Робенакоксиб для людей инструкция по применению

Pharmacology and mechanism of action

Robenacoxib is an NSAID. Like other drugs in this class, robenacoxib has analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins. The enzyme inhibited by NSAID is the cyclooxygenase (COX) enzyme. The COX enzyme exists in two isoforms: COX-1 and COX-2. COX-1 is primarily responsible for synthesis of prostaglandins important for maintaining a healthy gastrointestinal tract, kidney function, platelet function, and other normal functions. COX-2 is induced and responsible for synthesizing prostaglandins that are important mediators of pain, inflammation, and fever. However, it is known that there is some crossover of COX-1 and COX-2 effects and COX-2 activity is important for some biological effects. Robenacoxib is more selective for COX-2 using in vitro assays compared with older nonselective NSAIDs, but it is not known if the specificity for COX-1 or COX-2 is associated with efficacy or safety. Robenacoxib has a short half-life in both dogs and cats, but tissue concentrations persist for much longer, which may explain the efficacy with once-daily dosing despite a short half-life. The half-life is 0.6-1.1 hours in dogs and 1.49, 1.87, 0.84, and 0.78 hours in cats (depending on the study). The volume of distribution in dogs is 0.24 L/kg and 0.13 and 0.19 L/kg in cats, depending on the study. Oral absorption is 84% in dogs (nonfed) or 62% (fed) and in cats, 49% (nonfed), and 10% (fed). Protein binding is 98% and 99.9% in dogs and cats, respectively. Thus it appears that feeding greatly influences oral absorption. Therefore, it is recommended in cats that it should be administered without food to maximize oral absorption.

Robenacoxib

Robenacoxib is a member of the coxib class of NSAIDs. In vitro and in vivo data support robenacoxib as a COX-1–sparing (COX-2–selective) drug in both dogs and cats. Robenacoxib is approved for only dogs or both dogs and cats depending on the country. Indications in the dog are for treatment of pain and inflammation associated with orthopedic or soft-tissue surgery as well as the treatment of pain and inflammation associated with chronic OA (depending on the country). Robenacoxib has been shown to maintain elevated concentrations in inflamed joints (either experimentally induced or with chronic OA) when compared with the serum concentrations over time. In the cat, approved indications (depending on the country) may include treatment of postoperative pain and inflammation associated with orthopedic and soft tissue surgeries as well as the acute pain and inflammation associated with musculoskeletal disorders. Length of approved treatment times in the cat varies from 3 to 11 days. Robenacoxib was shown to have a very good safety profile with daily administration in studies of 28 and 42 days in healthy young cats (5 to 8.5 months of age).

Robenacoxib

Robenacoxib is a novel specific COX-2 inhibitor licensed for use in dogs and cats (King et al., 2009), producing good anti-inflammatory, analgesic and antipyretic effects in experimentally-induced inflammation in cats (Giraudel et al., 2009). The drug has a short residence time in blood but accumulates in inflammatory exudate (King et al., 2009). Using in vitro whole blood assays, the IC₅₀ COX-1:COX-2 ratio in cats was 502 and in dogs was 129; whereas the more clinically relevant IC₂₀ COX-1:IC₈₀ COX-2 ratio in cats was 17 and in dogs was 20 (Giraudel et al., 2009b; King et al., 2010). The use of 2 mg/kg in cats resulted in 5% inhibition of COX-1 and 90% inhibition of COX-2 over 12 hours (Giraudel et al., 2009b). Bioavailability was 84–88% after SC or PO administration in fasted dogs, but dropped to 62% in fed dogs (Jung et al., 2009).

Postoperative Analgesia

Clinical Choices

There seems to be little difference in the efficacy of the various NSAIDs in the acute perioperative setting, and all provide good analgesia in the majority of cats for up to 24 hours.²⁹ More recently, robenacoxib was shown to perform better than meloxicam for the control of postoperative pain after a variety of surgical procedures.³¹ Choice of agent depends on personal preference, convenience of administration, duration of use, and availability of licensed products. For long-term use, meloxicam is currently the best choice and the only NSAID labeled for treatment of chronic musculoskeletal disorders in cats, at least in some countries. Once an NSAID has been chosen, the cat should not be placed on a different one without a period of washout, which is arbitrarily said to be 5 to 7 days.

With the availability of newer NSAIDs the efficacy and safety of which are established, there appears to be little justification for use of the older NSAIDs such as aspirin, flunixin, and phenylbutazone to provide analgesia in cats. Paracetamol, ibuprofen, indomethacin, and naproxen are extremely toxic in cats and should never be used.

