical site. and alveolar bone. Inflamed gingiva can bleed • Rimadyl is not a DEA-controlled substance, when touched with a probe or ultrasonic scaler. so the extra recordkeeping steps required In such patients, it is assumed that manipu- for scheduled drugs are eliminated. lation of the inflamed tissue during a dental cleaning activates the nociceptive pathway (i.e., Ultimately, the final decision on which drug or is painful). In cases of advanced periodontal combination of drugs to use must be made on a disease, extraction of teeth may be necessary, case-by-case basis taking into consideration and surgical removal will inevitably result in pain the physiological status of the patient and the and swelling. degree of pain associated with the surgery. Rimadyl Injectable inhibits prostaglandins which Pre-Operative vs Post-Operative are responsible for the primary inflammation Rimadyl Injectable and the pain associated with the inflammatory cascade. Even when teeth or tooth extractions As discussed, the inflammatory response to are not performed, pre-operative administration surgical trauma is initiated by COX-2 enzyme- of Rimadyl Injectable can offer great benefit. mediated synthesis of prostaglandins. The injectable route of administration provides Increased synthesis of COX-2 enzymes occurs 31 analgesia in the fasted anesthetic patient under- within 2 to 8 hours after trauma. When going dental procedures, and a single SC Rimadyl is administered 2 hours prior to Rimadyl injection provides 24 hours of surgery, the time required to reach therapeutic analgesia. Eliminating the need for additional tissue levels coincides with the up-regulation of oral dosing for a full day eliminates both the COX-2 enzymes; but if administered post- need for client compliance during the operatively, inhibition of inflammation and 40,48 immediate post-operative period as well as the injury-related pain control is delayed. administration of an oral medication to a dog However, differences in analgesia between the that may be experiencing oral pain. 2 dosing strategies does not last through the entire post-operative period (no significant Dental procedures in dogs are performed under differences by 4 hours post-surgery). Therefore, general anesthesia. A pre-anesthetic patient the decision to administer injectable Rimadyl assessment (including physical exam, blood before surgery vs afterwards should be deter- work, urine specific gravity, and other mined on a case-by-case basis. If Rimadyl diagnostics) is essential in helping to choose Injectable is not used pre-operatively for control the most appropriate drug regimen for pre- of post-operative pain, care should be taken to medication, induction, and post-operative provide other analgesics to prevent or minimize analgesia. It is critical that the patient be well initiation of peripheral and central sensitization. hydrated and normovolemic during surgery. Since many patients are fasted prior to surgery, Rimadyl Injectable for Dental Patients judicious use of intravenous (IV) fluids should be Rimadyl is an excellent choice for controlling a part of all anesthetic protocols.60,61 As with peri-operative pain associated with canine any anesthetic event, appropriate monitoring is dental procedures because such pain is often essential and should include blood pressure related to inflammation58 involving the gingiva, monitoring throughout the procedure.

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Zoetis NSAID Technical Bulletin

SAFETY OF RIMADYL INJECTABLE toxic metabolites. Idiosyncratic reactions are rare and typically occur early in the course of Known NSAID Safety Profile treatment,63 but can be severe and life threat- Although generally considered safe, all ening. For NSAIDs, hepatotoxicity is a potential approved veterinary NSAIDs have the potential idiosyncratic reaction. to cause side effects, regardless of their COX-1 and COX-2 selectivity or route of administration. Rimadyl Injectable Pharmacovigilance As a class, NSAIDs have the potential for Pharmacovigilance refers to the collection, causing GI, renal, and hepatic side effects. assessment, reporting, detection, and prevention of drug reactions associated with a When discussing the safety profile of a drug, it pharmaceutical product. Reports on drug is important to understand the difference reactions for companion animal medicines are between inducible and idiosyncratic reactions. submitted by veterinarians and pet owners. Inducible adverse reactions are predicable, are When reporting adverse events, frequency is associated with the drug’s mechanism of often qualified by descriptive terms such as action, and are dose dependent (the frequency common, infrequent, and rare or very rare, as and severity of the adverse reaction increases defined in Table 3.64 A summary of these reports with increased dosage). Inducible reactions are involving Rimadyl Injectable from 2003 to 2013 the most common type of adverse events.62 is presented in Table 4 (data for 2003 represent For NSAIDs, these include the potential for a partial year, after approval of Rimadyl Inject - dysfunction of the kidneys and platelets, and able in March).65 Data for each year is presented disruption of GI tract integrity. by system or organ class, quantifying the total number of reports, and reports per 10,000 Idiosyncratic reactions are unpredictable, are treated dogs (number of dogs treated calcu- not associated with the mechanism of action, lated from market research data tracking dogs and are not dose related. The underlying causes treated on an annual basis). A ‘case’ represents of idiosyncratic reactions are not well under- an adverse event for one animal while a ‘report’ stood and may differ for each drug, each type represents a single symptom or clinical sign of reaction, and each individual patient. (multiple clinical signs or reports could be Possible underlying causes include a hypersen- included in a single case). Thus, the number of sitivity to the drug or an individual’s inability to reports is greater than the number of cases. The appropriately metabolize the drug. Metabolic total annual number of cases is reported at the alterations can result in the development of bottom of the column for each year. toxic metabolites or inability to rapidly eliminate All adverse-event reports submitted for Rimadyl Injectable are included in Table 4 regardless of Table 3 – World Health Organization: Definitions used to describe causality. In other words, even if the circum- the frequency of adverse drug reactions.64 stances under which the adverse event occurred indicated that some other cause was more likely than Rimadyl Injectable adminis- tration to result in the clinical signs (such as Descriptive term Frequency underlying disease or administration of another drug), the report was still included. Data in Table 4 indicate that adverse event reports for ≥ 1/10 Very Common Rimadyl Injectable for a specific system or organ class were ‘rare’ or ‘very rare’, and that Common (frequent) ≥ 1/100 but < 1/10 the reported rates have either remained constant or decreased over time. Infrequent (uncommon) ≥ 1/1000 but < 1/100 The following discussion reviews the safety Rare ≥ 1/10,000 but < 1/1000 considerations and potential effects on different organ systems that have been reported for NSAIDs as a class, followed by a review of Very rare < 1/10,000 studies that evaluated the safety of Rimadyl in these organ systems.

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Table 4 – Pharmacovigilance reports of drug reactions in dogs involving Rimadyl Injectable from 2003 to 2013.65

2003 2004 2005 2006

VeDDRA SOC No. of No. per No. of No. per No. of No. per No. of No. per N reports 10,000 reports 10,000 reports 10,000 reports 10,000 re

Digestive tract disorders 28 0.48 107 1.46 122 1.25 184 2.07

Hepato-biliary disorders 12 0.21 36 0.49 34 0.35 57 0.64

Renal and urinary disorders 13 0.22 22 0.30 31 0.32 55 0.62

Neurological disorders 3 0.05 38 0.52 38 0.39 48 0.54

Blood & lymphatic system disorders 26 0.45 74 1.01 95 0.98 82 0.92

Death (outcome) a 12 0.21 40 0.55 60 0.62 55 0.62

Behavioral disorders 3 0.05 22 0.30 22 0.23 22 0.25

Skin & appendages disorders 12 0.21 41 0.56 69 0.71 58 0.65

Immune system disorders 1 0.02 15 0.21 19 0.20 13 0.15

Injection site disorders 7 0.12 38 0.52 46 0.47 45 0.51

Total Cases 63 1.08 158 2.16 202 2.07 171 1.93

Approx no. dogs treated 580,856 731,159 973,598 887,871

Total cases / ~no. dogs treated 0.000108 0.0002161 0.00020748 0.0001926

a Death (includes euthanasia) as case outcome.