Nonsteroidal Antiinflammatory Drugs

Inflammation plays a significant role in the pain process, and therefore the use of NSAIDs to reduce or eliminate peripheral inflammation may be helpful. NSAIDs decrease the pain input to the CNS, which may aggravate central hypersensitivity.² There are several commercially available veterinary NSAIDs, including carprofen (Rimadyl), deracoxib (Deramaxx), meloxicam (Metacam), etodolac (Etogesic), tepoxalin (Zubrin), and robenacoxib (Onsior). The analgesic and antiinflammatory effects associated with NSAIDs are related to inhibition of cyclooxygenase (COX) enzyme isoforms. COX-1 is primarily responsible for basal prostaglandin production for normal homeostatic processes within the body, including gastric mucus production, platelet function, and, indirectly, hemostasis, whereas COX-2 is found at sites of inflammation (although COX-2 is responsible for some basal production of constitutive prostaglandins as well). Ideally, selective inhibition of prostaglandins produced primarily by COX-2 would provide analgesic and antiinflammatory effects without the unwanted adverse effects of COX-1 inhibition.¹⁶ At present, there is no pure COX-2 inhibitor; rather, certain NSAIDs have varying degrees of COX-1 inhibition. For this reason, NSAIDs should be used cautiously in patients with hypotension, hypovolemia, preexisting renal disease (due to the increased potential for renal vascular vasoconstriction, which would lead to worsening of renal insufficiency), and GI disease or gastric ulceration.^5,7,17

Ideally, enteral NSAIDs should be given with food when possible to decrease the incidence of gastric ulceration. In addition, NSAIDs should be used cautiously in the perioperative period because decreased platelet function may increase the incidence of operative hemorrhage. Injectable NSAIDs (e.g., carprofen, meloxicam) have an advantage over oral NSAIDs because injectable drug therapy can be administered to patients that cannot tolerate oral administration due to preoperative fasting for anesthesia, nausea, vomiting, or decreased mentation.⁵ Finally, although NSAIDs have a slow onset of action (requiring up to 45 to 60 minutes to take effect), they provide analgesia for an extended period of time.¹⁸ Carprofen has a 12-hour dosing frequency, whereas other NSAIDs (e.g., deracoxib, meloxicam, etodolac) are labeled for once-daily dosing.¹⁶ The new feline-specific NSAID Onsior contains robenacoxib and is a COX-2 inhibitor with a high safety index in cats.¹⁹ It has analgesic, antiinflammatory, and antipyretic effects in cats and selectively distributes to inflamed tissues, while sparing COX-1 at the clinically recommended dose.²⁰ It can be given subcutaneously (SC) between the shoulder blades (2 mg/kg) or orally (PO) (6 mg per cat q24h for cats weighing 2.5 to 6 kg and 12 mg per cat q24h for cats weighing 6.1 to 12 kg for 3 days).^20,21 Robenacoxib has a terminal half-life of 1.9 hours in cats, with efficacy persisting for 22 hours.²⁰

As mentioned previously, NSAIDs can be used in combination with opioids for a combined therapeutic effect. However, the concurrent use of NSAIDs and corticosteroids is not recommended due to the potentiated adverse GI effects of COX-1 inhibition.⁵

Nonsteroidal Antiinflammatories

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of effectively managing certain types of chronic pain in humans, cats, and dogs, especially those associated with tissue inflammation.^47,48 NSAIDs interact variably with cyclooxygenase and lipoxygenase enzymes (COX-1, COX-2 and LOX). Inhibition of these enzymes affects the breakdown of arachidonic acid into the prostanoids responsible for the transmission and mediation of pain and inflammation in the periphery.⁴⁹ The homeostatic importance of COX enzymes is widely known and their inhibition causes adverse events when administering NSAIDs in small animals.^47,50 In general, NSAID use in cats is more of a concern due to their relatively decreased rate of glucuronidation, but while this affects the pharmacokinetics of some NSAIDs, others are metabolized via oxidative pathways, which may lead to more predictable pharmacokinetics and/or an increased safety profile.⁵¹ There is an extensive literature review regarding the use of NSAIDs in cats by Lascelles et al, along with descriptions of their pharmacology and pharmacokinetics.⁴⁷