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Zoetis NSAID Technical Bulletin

2007 2008 2009 2010 2011 2012 2013

r No. of No. per No. of No. per No. of No. per No. of No. per No. of No. per No. of No. per No. of No. per 0 reports 10,000 reports 10,000 reports 10,000 reports 10,000 reports 10,000 reports 10,000 reports 10,000

170 1.63 120 1.24 130 1.35 109 1.12 115 1.05 117 1.02 68 0.59

50 0.48 38 0.39 29 0.30 29 0.30 44 0.40 34 0.30 40 0.35

71 0.68 46 0.48 33 0.34 40 0.41 33 0.30 44 0.38 30 0.26

38 0.36 45 0.47 52 0.54 22 0.23 47 0.43 33 0.29 31 0.27

93 0.89 63 0.65 45 0.47 51 0.52 36 0.33 49 0.43 35 0.31

42 0.40 45 0.47 39 0.41 28 0.29 32 0.29 24 0.21 18 0.16

24 0.23 28 0.29 18 0.19 10 0.10 17 0.16 13 0.11 17 0.15

34 0.33 27 0.28 22 0.23 25 0.26 38 0.35 47 0.41 30 0.26

20 0.19 19 0.20 10 0.10 8 0.08 10 0.09 9 0.08 7 0.06

36 0.34 40 0.41 38 0.40 23 0.24 54 0.49 79 0.69 31 0.27

181 1.73 148 1.46 152 1.58 113 1.16 141 1.29 133 1.16 155 1.35

1,043,902 964,985 960,977 974,348 1,095,689 1,147,106 1,329,902

0.00017339 0.00015337 0.00015817 0.00011597 0.00012869 0.00011594 0.00011655

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Renal Effects: COX Enzymes, creatinine).72-75 Another study evaluated the Prostaglandins, and Renal Homeostasis effects of pre- or post-operative administration of Rimadyl Injectable (4 mg/kg, IV*) on renal Regulation of renal homeostasis is complex function in dogs with low blood pressure (mean with a number of checks and balances, arterial pressure maintained at 65 mm Hg).76 No including the production and function of prosta - significant differences in hematological, serum glandins. NSAIDs can affect renal function by biochemical, urinalysis, angiotensin II and inhibiting synthesis of renal prosta glandins, arginine-vasopressin values, or GFR (measured which are important for sodium and potassium with scintigraphy) were detected compared to homeostasis and for maintaining renal blood placebo (saline) controls. flow in the volume-depleted state.66-69 COX enzymes are constitutively expressed in the A research team evaluated creatinine clearance kidneys. In the dog, COX-1 is found predomi- (CC) in dogs 24 hours after undergoing nantly in the collecting tubules and renal vascu- castration.77 Mean CC was significantly lower lature, and COX-2 in the macula densa, (P < 0.01) for dogs treated with Rimadyl (4 medullary interstitial cells, and the thick 70 mg/kg, SC) or with ketoprofen (2 mg/kg, SC) ascending limb. COX enzymes regulate compared to control animals (CC values: 2.29 sodium and water absorption through PGE2 ± 0.17 mL/kg/m; 2.07 ± 0.45 mL/kg/m; 3.12 ± production and potassium levels through PGI2 71 0.85 mL/kg/m, respectively). Although mean CC production. COX inhibition has little effect on values for the Rimadyl and ketoprofen groups electrolyte homeostasis in the normovolemic were lower than that of control dogs, values dog. Under normal conditions, prostaglandins were within the normal range (2-5 mL/kg/m) for have little influence on renal blood flow (RBF) or non-anesthetized dogs and similar to another glomerular filtration rate (GFR). However, if renal study evaluating GFR using CC in anesthetized blood flow is impaired due to hypotension or dogs.75 No differences between the Rimadyl hypovolemia, COX-2 enzymes are up-regulated and ketoprofen groups were detected. and synthesis of PGI2 and PGE2 increases in Confounding factors in this study included the response to vasoconstriction of the renal 6,7,70 lack of baseline measurements, use of two artery. Under volume-contracted states, anesthetic agents known to cause hypotension increased levels of catecholamines, angio - (acepromazine and thiopentone), and no peri- tensin, and vasopressin contract renal arteries. operative administration of IV fluids or monitor - Prostaglandins counteract the vasoconstrictive ing of blood pressure. Although all treated dogs effects of these hormones, preserving RBF 8 had CC values within normal limits, the and GFR. Therefore, use of COX-2 inhibitors researchers concluded that pre-operative use of should have little effect on renal blood flow or NSAIDs should be undertaken with care. electrolyte balance in the normovolemic or normotensive patient, but may prevent the A renal function study evaluated 40 dogs (10 cytoprotective effects that the COX-2-derived dogs/group) treated with either Rimadyl (4.0 prostaglandins provide in maintaining renal mg/kg SC), ketoprofen (1.0 mg/kg SC), or perfusion and GFR in the hypovolemic or ketorolac (0.5 mg/kg SC) compared to a hypotensive patient. morphine control group (0.1 mg/kg SC).78 Renal function was assessed using urine specific Renal Safety of Rimadyl Injectable gravity (USG), creatinine, BUN, fractional Zoetis pharmacovigilance found the reporting clearance of sodium (FCNa), and urine enzymes rate for renal adverse events to be very rare. including urine GGT, urine GGT:creatinine ratio, Four separate studies found that pre-operative urine alkaline phosphatase (ALP), and urine administration of Rimadyl Injectable in normo - ALP:creatinine ratio. No differences were volemic and normotensive dogs resulted in no observed in urine enzymes or urine ALP: significant difference, compared to placebo- creatinine ratio. Transient azotemia was controlled groups, on various renal parameters reported in 2 dogs in each of the ketorolac and including GFR, serum blood urea nitrogen ketoprofen groups. The azotemia persisted (BUN), serum creatinine, urine protein, urine through 48 hours after anesthesia in both creatinine, or the ratio of urine γ-glutamyltrans- ketorolac-treated dogs and 1 ketoprofen- ferase (GGT) to urine creatinine (urine GGT: treated dog. Renal tubular epithelial cells were

*US approval of Rimadyl Injectable is at 4.4 mg/kg/day administered as SC injection. Studies using a dose of 4.0 mg/kg reflect the approved label dose in Europe. 18 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 19

Zoetis NSAID Technical Bulletin

found in urinalysis of 4 dogs from the morphine prior precautions regarding the concurrent use group, 2 dogs from the ketorolac group, and 1 of these two classes of drugs. These studies dog each from the Rimadyl and ketoprofen also suggest that use of NSAIDs in volume- groups. In this study, FCNa >1 was used as an depleted dogs can have transient effects on the indicator of acute tubular dysfunction. FCNa >1 kidneys, and supports previous precautions was reported in 4 ketorolac-, 5 ketoprofen-, and regarding NSAID use in these situations. 2 Rimadyl-treated dogs at 24 hours, but decreased to <1 by 48 hours. However, since In summary, NSAIDs have little effect on renal FCNa >1 was reported for several dogs at the perfusion in healthy dogs, but may interfere with pre-surgical assessment, the authors the autoregulatory function of prostaglandins, questioned the sensitivity of FCNa >1 as an which becomes important during hypotension indicator of acute tubular dysfunction and or hypovolemia. Inhibition of COX-2 enzymes attributed the change in FCNa over the 24- to and prostaglandins may interfere with the 48-hour post-surgery period to factors related body’s ability to compensate for reductions in to anesthesia and independent of renal renal blood flow, potentially leading to kidney dysfunction. They concluded that peri-operative damage. Studies evaluating the effects of use of NSAIDs was not contraindicated and pre-operative Rimadyl administration have that Rimadyl had the least effect on renal found no clinically relevant effects in healthy function and integrity. dogs that are normotensive or have low blood pressure.72-76,78 Transient renal effects were Two separate studies evaluated the effects of identified in dogs that were artificially ‘volume oral Rimadyl, ibuprofen, or etodolac on renal depleted’ from 8 days of concurrent adminis- function alone or in combination with tration with furosemide, but all parameters furosemide.79,80 Furosemide administration was returned to normal after drug withdrawal.79,80 used as a model representing volume-depleted dogs. The studies employed a randomized Pre-operative use of NSAIDs for control of cross-over design and measured parameters post-operative pain is appropriate in normal, included USG, BUN, creatinine, electrolytes, healthy patients. The benefits of using Rimadyl GFR, and renal plasma blood flow (RBF) prior Injectable pre-operatively to control post- to treatment and after 8 days of treatment. operative pain and inflammation have been A wash-out period of 10 to 13 days was documented in numerous studies.46,55 However, allowed between treatments. Results showed as with any surgical procedure, patients should that administration of Rimadyl, ibuprofen, or be monitored and attention should be focused etodolac, alone, did not have a significant effect on keeping the patient hydrated, normo tensive, on any of the parameters. Dogs treated with and normovolemic. 60,61 Since many anesthetic furosemide alone had significantly lower USG drugs (e.g., acepromazine, propofol, gas and significantly higher BUN and creatinine inhalants) can cause hypotension and hypo - compared to placebo control, but the GFR and thermia,81,82 blood pressure, heart rate, body RBF were not significantly different. However, temperature, etc., should be monitored combination treatment involving furosemide throughout the entire anesthetic event, plus any of the NSAIDs significantly lowered including recovery, so that appropriate and USG and GFR and significantly increased BUN timely adjustments can be made if a patient’s and creatinine compared to placebo controls or status changes. NSAIDs alone. Additionally, GFR values for dogs treated with furosemide+Rimadyl or Patients at risk for renal toxicity are those that furosemide+ibuprofen were significantly lower are dehydrated, on concomitant diuretic than dogs treated with furosemide alone. These therapy, or have renal, cardiovascular, or reductions of GFR were considered mild hepatic dysfunction. NSAID therapy should be because they did not result in azotemia or avoided in dogs with decreased renal perfusion illness. After drug withdrawal, all parameters due to shock, dehydration, and hemorrhage. If returned to pre-treatment values for all groups. intra-operative hypotension or hypovolemia is a This study showed that transient changes in concern, then NSAID administration can be renal function occur when NSAIDs are adminis- postponed until cardiovascular homeostasis tered concurrently with diuretics, and confirms has been restored.

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Platelet Effects: COX Enzymes, Platelet Safety of Rimadyl Injectable Prostaglandins, and Hemostasis The effects of Rimadyl Injectable on coagulation The use of NSAIDs before surgery is sometimes were evaluated in studies submitted to the FDA discouraged because some drugs in this class, to support the indication for control of post- such as aspirin, have been associated with operative pain and inflammation.46 No sig nifi - increased peri-operative bleeding. Platelet cant differences were noted in the coagulation function is regulated by thromboxane (causes parameters of dogs treated with Rimadyl (4.4 vasoconstriction and platelet aggregation) and mg/kg SC) 2 hours before surgery compared to prostacyclin (acts as a vasodilator and an anti- placebo control dogs. Zoetis pharmacovigi- coagulant). Thromboxane synthesis from lance data show the rate of reported blood platelets is induced by COX-1. COX-1 inhibition abnormalities to be rare to very rare. causes irreversible inhibition of thromboxane synthesis since platelets lack a nucleus and are Additional studies were conducted after unable to synthesize additional COX-1 enzymes approval of Rimadyl Injectable. One study or thromboxane. Therefore, the only way to evaluated the hemostatic effects of Rimadyl synthesize additional thromboxane after COX-1 Injectable administered SC at 4 mg/kg* 1 hour inhibition is through the generation of new before orthopedic surgery, or just after platelets. In contrast, prostacyclin synthesis extubation, followed with oral Rimadyl (4 mg/kg) from endothelial cells is induced by COX-2 once daily for 4 days.72 Hemostatic variables enzymes, and is reversible since endothelial measured in the study included prothombin cells are capable of synthesizing additional time (PT), activated partial thromboplastin time prostacyclin. Since COX-1 and COX-2 enzymes (APTT), platelet count, bleeding time, and are involved in the maintenance of hemostasis, platelet aggregation. Most hemostatic values use of NSAIDs can interfere with hemostasis. did not significantly differ between the 2 groups. Bleeding times were within reference range for NSAIDs that indiscriminately inhibit both COX-1 all animals at all time points during the study. and COX-2 (such as aspirin) increase the risk of However, PT, APTT, and platelet aggregation bleeding, because the net effect of these drugs values were outside reference ranges for many is to irreversibly inhibit thromboxane but not dogs before surgery and before Rimadyl admin- prostacyclin, therefore shifting the hemostatic istration. These changes were considered to be balance away from coagulation. Alternatively, trauma-induced and were not clinically signif- COX-1-sparing drugs inhibit prostacyclin to a icant at any time during the study. Most values greater degree than thromboxane. These drugs returned to normal during the 4-day post- have the potential to increase the risk of devel- operative period. The authors concluded that oping thrombosis because the hemostatic administration of Rimadyl Injectable did not balance has shifted toward coagulation. have any clinically relevant effects on Increased incidence of myocardial infarction hemostasis in dogs anesthetized for fracture has been reported in human medicine, repair, even when administered to dogs that especially with drugs highly selective for COX-2 had trauma-induced alterations in hemostasis. enzyme. In fact, patients that received Vioxx® (rofecoxib), a COX-2-selective NSAID, experi- Other studies evaluating the short-term effects enced an increased incidence of myocardial of Rimadyl oral formulation on hemostasis have infarction,83 prompting the FDA to withdraw the shown variable results. One report determined drug from the market in 2004. In human that oral Rimadyl administration at 4.4 mg/kg medicine, myocardial infarctions are typically once daily for 7 days did not significantly affect associated with arthrosclerosis. However, the platelet function, platelet aggregation, PT, APTT, incidence of atherosclerosis in dogs is very rare or fibrinogen when compared to baseline.85 because metabolism of fats does not result in Other studies evaluated the hemostatic effects low-density lipoproteins and cholesterol of several NSAIDs, including Rimadyl given 2.2 formation,84 so dogs are not predisposed to mg/kg PO twice daily; Rimadyl given at 4.0 or myocardial infarctions. Increased risk of throm- 4.4 mg/kg PO once daily; meloxicam given 0.2 bosis associated with COX-1-sparing drugs has mg/kg PO on day 1 followed by 0.1 mg/kg PO not been reported in veterinary medicine and is once daily; or deracoxib 2 mg/kg PO once likely related to the fact that dogs are not daily.86-88 Dogs received each treatment for 5-7 predisposed to development of myocardial days in a crossover design with an appropriate infarctions.

*The approved label dose for Rimadyl is 4.4 mg/kg/day in the US. 20 Studies using a dose of 4.0 mg/kg reflect the approved label dose in Europe. Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 21

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wash-out period between treatments. Although aspirin followed by endoscopic and histopatho- variable results were seen in platelet function logical evaluation of the gastric and duodenal across treatments, no differences in bleeding mucosa.97 All dogs treated with buffered aspirin times were noted. The overall conclusion from had significantly greater gastric erosions and these studies is that NSAIDs may affect in vitro sub-mucosal hemorrhagic lesions compared to measurements of platelet function. However, the other groups. Only minor lesions of the these in vitro assessments were not associated gastric mucosa were observed in dogs treated with clinically relevant changes. with Rimadyl or etodolac, and these changes were similar to changes noted in the placebo In summary, studies evaluating hemostatic control group. effects of injectable or oral Rimadyl formulations for up to 7 days did not find any clinically A recent in vitro study found that Rimadyl and relevant impacts on platelet function or coagu- meloxicam increased gastric permeability and lation. However, since all NSAIDs exert some appeared to compromise gastric mucosal degree of COX-1 inhibition, platelet function barrier integrity and barrier function at the and coagulation parameters should be doses administered.98 However, the clinical assessed in advance of peri-operative NSAID relevance of this study is questionable since an use whenever risk factors for bleeding are in vivo study found that neither drug affected present. Use of NSAIDs in dogs with known gastric permeability.99 Furthermore, in a clinical platelet deficiencies or coagulation defects is study that evaluated adverse effects of long- not recommended.1,89-91 term use of a number of NSAIDs, drugs that were more COX-1 sparing (such as Rimadyl and Gastrointestinal (GI) Effects: meloxicam) generated fewer adverse effects COX Enzymes and GI Integrity than drugs with greater inhibitory effects on COX-1 (including etodolac, flunixin meglamine, Potential GI toxicity is a consideration when any and ketoprofen).100 Other studies comparing GI NSAID is used, whether peri-operatively or for effects of various FDA-approved canine NSAIDs chronic pain (such as osteoarthritis). The found no significant impacts on clinical gastro-protectant effects of COX enzymes are outcomes (based on GI endoscopic and due to PGE2 and PGI2 synthesis via several histopathological evaluation).101-103 mechanisms including:92 • reduction of gastric acid production; Direct irritation of the GI mucosa is a potential • increase of gastric blood-flow due to effect of orally administered NSAIDs when vasodilation; gastric emptying is delayed.2 A study in human • increase of mucous production and patients showed that IV aspirin caused no GI bicarbonate secretion. bleeding, but oral administration of unbuffered aspirin at the same dose and for the same COX-1-induced prostaglandins are maintained duration caused substantial GI bleeding.104 A in healthy GI mucosa,93 but in inflamed and similar study, comparing the GI effects of oral vs ulcerated GI mucosa, COX-1 production injectable Rimadyl formulations, has not been decreases and COX-2-induced prostaglandins conducted in canine surgical patients. Although become responsible for maintaining GI homeo - orally administered canine NSAIDs approved for stasis.94,95 Although COX-1-sparing NSAIDs control of post-operative pain and inflammation provide a better GI safety profile than non- have been demonstrated to be safe and selective NSAIDs (such as aspirin),96 COX-2- effective, an injectable formulation may offer a selective drugs may delay healing when the better option in some dogs where a delay in gastric mucosa integrity is compromised. These gastric emptying is known or suspected. data indicate that both COX-1 and COX-2 are Delayed gastric motility could either delay important for production of prostaglandins absorption and onset of action, or increase involved with ulcer healing.10 topical exposure of the gastric mucosa to the orally administered NSAID. Delayed gastric GI Safety of Rimadyl Injectable emptying can be caused by outflow obstruction (such as gastric polyps or tumors), foreign Rimadyl is considered to be COX-1 sparing, bodies, illeus, or pyloric stenosis. Defects in and the importance of a canine-approved, gastric motility due to stress, trauma, or surgery COX-1-sparing NSAID was illustrated in a study can also delay gastric emptying. where dogs received Rimadyl, etodolac, or 21 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 22