Currently meloxicam is the only NSAID registered for long-term use in cats for the control of chronic musculoskeletal pain in Europe and Australia, and there is also published clinical data on its long-term use in both on- and off-label contexts in cats. It is hoped that in due time studies supporting the efficacy and safety of long-term use of other NSAIDs, such as robenacoxib, will emerge. Additionally, local rules and regulations (as well as availability) may affect the ability of a clinician to use one or more of these drugs. Despite licensing/registration differences, there is a growing body of evidence supporting the long-term safety and clinical efficacy of certain NSAIDs in managing chronic pain associated with musculoskeletal disease.^12,49,52,53 It is worth pointing out that dosages of some long-term studies may differ from the label dose. The COX-2 preferential (e.g., meloxicam) and COX-2 specific NSAIDs (e.g., robenacoxib) theoretically offer improved safety profiles compared with nonselective NSAIDs. However, no “safe” NSAID exists, as all have the potential for adverse effects if used inappropriately, if given at an excessively high dose, and/or if given for a prolonged period of time. There are numerous considerations to adhere to when prescribing NSAIDs, especially to older cats. Judicious patient selection and client education is of critical importance. Establishing the health profile of an individual and the relative stability of any concurrent diseases prior to instituting therapy is prudent. More extensive consensus guidelines covering the long-term use of NSAIDs in cats have been published and are freely available online (see Additional Resources at the end of the chapter).⁴⁹

A common dilemma facing veterinarians managing older cats is that these patients often suffer chronic painful disorders as well as chronic kidney disease. Chronic kidney disease (CKD) is currently a labeled contraindication for the use of all NSAIDs. This should not totally preclude the use of NSAIDs, but rather a cautious and considered approach in their prescription is warranted. There are two clinical retrospective studies evaluating the long-term use of NSAIDs in cats with concurrent CKD.^52,53 In another study, meloxicam did not have an effect on glomerular filtration rates in euvolemic cats with reduced renal mass equivalent to International Renal Interest Society IRIS stage 2 and 3 CKD.⁵⁴ The results of this study were consistent with the hypothesis that glomerular filtration rates of cats with normal or reduced renal function are not dependent on cyclooxygenase function in euvolemic states. This serves to illustrate that with judicious patient screening, regular monitoring, client information and education, hydration maintenance, and appropriate dose selection, NSAIDs may be used in cats with CKD.

It is common practice to reduce the dose for long-term NSAID administration. For meloxicam, doses between 0.01mg/kg and 0.03 mg/kg PO every 24 hours have been reported.^49,52,53 It is suspected that these lower empiric dose rates were selected to reduce the potential for adverse events, balancing the perceived risk with client observed clinical response. There are no controlled studies assessing the effects of dose length, dose titration, or how reduced dose frequency affects chronic pain control in cats. Studies in dogs with DJD support the prolonged use of NSAIDs in managing chronic pain, as it has been shown that with prolonged and consistent use, there was a continued positive clinical effect.⁴⁸ Downward dose titration of NSAIDs has been found to be effective in certain individual dogs and consistent levels of analgesia have been shown to deliver more effective pain control.^48,55 Similarly, a study in people found that continuous administration of NSAIDs resulted in significantly better pain management than intermittent or pulse dosing.⁵⁶ Dose titration is therefore a common sense approach to using NSAIDs in cats long term, but while there is good evidence that efficacy of meloxicam in managing DJD is maintained at doses below the official label dose, this may not be true of all cats or other diseases, especially where pain may be more severe.

When used for certain types of pain or in association with other types of medication, NSAIDs may not be appropriate. In humans, NSAIDs are believed to be relatively ineffective at managing neuropathic pain.⁴⁶ The employment of multimodal therapy and CDT is of benefit in the clinical management of patients suspected of suffering pain refractory to NSAIDs and neuropathic pain, for example patients with significant spinal DJD. Furthermore, for management of neoplasia or certain other conditions (such as inflammatory bowel disease), glucocorticoids may be an important part of therapy. The use of glucocorticoids is one of the recognized contraindications to using NSAIDs and in such cases alternative approaches to the provision of analgesia should be sought.

The authors regard NSAIDs as the base modality for controlling chronic pain as they have the most evidence of safety and efficacy supporting their rational use. However, they are often best used in a multimodal setting and/or in CDT (Box 15-4).

TRADITIONAL ANALGESIC THERAPY

A three-step analgesic ladder for treating cancer pain has been proposed by the World Health Organization (WHO).^1,2,3-6,8 Mild pain is treated initially with non-opiate drugs, generally non-steroidal anti-inflammatory drugs (NSAIDs). When pain persists, or with moderate pain, a “weak opiate” can be added. If still not controlled, or with severe pain, stronger opiates, preferably full muagonists, are added on the final rung. Adjuvant analgesic drugs can be incorporated at any step. Further steps are added for human patients with painful advanced cancer with intrathecal administration of opiates, neurostimulation, or peripheral neuroablation as a fourth step, and central neuroablative procedures as a fifth step.⁸ An inverted pyramid is used by others when chronic pain with central sensitization is suspected.⁶ This refers to use of a multimodal approach first to reverse such changes, before gradually eliminating one drug at a time, as proper pain control is achieved.