When using an injectable NSAID for controlling tered medications, including OTC agents, post-operative pain and inflammation, then aspirin, and topical medications that contain continuing to an oral NSAID, it is recommended glucocorticoids. When administering NSAIDs on to avoid switching NSAIDs.2 Although one study a long-term basis and the need arises to switch found that Rimadyl Injectable followed by either from one NSAID to another, an appropriate 4 days of oral Rimadyl or deracoxib did not wash-out period is strongly recommended. induce clinically relevant GI lesions, this was a Recommendations for wash-out periods are laboratory study conducted in 6 conditioned based on the pharmacological properties of the dogs that did not undergo an anesthetic/ drugs, but have not been confirmed in studies. surgical event, so the study did not properly However, based on the premise that the represent possible risk associated with majority of the drugs are eliminated within 4 to combined use in a peri-operative setting.101 In 5 half-lives, a wash-out period of 5 to 7 days is order to minimize possible GI effects, most typically recommended for most approved experts recommend continuing with the same canine NSAIDs. A longer wash-out period of 7 injectable and oral NSAID peri-operatively.2 to 14 days is recommended for aspirin due to the extensive COX-1 inhibition associated with Though NSAIDs are well tolerated in the vast this drug. majority of dogs, GI signs are the most common adverse events associated with this Bone Healing: COX Enzymes, class of drugs.46,89-91 In clinical studies, the Prostaglandins, and Bone Repair frequency of GI adverse effects following a single peri-operative injection of Rimadyl was The effects of COX-2 enzymes on bone healing low,65 comparable to the incidence rate in were first identified in studies involving geneti- placebo controls.46 Zoetis pharmacovigilance cally engineered mice that were completely deficient in COX-2 enzyme and exhibited data collected since 1999 indicate that the 105,106 annual rate of reported GI signs are rare to very delayed bone resorption and bone healing. rare.65 Since many dogs continue post- The role of COX-2 enzymes in bone metabolism operative treatment with oral Rimadyl for was defined as a result of these and other several days or longer following the peri- experimental studies. In healthy bones, operative injection, clients should be advised of prostaglandin synthesis mediated by COX-2 the potential for GI side-effects and monitor enzymes maintains the pre-osteoblast their dogs accordingly. Reported clinical signs population of cells. After bone injury, COX-2 associated with GI adverse events include enzymes are induced and stimulate osteoblast differentiation and proliferation through up- depression, anorexia, reduced appetite, 106 vomiting, diarrhea, hematochezia, melena, and regulation of PGE2 production. A study in rats gastric ulceration. These clinical manifestations showed that COX-1 concentration at the should be discussed with dog owners when - fracture site remains low, while COX-2 expres - sion significantly increases from day 3-14 and ever oral NSAIDs are prescribed. Additionally, 107 owners should be instructed to discontinue returns to baseline levels by day 21. administration of the NSAID and call the veteri- Additional research confirmed that inflammation narian should their dog exhibit any of these and early induction of COX-2 was crucial for clinical signs. An Owner Information Sheet bone healing, and that elimination of COX-2 at the early stage of healing could lead to detri- (Attachment 1) which provides important infor- 108 mation on Rimadyl is a useful tool for client mental effects on cortical bone repair. It is education. Owner information sheets are now accepted, based on the evidence, that for available for all veterinary approved NSAIDs mammalian species the inflammatory response and should be given to all owners when their is essential for normal bone repair after injury, dogs receive a drug from this class. and COX-2 enzymes, along with a number of growth factors, play a role in bone healing. Proper patient selection is important, including avoiding use of NSAIDs in dogs with a history of In human clinical medicine, the use of NSAIDs NSAID intolerance, pre-existing GI disease, or for pain management immediately after renal or hepatic dysfunction. NSAIDs should not orthopedic surgery has been questioned by be administered concurrently with glucocorti- some based on laboratory animal and in vitro coids or other NSAIDs, and the veterinarian studies. In most of these studies, delayed bone should be aware of all concurrently adminis- healing was associated with NSAIDs that were administered at super-therapeutic doses and/or for a prolonged period of time.109 Therefore, 22 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 23

Zoetis NSAID Technical Bulletin

the clinical relevance of these studies is study design factors limited extrapolation of questionable and the conclusions cannot be results from this laboratory study to clinical extrapolated to practical situations where situations. First, the method of fixation included therapeutic doses are administered for the placement of an intramedullary pin without appropriate period of time. providing rotational stability, a method that would not be acceptable in the clinical situation. More recent laboratory studies in rats evaluated A study conducted in rats showed that NSAIDs the effects of NSAID treatment duration on did not affect bone healing in stable fractures bone healing.110 Results indicated that short- but did delay healing in unstable femoral term treatment (14 days) with either non- fractures.115 Furthermore, 120 days of treatment selective or selective COX-2 inhibitors had no for a traumatic fracture is longer than typically effect on bone healing. Longer-term use of 21 practiced. The healing effects of a shorter, more days did delay bone healing, but these effects appropriate course of Rimadyl treatment were resolved within 14 days after cessation of the not evaluated. In contrast, other studies NSAIDs. Duration of treatment was also shown confirmed that if NSAID-associated delay in to affect bone growth in rabbits, where 2 weeks bone healing was observed, these changes of treatment with NSAIDs did not affect bone resolved quickly after discontinuation of growth but 6 weeks of treatment resulted in therapy.110 The authors did not conclude that delayed growth.111 NSAIDs were an inappropriate analgesic choice in orthopedic surgeries, but did recommended Recent human clinical studies have found no caution when treating fractures that have delays correlation between NSAID use and occurrence in healing or in dogs with diseases that of non-unions after surgical repair of factures. A predispose animals to delays in bone healing. large-cohort study evaluating the role of NSAIDs in non-union of humeral shaft fractures Clinical studies evaluating the effects of short- found that neither NSAIDs nor opioids were term or long-term treatment with NSAIDs on associated with non-unions when administered canine traumatic fracture repair have not been for up to 60 days following surgery.112 However, conducted. Judicious use of NSAIDs after a significant association with non-unions was fracture repair is common practice in veterinary observed when either NSAIDs or opioids were patients, and is recommended for several days taken for 61 to 90 days. The authors concluded after treatment for bone fractures or other that the association of non-unions with longer- orthopedic surgery.116 It should also be noted term use of NSAIDs or opioids was less likely that although the use of NSAIDs to control due to long-term NSAID or opioid effect on post-operative pain associated with fractures is bone healing but more likely a result of a a common practice, the rate of non-union prolonged need for analgesia by patients with fractures reported for dogs is 3.4%,117 and painful non-healing fractures. A more recent factors that influence non-union after fracture 2010 meta-analysis of human clinical studies repair include location of fracture, (radial and evaluating the effects of NSAIDs on bone ulna fracture), inadequate immobilization, inade- healing found that NSAID use was not quate reduction, impairment of blood flow due associated with an increased risk of non-unions to trauma (original or surgical), infection, and in patients with fractures, osteotomies, or loss of bone or bone fragments.117-119 Other fusions.113 general factors such as age, high-dose corti- costeroid therapy, or metabolic alteration of Rimadyl and Bone Healing osteoblastic activity may also affect the rate of bone healing but are uncommon factors Similar large-cohort studies or meta-analyses contributing to delayed union or non-union have not been conducted to assess the effects fractures. The benefits of NSAIDs to provide of NSAIDs on bone healing in dogs. However, analgesia and thus achieve earlier mobilization, the effects of Rimadyl on bone healing was weight bearing, and return to function should be evaluated in a laboratory study where a mid- weighed against the risk of delayed bone diaphyseal transverse tibial osteotomy was healing. Evidence supports use of NSAIDs for repaired with an intramedullary pin.114 Rimadyl control of post-operative pain after orthopedic was administered to 6 of the dogs (2.2 mg/kg q surgeries, providing the drugs are administered 12 hours for 120 days) and results were at therapeutic doses and for appropriate compared to 6 control dogs. Results showed treatment durations to control pain and there evidence of delayed healing in the Rimadyl are no predisposing factors that would group compared to the control group. However, 23 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 24

contribute to delayed healing. Determination of additional diagnostics pursued when warranted. treatment duration should be based on the Although peri-operative use of Rimadyl need for analgesia, the response to treatment, Injectable is not expected to increase the risk of and the progress of bone healing. hepatotoxicity in dogs, pre-existing conditions need to be evaluated and considered when Hepatic Effects of NSAIDs choosing peri-operative analgesics. As mentioned earlier, hepatotoxicity associated with drug administration is typically an DOSING FLEXIBILITY AND idiosyncratic reaction. No study has reported CONTINUITY OF ANALGESIA hepatotoxicity associated with peri-operative administration of Rimadyl, and hepatobiliary Rimadyl is the only NSAID available in both adverse reactions reported for Rimadyl Inject - injectable and oral formulations where both are able are very rare (<1/10,000 cases).65 A 1998 indicated for controlling post-operative pain and report documented 21 cases of hepatotoxicity inflammation associated with soft-tissue and associated with oral Rimadyl administration to orthopedic surgeries for dogs, and is backed by dogs with osteoarthritis.120 Most signs of over 10 years of research. Rimadyl is the only hepatotoxicity occurred within the first 30 days canine NSAID approved for use in puppies as of treatment, and 17 of the 21 dogs responded young as 6 weeks of age.1 Both formulations to treatment. Other researchers evaluated 805 can be administered as a single daily dose of dogs with osteoarthritis that were treated with 4.4 mg/kg (2.0 mg/lb) or divided into twice-daily Rimadyl for 84 days.121 Two dogs demonstrated doses at 2.2 mg/kg (1.0 mg/lb). signs consistent with hepatotoxicity, and both dogs recovered within a few days after Rimadyl Injectable is labeled for administration Rimadyl was discontinued and appropriate via SC injection, a convenient method of medical treatment was provided. Another study administration that does not require IV access. evaluated 71 dogs that received a glucosamine/ The pharmacokinetic profiles of the oral and chondroitin nutraceutical, meloxicam, Rimadyl, injectable formulations of Rimadyl are similar or placebo for 60 days.122 One dog in the and total drug exposure is considered bio - Rimadyl group developed hepatotoxicity and equivalent, so both dosage forms can be used recovered with treatment. Several other studies interchangeably.46,53 The availability of Rimadyl evaluating long-term Rimadyl treatment (60, 90, in both an injectable and oral form allows or 120 days) in dogs with osteoarthritis did not veterinarians to offer continuity of analgesia by detect any evidence of hepatotoxicity.100,123,124 using the same medication throughout the Idiosyncratic hepatotoxicity is not unique to entire peri-operative period. Pre-operative use Rimadyl as this condition has also been of Rimadyl Injectable at 4.4 mg/kg provides reported for the other canine NSAIDs.125 24 hours of pain management. The oral formu- lation, either caplet or chewable tablet, can be Labrador Retrievers were the most commonly used to continue post-operative pain manage - reported breed to show hepatotoxicity in the ment once the patient returns home. Also, with 1998 report.120 The study did not differentiate the trend to perform spays and neuters on very for breed prevalence within the hospital young puppies, Rimadyl provides veterinary population, and the increased numbers of practitioners a suitable option for providing pain Labradors in this study were most likely due to relief in dogs as young as 6 weeks of age. both the popularity of Labrador Retrievers and high occurrence of osteoarthritis and other Although the oral and injectable forms of musculoskeletal conditions in this breed. No Rimadyl are approved for pre-operative admin- evidence exists to indicate that Labrador istration for control of post-operative pain, use Retrievers are more susceptible to idiopathic of the injectable formulation may provide some hepatotoxicity associated with NSAIDs.2 additional benefits. Many anesthetic pre- However, Labrador Retrievers and several other medications can cause vomiting and could breeds (e.g., Bedlington Terriers, Skye Terriers, potentially result in elimination of an orally Doberman Pinchers, and Dalmatians) are administered drug prior to its complete predisposed to copper-associated chronic absorption. Also, the stress experienced during hepatitis (CACH) which can affect dogs of the peri-operative period and the effect of various ages and is often asymptomatic. Eleva- anesthetic drugs on GI motility may interfere tions of ALP or alanine amino transferase (ALT) with normal absorption of the NSAID, resulting enzymes during routine blood work (with a in suboptimal post-operative analgesia. greater relative increase in ALT vs ALP) is often Additionally, injury to the gastric mucosa can be the first evidence of CACH.126,127 Diagnosis is initiated topically if there is delay in gastric confirmed by identifying histopathological emptying.62 Using Rimadyl Injectable pre-opera- changes consistent with chronic hepatitis and tively eliminates variations in absorption of elevated hepatic copper levels of liver biopsies. orally administered drugs that may occur during Initial screening and routine monitoring of blood the peri-operative period and provides a work is recommended pre-operatively and predictable level of pain management during and after the procedure, for up to 24 hours. 24 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 25

Zoetis NSAID Technical Bulletin

CONCLUSIONS NSAIDs are a mainstay of peri-operative pain NSAID. Timing of Rimadyl Injectable adminis- management in canine surgery. Because inflam- tration should take into consideration the mation is a key driver in the development of individual patient’s health status. If there is a surgical pain, the anti-inflammatory activity of concern regarding renal perfusion or hemo - NSAIDs make this class of drugs a good choice stasis before or during surgery, another class for post-operative analgesia. Clinical and of analgesic drugs should be considered. pharmacokinetic studies support the benefits of However, in stable canine patients, the benefits administering Rimadyl Injectable pre-operatively of administering Rimadyl Injectable pre- to control post-operative pain in dogs, as dogs operatively outweigh the risks and will provide that received Rimadyl prior to surgery had up to 24 hours of analgesia. better immediate post-operative analgesia than dogs that received Rimadyl after surgery. Patient selection is also key for ensuring that Reasons for improved pain management with NSAID benefits outweigh the risk of adverse pre-operative administration vs post-operative effects. The use of NSAIDs should be avoided administration can be attributed to many factors in patients with underlying liver, kidney, or GI including: disease. Also avoid concurrent use of NSAIDs 1) the pharmacokinetic properties of Rimadyl; with corticosteroids, including oral, topical, or 2) the effects of anesthetic drugs on tissue injectable formulations, or other NSAIDs. Since concentrations; most NSAID-associated adverse events are 3) use of preemptive analgesia. inducible, higher rates of adverse events can be Preemptive pain management, followed by seen with overdosing.62,128 Although Rimadyl appropriate intra-operative and post-operative has a wide margin of safety (up to 5× the dose analgesia, can circumvent central sensitization for 1 year in laboratory studies), prudence and prevent the onset of chronic, intractable dictates that Rimadyl be administered only at pain. Rimadyl Injectable not only provides the approved label dose of 4.4 mg/kg/day. Pet analgesia but also decreases swelling at the owners should be instructed to securely store surgical site, another advantage of the anti- prescribed oral NSAIDs in an area inaccessible inflammatory effects of this drug which is not to the pet, to prevent accidental over-ingestion. provided by other classes of analgesics. In all cases, pet owners should be made aware of all potential risks associated with this class of The mechanism of action that allows NSAIDs to drugs. They should also be counseled to provide effective analgesia may also be respon- recognize clinical signs associated with NSAID sible for adverse reactions in some patients. toxicity, and should be advised to discontinue FDA-approved canine NSAIDs offer a better NSAID administration and seek veterinary safety profile than aspirin and other non- advice if these signs should occur. Whenever veterinary NSAIDs. An individual patient’s risk of Rimadyl is dispensed, the pet owner should experiencing an adverse reaction to any of the always receive a Client Information Sheet (see approved canine NSAIDs depends on their following page). medical status and tolerance for a specific

IMPORTANT SAFETY INFORMATION: As a class, NSAIDs may be associated with gastro - intestinal, kidney, and liver side effects. These are usually mild, but may be serious. Pet owners should discontinue therapy and contact their veterinarian immediately if side effects occur. Evaluation for pre-existing conditions and regular monitoring are recommended for pets on any medication, including RIMADYL. Use with other NSAIDs or corticosteroids should be avoided. See full Prescribing Information, attached.

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Dog Owner Information about Caplets/Chewable Tablets Rimadyl® (pronounced “Rim-a-dill”) for Osteoarthritis and Post-Surgical Pain. Generic name: carprofen (“car-pro-fen”)- This summary contains important information about Rimadyl. You should Tell your veterinarian if your dog is: read this information before you start giving your dog Rimadyl and Pregnant, nursing or if you plan to breed your dog. review it each time the prescription is filled. This sheet is provided only as a summary and does not take the place of instructions from your What are the possible side effects that may occur in veterinarian. Talk to your veterinarian if you do not understand any my dog during Rimadyl therapy? of this information or if you want to know more about Rimadyl. Rimadyl, like other drugs, may cause some side effects. Serious but What is Rimadyl? rare side effects have been reported in dogs taking NSAIDs, including Rimadyl is a nonsteroidal anti-inflammatory drug (NSAID) that is used Rimadyl. Serious side effects can occur with or without warning and to reduce pain and inflammation (soreness) due to osteoarthritis and in rare situations result in death. surgery in dogs. A licensed veterinarian must prescribe Rimadyl for your The most common NSAID-related side effects generally involve the dog. It is available as a caplet and chewable tablet and is given to dogs stomach (such as bleeding ulcers). Kidneys and liver can also be by mouth. affected. Look for the following side effects that can indicate your Osteoarthritis (OA) is a painful condition caused by “wear and tear” of dog may be having a problem with Rimadyl or may have another cartilage and other parts of the joints that may result in the following medical problem: changes or signs in your dog: Decrease or increase in appetite Limping or lameness Vomiting Decreased activity or exercise (difficulty or reluctance in standing, Change in bowel movements (such as diarrhea, or black, tarry or climbing stairs, jumping or running) bloody stools) Stiffness or decreased movement of joints Change in behavior (such as decreased or increased activity level, To control surgical pain (for example, for surgeries such as spays, ear incoordination, seizure or aggression) procedures or orthopedic repairs), your veterinarian may administer Yellowing of gums, skin, or whites of the eyes (jaundice) Rimadyl before the procedure and recommend that your dog be Change in drinking habits (frequency, amount consumed) treated for several days after going home. Change in urination habits (frequency, color or smell) What kind of results can I expect when my dog is on Change in skin (redness, scabs or scratching) Rimadyl for OA? It is important to stop therapy and contact your veterinarian immediately While Rimadyl is not a cure for osteoarthritis, it can relieve the pain and if you think your dog has a medical problem or side effect from Rimadyl inflammation of OA and improve your dog’s mobility. therapy. If you have additional questions about possible side effects, talk to your veterinarian. Response varies from dog to dog but can be quite dramatic. In most dogs, improvement can be seen in a matter of days. Can Rimadyl be given with other medicines? If Rimadyl is discontinued or not given as directed, your dog’s Rimadyl should not be given with other NSAIDs (for example, pain and inflammation may come back. aspirin, etodolac) or steroids (for example, cortisone, prednisone, Who should not take Rimadyl? dexamethasone, triamcinolone). Tell your veterinarian about all medicines you have given your dog in the Your dog should not be given Rimadyl if he/she: past, and any medicines that you are planning to give with Rimadyl. This Has had an allergic reaction to carprofen, the active ingredient should include other medicines that you can get without a prescription. of Rimadyl. Your veterinarian may want to check that all of your dog’s medicines Has had an allergic reaction to aspirin or other NSAIDs (for example, can be given together. etodolac, meloxicam or deracoxib) such as hives, facial swelling, or red or itchy skin. What do I do in case my dog eats more than the prescribed amount of Rimadyl? Rimadyl should be given to dogs only. Cats should not be given Rimadyl. Call your veterinarian immediately if your cat receives Rimadyl. People Contact your veterinarian immediately if your dog eats more than the should not take Rimadyl. Keep Rimadyl and all medicines out of reach of prescribed amount of Rimadyl. children. Call your physician immediately if you accidentally take Rimadyl. How to store Rimadyl Chewable Tablets. How to give Rimadyl to your dog. Rimadyl Chewable Tablets are designed to taste good to animals. Rimadyl should be given according to your veterinarian’s instructions. Keep Rimadyl Chewable Tablets in a secured storage area Your veterinarian will tell you what amount of Rimadyl is right for your out of the reach of your dog and other pets. If your dog dog and for how long it should be given. Rimadyl Caplets should be ingests more than your veterinarian prescribed, or if your other pets given by mouth. Most dogs will take Rimadyl Chewable Tablets right take Rimadyl Chewable Tablets, contact your veterinarian right away. out of your hand or the tablet can be placed in the mouth. Rimadyl may What else should I know about Rimadyl? be given with or without food. This sheet provides a summary of information about Rimadyl. If you What to tell/ask your veterinarian before giving Rimadyl. have any questions or concerns about Rimadyl or osteoarthritis or Talk to your veterinarian about: surgical pain, talk to your veterinarian. As with all prescribed medicines, Rimadyl should only be given to the The signs of OA you have observed (for example, limping, stiffness). dog for which it was prescribed. It should be given to your dog only The importance of weight control and exercise in the management for the condition for which it was prescribed. of OA. What tests might be done before Rimadyl is prescribed. It is important to periodically discuss your dog’s response to Rimadyl at regular checkups. Your veterinarian will best determine if your dog is How often your dog may need to be examined by your veterinarian. responding as expected and if your dog should continue receiving Rimadyl. The risks and benefits of using Rimadyl. To report a suspected adverse reaction call Zoetis at 1-888-963-8471. Tell your veterinarian if your dog has ever had the following medical problems: Issued October 2014 Experienced side effects from Rimadyl or other NSAIDs, such as aspirin Digestive upset (vomiting and/or diarrhea) Distributed by: Liver disease Kidney disease

A bleeding disorder (for example, Von Willebrand’s disease) Div. of Zoetis Inc Tell your veterinarian about: Kalamazoo, MI 49007 Any other medical problems or allergies that your dog has now or has had. All medicines that you are giving your dog or plan to give your dog, www.rimadyl.com © 2014 Zoetis Inc. 14029100 including those you can get without a prescription. Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 27

® Cl O Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study with the Injectable Observation Rimadyl (n=168) Placebo (n=163) Vomiting 10.1 9.2 (carprofen) OH Diarrhea/soft stool 2.4 3.7 Dermatitis 0.6 1.2 Caplets/Chewable Tablets N Dysrhythmia 0.6 0.6 CH3 Swelling 0 1.2 For oral use in dogs only Dehiscence 1.2 0 Sterile Injectable Solution 50 mg/mL H WBC increase 13.7 6.7 For subcutaneous use in dogs only * A single dog may have experienced more than one occurrence of an event. Post-Approval Experience: Non-steroidal, anti-inflammatory drug Although not all adverse reactions are reported, the following adverse reactions are based on voluntary post-approval adverse drug experience reporting. The categories of adverse reactions are listed in decreas ing order of frequency by body system. CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. Gastrointestinal: Vomiting, diarrhea, constipation, inappetence, melena, hematemesis, gastrointestinal ulceration, gastrointestinal bleeding, pancreatitis. DESCRIPTION: Rimadyl (carprofen) is a non-steroidal anti-inflamma tory drug (NSAID) of the propionic acid class that includes ibuprofen, naproxen, and Hepatic: Inappetence, vomiting, jaundice, acute hepatic toxicity, hepatic enzyme elevation, abnormal liver function test(s), hyperbilirubinemia, bilirubinuria, ketoprofen. Carprofen is the nonproprietary designation for a substi tuted carbazole, 6-chloro-_-methyl-9H-carbazole-2-acetic acid. The empirical formula hypoalbuminemia. Approximately one-fourth of hepatic reports were in Labrador Retrievers. is C15H12ClNO2 and the molecular weight 273.72. The chemical structure of carprofen is shown above. Carprofen is a white, crystalline compound. It is Neurologic: Ataxia, paresis, paralysis, seizures, vestibular signs, disorientation. freely soluble in ethanol, but practically insoluble in water at 25°C. Urinary: Hematuria, polyuria, polydipsia, urinary incontinence, urinary tract infection, azotemia, acute renal failure, tubular abnormalities including acute 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 tubular necrosis, renal tubular acidosis, glucosuria. 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, Behavioral: Sedation, lethargy, hyperactivity, restlessness, aggressiveness. and water for injection. Hematologic: Immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, blood loss anemia, epistaxis. CLINICAL PHARMACOLOGY: Carprofen is a non-narcotic, non-steroidal anti-inflammatory agent with characteristic analgesic and antipyretic activity Dermatologic: Pruritus, increased shedding, alopecia, pyotraumatic moist dermatitis (hot spots), necrotizing panniculitis/vasculitis, ventral ecchymosis. approximately equipotent to indomethacin in animal models.1 In rare situations, injection site reactions including necrosis, abscess and seroma formation, and granulomas have been reported with the injectable formulation. The mechanism of action of carprofen, like that of other NSAIDs, is believed to be associated with the inhibition of cyclooxygenase activity. Two unique 2 Immunologic or hypersensitivity: Facial swelling, hives, erythema. cyclooxygenases have been described in mammals. The constitutive cyclooxygenase, COX-1, synthesizes prostaglandins necessary for normal gastro- In rare situations, death has been associated with some of the adverse reactions listed above. intestinal and renal function. The inducible cyclooxygenase, COX-2, generates prostaglandins involved in inflammation. Inhibition of COX-1 is thought to To report a suspected adverse reaction call 1-888-963-8471. 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 DOSAGE AND ADMINISTRATION: Always provide Client Information Sheet with prescription. Carefully consider the potential benefits and risk of Rimadyl 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 and other treatment options before deciding to use Rimadyl. Use the lowest effective dose for the shortest duration consistent with individual response. in two inflammatory cell systems: rat polymorphonuclear leukocytes (PMN) and human rheumatoid synovial cells, indicating inhibition of acute (PMN 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 system) and chronic (synovial cell system) inflammatory reactions.1 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 Several studies have demonstrated that carprofen has modulatory effects on both humoral and cellular immune responses.5–9 Data also indicate that 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 carprofen inhibits the production of osteoclast-activating factor (OAF), PGE , and PGE by its inhibitory effect in prostaglandin biosynthesis.1 1 2 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 Based upon comparison with data obtained from intravenous administration, carprofen is rapidly and nearly completely absorbed (more than 90% dog consumes the complete dose. 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 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 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% 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 post-operative pain, administer bound to plasma protein and exhibits a very small volume of distribution. approximately 2 hours before the procedure. Comparison of a single 25 mg dose in Beagle dogs after subcutaneous and oral administration demonstrated that the dorsoscapular subcutaneous PALATABILITY: A controlled palatability study was conducted which demonstrated that Rimadyl chewable tablets were readily accepted and consumed administration results in a slower rate of drug input (as reflected by mean peak observed concentrations) but comparable total drug absorption within a on first offering by a majority of dogs. 12 hour dosing interval (as reflected by area under the curve from hours zero to 12 postdose). EFFECTIVENESS: Confirmation of the effectiveness of Rimadyl for the relief of pain and inflammation associated with osteoarthritis, and for the control Carprofen is eliminated in the dog primarily by biotransformation in the liver followed by rapid excretion of the resulting metabolites (the ester glucuronide of of postoperative pain associated with soft tissue and orthopedic surgeries, was demonstrated in 7 placebo-controlled, masked studies examining the 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%). anti-inflammatory and analgesic effectiveness of Rimadyl caplets and injectable in various breeds of dogs. Some enterohepatic circulation of the drug is observed. Separate placebo-controlled, masked, multicenter field studies confirmed the anti-inflammatory and analgesic effectiveness of Rimadyl caplets when INDICATIONS: Rimadyl is indicated for the relief of pain and inflammation associated with osteoarthritis and for the control of postoperative pain associated 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 with soft tissue and orthopedic surgeries in dogs. statistically significant overall improvement based on lameness evaluations by the veterinarian and owner observations when administered Rimadyl at CONTRAINDICATIONS: Rimadyl should not be used in dogs exhibiting previous hypersensitivity to carprofen. labeled doses. WARNINGS: Keep out of reach of children. Not for human use. Consult a physician in cases of accidental ingestion by humans. For use in dogs only. Based upon the blood level comparison between subcutaneous and oral administration, Rimadyl effectiveness for osteoarthritis after dorsoscapular Do not use in cats. subcutaneous and oral administration should be similar, although there may be a slight delay in the onset of relief after subcutaneous injection. All dogs should undergo a thorough history and physical examination before initiation of NSAID therapy. Appropriate laboratory tests to establish Separate placebo-controlled, masked, multicenter field studies confirmed the effectiveness of Rimadyl caplets and injectable for the control of postoperative hematological and serum biochemical baseline data prior to, and periodically during, administration of any NSAID should be considered. Owners should 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 be advised to observe for signs of potential drug toxicity (see Information for Dog Owners, Adverse Reactions, Animal Safety and Post-Approval surgeries were administered Rimadyl preoperatively and for a maximum of 3 days (soft tissue) or 4 days (orthopedic) postoperatively. In general, dogs Experience). administered Rimadyl showed statistically significant reduction in pain scores compared to controls. PRECAUTIONS: As a class, cyclooxygenase inhibitory NSAIDs may be associated with gastrointestinal, renal and hepatic toxicity. Effects may result from ANIMAL SAFETY: Laboratory studies in unanesthetized dogs and clinical field studies have demonstrated that Rimadyl is well tolerated in dogs after oral decreased prostaglandin production and inhibition of the enzyme cyclooxygenase which is responsible for the formation of prosta glandins from arachidonic administration. acid.11–14 When NSAIDs inhibit prosta glandins that cause inflammation they may also inhibit those prosta glandins which maintain normal homeostatic function. These anti-prostaglandin effects may result in clinically sig nificant disease in patients with underlying or pre-existing disease more often than in 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 healthy patients.12,14 NSAID therapy could unmask occult disease which has previously been undiagnosed due to the absence of apparent clinical signs. 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 Patients with underlying renal disease for example, may experience exacerbation or decompensation of their renal disease while on NSAID therapy.11–14 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 The use of parenteral fluids during surgery should be considered to reduce the potential risk of renal complications when using NSAIDs perioperatively. 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. 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 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 greatest risk for renal toxicity are those that are dehydrated, on concomitant diuretic therapy, or those with renal, cardiovascular, and/or hepatic 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 dysfunction. Concurrent administration of potentially nephrotoxic drugs should be approached cautiously, with appropriate monitoring. Concomitant use 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 Rimadyl with other anti-inflammatory drugs, such as other NSAIDs or corticosteroids, should be avoided because of the potential increase of adverse exam of these areas revealed no evidence of ulceration, but did show minimal congestion of the lamina propria in 2 of the 5 dogs. reactions, including gastrointestinal ulcerations and/or perforations. Sensitivity to drug-associated adverse reactions varies with the individual patient. 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 Dogs that have experienced adverse reactions from one NSAID may experience adverse reactions from another NSAID. Rimadyl treatment was not 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 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 in any of the treated animals. In both studies, dogs receiving the highest doses had average increases in serum L-alanine aminotransferase (ALT) of parenterally injected product, good hygienic procedures should be used when administering Rimadyl Injectable. approximately 20 IU. Rimadyl is not recommended for use in dogs with bleeding disorders (e.g., Von Willebrand’s disease), as safety has not been established in dogs with 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 these disorders. The safe use of Rimadyl in animals less than 6 weeks of age, pregnant dogs, dogs used for breeding purposes, or in lactating bitches described as slight redness or rash and were diagnosed as non-specific dermatitis. The possibility exists that these mild lesions were treatment related, has not been established. Safety has not been established for IV or IM administration. Studies to determine the activity of Rimadyl when administered but no dose relationship was observed. concomitantly with other protein-bound or similarly metabolized drugs have not been conducted. Drug compatibility should be monitored closely in 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 patients requiring additional therapy. Such drugs commonly used include cardiac, anticonvulsant and behavioral medications. It has been suggested that 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 treatment with carprofen may reduce the level of inhalant anesthetics needed.15 It is suggested to use different sites for additional injections. If additional tolerated and the incidence of clinical adverse reactions for Rimadyl-treated animals was no higher than placebo-treated animals (placebo contained pain medication is warranted after administration of the total daily dose of Rimadyl, alternative analgesia should be considered. The use of another NSAID 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 is not recommended. Consider appropriate washout times when switching from one NSAID to another or when switching from corticosteroids use to less than pre-treatment values for dogs receiving Rimadyl and placebo, respectively. Differences were not statistically significant. For animals receiving NSAID use. 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 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 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 quantities of tablets are ingested. If you suspect your dog has consumed Rimadyl chewable tablets above the labeled dose, please call your veterinarian for therapy. One placebo-treated dog had a greater than 2-fold increase in ALT. None of these animals showed clinical signs associated with laboratory immediate assistance and notify Zoetis at 1-888-963-8471. value changes. Changes in the clinical laboratory values (hematology and clinical chemistry) were not considered clinically significant. The 1 mg/lb twice INFORMATION FOR DOG OWNERS: daily course of therapy was repeated as needed at 2-week intervals in 244 dogs, some for as long as 5 years. 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 Clinical field studies were conducted in 297 dogs of different breeds undergoing orthopedic or soft tissue surgery. Dogs were administered 2 mg/lb of of the clinical signs associated with drug intolerance. Adverse reactions may include decreased appetite, vomiting, diarrhea, dark or tarry stools, 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 increased water consumption, increased urination, pale gums due to anemia, yellowing of gums, skin or white of the eye due to jaundice, lethargy, when used in conjunction with a variety of anesthetic-related drugs. The type and severity of abnormal health observation in Rimadyl- and placebo-treated incoordination, seizure, or behavioral changes. animals were approximately equal and few in number (see Adverse Reactions). The most frequent abnormal health observation was vomiting and was Serious adverse reactions associated with this drug class can occur without warning and in rare situations result in death (see Adverse Reactions). observed at approximately the same frequency in Rimadyl- and placebo-treated animals. Changes in clinicopathologic indices of hematopoietic, renal, Owners should be advised to discontinue Rimadyl therapy and contact their veterinarian immediately if signs of intolerance are observed. 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 The vast majority of patients with drug related adverse reactions have recovered when the signs are recognized, the drug is withdrawn, and veterinary 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 care, if appropriate, is initiated. Owners should be advised of the importance of periodic follow up for all dogs during administration of any NSAID. greater for dogs receiving placebo. ADVERSE REACTIONS: During investigational studies for the caplet formulation with twice daily administration of 1 mg/lb, no clinically significant adverse Clinical field studies on the use of Rimadyl Injectable were conducted on 331 dogs undergoing orthopedic or soft tissue surgery. Dogs were administered reactions were reported. Some clinical signs were observed during field studies (n=297) which were similar for carprofen caplet- and placebo-treated 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 dogs. Incidences of the following were observed in both groups: vomiting (4%), diarrhea (4%), changes in appetite (3%), lethargy (1.4%), behavioral changes surgery). Rimadyl was well tolerated when used in conjunction with a variety of anesthetic-related drugs. The type and severity of abnormal health (1%), and constipation (0.3%). The product vehicle served as control. observations in Rimadyl- and placebo-treated animals were approximately equal and few in number (see Adverse Reactions). The most frequent abnormal 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 observation was vomiting and was observed at approximately the same frequency in Rimadyl- and placebo-treated animals. Changes in clinico- health observations were reported. The product vehicle served as control. pathologic 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 Percentage of Dogs with Abnormal Health Observations Reported in Clinical Field Study (2 mg/lb once daily) and 0.7 IU greater for dogs receiving Rimadyl and placebo, respectively. Swelling and warmth were associated with the injection site after subcutaneous administration of Rimadyl Injectable. These findings were not clinically Observation Rimadyl (n=129) Placebo (n=132) significant. Long term use of the injectable has not been studied. Inappetence 1.6 1.5 Vomiting 3.1 3.8 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, Diarrhea/Soft stool 3.1 4.5 product may be stored at temperatures up to 25°C (77°F) for 28 days. Behavior change 0.8 0.8 HOW SUPPLIED: Rimadyl caplets and chewable tablets are scored, and contain 25 mg, 75 mg, or 100 mg of carprofen per caplet or tablet. Each caplet Dermatitis 0.8 0.8 size is packaged in bottles containing 30, 60, or 180 caplets. Each chewable tablet size is packaged in bottles containing 7, 30, 60, or 180 tablets. Rimadyl PU/PD 0.8 — Injectable is supplied in 20-mL, amber, glass, sterile, multi-dose vials. SAP increase 7.8 8.3 ALT increase 5.4 4.5 REFERENCES: AST increase 2.3 0.8 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. BUN increase 3.1 1.5 2. Vane JR, Botting RM: Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol 25:102, pp. 9–21, 1996. Bilirubinuria 16.3 12.1 3. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by Ketonuria 14.7 9.1 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 nonsteroi dal anti-inflammatory Clinical pathology parameters listed represent reports of increases from pre-treatment values; medical judgment is necessary to determine clinical drugs. Am J Vet Res 59:11, pp. 1441–1446, November 1998. relevance. 5. Ceuppens JL, et al: Non-steroidal anti-inflammatory agents inhibit the synthesis of IgM rheumatoid factor in vitro. Lancet 1:528, 1982. During investigational studies of surgical pain for the caplet formulation, no clinically significant adverse reactions were reported. The product vehicle 6. Ceuppens JL, et al: Endogenous prostaglandin E2 enhances polyclonal immunoglobulin production by ionically inhibiting T suppressor cell activity. Cell served as control. Immunol 70:41, 1982. 7. Schleimer RP, et al: The effects of prostaglandin synthesis inhibition on the immune response. Immunopharmacology 3:205, 1981. Percentage of Dogs with Abnormal Health Observations Reported in Surgical Pain Field Studies with Caplets (2 mg/lb once daily) 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 Immunopharma cology 4:195, 1982. Observation* Rimadyl (n=148) Placebo (n=149) 9. Veit BC: Immunoregulatory activity of cultured-induced suppressor macrophages. Cell Immunol 72:14, 1982. Vomiting 10.1 13.4 10. Schmitt M, et al: Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs. Biopharm Drug Dispos 11(7):585, Diarrhea/Soft stool 6.1 6.0 1990. Ocular disease 2.7 0 11. Kore AM: Toxicology of nonsteroidal anti-inflammatory drugs. Veter inary Clinics of North America, Small Animal Practice 20, March 1990. Inappetence 1.4 0 12. Binns SH: Pathogenesis and pathophysiology of ischemic injury in cases of acute renal failure. Compend for Cont Ed 16:1, January 1994. Dermatitis/Skin lesion 2.0 1.3 13. Boothe DM: Prostaglandins: Physiology and clinical implications. Compend for Cont Ed 6:11, November 1984. Dysrhythmia 0.7 0 14. Rubin SI: Nonsteroidal anti-inflammatory drugs, prostaglandins, and the kidney. JAVMA 188:9, May 1986. Apnea 1.4 0 15. Ko CH, Lange DN, Mandsager RE, et al: Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. JAVMA Oral/Periodontal disease 1.4 0 217:1025–1028, 2000. Pyrexia 0.7 1.3 Urinary tract disease 1.4 1.3 For a copy of the Material Safety Data Sheet (MSDS) call 1-888-963-8471. To report adverse reactions call Zoetis Inc. at 1-888-963-8471. Wound drainage 1.4 0 NADA #141-053, NADA #141-111, NADA #141-199 Approved by FDA * A single dog may have experienced more than one occurrence of an event. Distributed by: During investigational studies for the chewable tablet formulation, gastrointestinal signs were observed in some dogs. These signs included vomiting and Zoetis Inc. soft stools. Kalamazoo, MI 49007 Revised: October 2014 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. Printed in USA Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 28

REFERENCES 15. King JN, Arnaud JP, Goldenthal EI, et al. Robena- coxib in the dog: target species safety in relation to 1. Rimadyl product label, NADA 141-199, 2014. extent and duration of inhibition of COX-1 and COX- 2. J Vet Pharm Therap 2010; 34:298-311. 2. KuKanich B, Bidgood T, Knesl O. Clinical pharma- cology of nonsteroidal anti-inflammatory drugs in 16. Lees P. Pharmacology of drugs used to treat dogs. Vet Anaesth Analg 2012; 39:69-90. osteoarthritis in veterinary practice. Inflammophar- mocology 2003; 11:385-399. 3. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge 17. FDA-CVM website accessed July 10th 2013. and proposed mechanism. Am J Physiology 1983; 245:G601-623. 18. Thurmon JC, Tranquilli WJ, Benson GJ. Essen- tials of small animal anesthesia & analgesia. 4. Whelton A. Nephrotoxicity of nonsteroidal anti- Lippincott Williams & Wilkins. Baltimore, MD. 1999; inflammatory drugs: physiologic foundations and chapter 2:28-60. clinical implications. Am J Med 1999; 106:13S-24S. 19. Willer JC. Comparative study of perceived pain 5. Vane JR, Bakhle YS, Botting RM. Cyclooxyge- and nociceptive flexion reflex in man. Pain 1977; nases 1 and 2. Ann Rev Pharmacol Toxicol 1998; 3:69-80. 38:97-120. 20. Durnett-Richardson J, Vasko, MR. Cellular 6. Jackson EK, Gerkens JF, Brash AR, et al. Acute mechanisms of neurogenic inflammation. J Pharm renal artery constriction increases prostaglandin I2 Exp Therap 2002; 302:839-845. biosynthesis and renin release in the conscious dog. J Pharm Exp Therap 1982; 222:410-413. 21. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system 7. Hao CM, Breyer MD. Physiological regulation of to damage. Ann Rev Neuro 2009; 32:1-32. prostaglandins in the kidneys. Ann Rev Physiol 2008; 70: 357-377. 22. Woolf CJ. Somatic pain - pathogenesis and prevention. Brit J Anaesthesia 1995; 75:169-175. 8. Miller SB. Prostaglandins in health and disease: an overview. Semin Arthritis Rheum 2006; 36:37-49. 23. Coutaux A, Adam F, Willer J-C, et al. Hyperal- gesia and allodynia: peripheral mechanisms. Joint 9. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnor- Bone Spine 2005; 72:359-371. malities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature 1995; 24. Julius D, Basbaum AI. Molecular mechanisms of 378:406-409. nociception. Nature 2001; 413:203-210. 10. Brzozowski T, Konturek PC, Konturek SJ, et al. 25. Bhave G, Gereau RW IV. Posttranslational Classic NSAID and selective cyclooxygenase (COX)- mechanism of peripheral sensitization. J Neurobiol 1 and COX-2 inhibitors in healing of chronic gastric 2004; 61:88-106. ulcers. Microscopy Res Tech 2001; 53:343-353. 26. Gold MS, Reichling DB, Shuster MJ, et al. Hyper- + 11. Lees P, Landoni MF, Giraudel J, et al. Pharmaco- algesic agents increase a tetrodotoxin-resistant Na dynamics and pharmacokinetics of nonsteroidal anti- current in nociceptors. Proc Natl Acad Sci, Neurobi- inflammatory drugs in species of veterinary interests. ology 1996; 93:1108-1112. J Vet Pharm Therap 2004; 27:479-490. 27. Woolf C J, Salter MW. Neuronal plasticity: 12. Brideau C, Van Staden C, Chan CC. In vitro increasing the gain in pain. Science 2000; 288:1765- effects of cyclooxygenase inhibitors in whole blood 1768. of horses, dogs and cats. Amer J Vet Res 2001; 28. Woolf CJ, King AE. Dynamic alterations in the 62:1755-1760. cutaneous mechanoreceptive fields of dorsal horn 13. Rickets AP, Lundy KM, Seibel SB. Evaluation of neurons in the rat spinal cord. J Neuroscience 1990; selective inhibition of canine cyclooxygenase 1 and 2 10:2717-2726. by carprofen and other nonsteroidal anti-inflam- 29. Ali Z, Meyer RA, Campbell JN. Secondary hyper- matory drugs. Amer J Vet Res 1998; 59:1441-1446. algesia to mechanical but not heat stimuli following a 14. Kay-Mungford P, Benn SJ, LaMarre J, et al. In capsaicin injection in hairy skin. Pain 1996; 68:401- vitro effects of nonsteroidal anti-inflammatory drugs 411. on cyclooxygenase activity in dogs. Amer J Vet Res 30. Torebjork YH, Lundberg LER, LaMotte RH. 2000; 61:802-810. Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiology 1992; 448:765-780.

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