Contraindications to the use of Arcoxia
- complete or incomplete combination of bronchial asthma, recurrent nasal polyposis or paranasal sinuses and intolerance to acetylsalicylic acid and other NSAIDs (including a history);
- erosive and ulcerative changes in the mucous membrane of the stomach or duodenum, active gastrointestinal bleeding, cerebrovascular or other bleeding;
- inflammatory bowel diseases (Crohn's disease, ulcerative colitis) in the acute phase;
- hemophilia and other bleeding disorders;
— severe heart failure (II-IV functional classes according to the NYHA classification);
- severe liver failure (more than 9 points on the Child-Pugh scale) or active liver disease;
- severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney disease, confirmed hyperkalemia;
— the period after coronary artery bypass grafting; peripheral arterial diseases, cerebrovascular diseases, clinically significant ischemic heart disease;
- persistent blood pressure values exceeding 140/90 mm Hg. Art. with uncontrolled arterial hypertension;
- pregnancy;
- lactation period (breastfeeding);
- children under 16 years of age;
- hypersensitivity to any component of the drug.
The drug should be used with caution in the presence of anamnestic data on the development of ulcerative lesions of the gastrointestinal tract, Helicobacter pylori infection, in the elderly, in patients who have used NSAIDs for a long time, frequently drinking alcohol, with severe somatic diseases, dyslipidemia/hyperlipidemia, with diabetes mellitus, arterial hypertension, edema and fluid retention, smoking, in patients with CC less than 60 ml/min, with concomitant therapy with the following drugs: anticoagulants (for example, warfarin), antiplatelet agents (for example, acetylsalicylic acid, clopidogrel), corticosteroids (for example, prednisolone), selective inhibitors serotonin reuptake (for example, citalopram, fluoxetine, paroxetine, sertraline).
Efficacy and tolerability of etoricoxib (Arcoxia) in rheumatic diseases
Nonsteroidal anti-inflammatory drugs, widely used for rheumatic diseases, differ in the severity of anti-inflammatory and analgesic activity, routes of drug administration into the body, area of application, spectrum of adverse events and selectivity of action on cyclooxygenase (COX). The selective COX-2 inhibitor etoricoxib (Arcoxia), which has high anti-inflammatory and analgesic activity and 100% bioavailability when taken orally, can significantly reduce the number of unwanted side effects from the gastrointestinal tract and significantly expands the possibilities of providing effective medical care to patients with rheumatic diseases .
Table 1. COX-2/COX-1 inhibition ratio of standard NSAIDs, NSAIDs with some COX-2 selectivity, and selective COX-2 inhibitors*
Rice. 1. Effect of etoricoxib on the synthesis of the gastroprotector prostaglandin E2
Rice. 2. Etoricoxib Dose Ranging Study: Overall Patient Assessment of RA Activity
Rice. 3. Use of etoricoxib and diclofenac in OA
Rice. 4. Incidence of perforation, ulceration and upper gastrointestinal bleeding with etoricoxib and non-selective NSAIDs [9]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in rheumatology in the treatment of a wide range of inflammatory and degenerative diseases of the joints and spine, including rheumatoid arthritis, ankylosing spondylitis and other spondyloarthritis, osteoarthritis, intervertebral osteochondrosis, microcrystalline arthropathy, diffuse connective tissue diseases, extra-articular soft tissue diseases, diseases accompanied by pain in the lower back. They are an obligatory component of the treatment of most diseases that are in the field of view of a rheumatologist, acting as the main symptom-modifying drugs and the means of choice for the initial therapy of arthritis and arthrosis.
The most common indication for the use of this class of pharmacological agents is both acute and chronic pain of various origins. NSAIDs are used in the treatment of post-traumatic and postoperative pain syndromes, especially those accompanied by inflammation, neuropathies of various origins, severe migraine attacks, oligomenorrhea, renal and biliary colic, in oncology for the prevention of colorectal cancer and possible metastasis, as well as for the prevention of thrombus formation [1]. Chronic pain syndrome is the main complaint of patients visiting a neurologist and rheumatologist. From 10 to 40% of people over 55 years of age take NSAIDs, 6% of them for more than 9 months a year. Epidemiological data indicate that both acute and chronic pain syndromes in most cases are caused by damage to the joints, muscles, periarticular tissues and the spine, with one in 5 European adults suffering from acute pain syndromes, and one in 3 from chronic pain syndromes. Pain significantly worsens quality of life of patients and leads to significant material, social and moral losses. Data from an epidemiological study have established that among the adult population, among acute pain lasting up to 10 days a year, the leading ones are headaches (73%), back pain (56%), muscle and joint pain (56% and 51%, respectively), and from 10 up to 100 days a year - joint pain (10%) and back pain (9%), far ahead of other causes of pain of the same duration.
The NSAID class includes a large number of drugs that differ in the severity of anti-inflammatory and analgesic activity, route of administration of the drug into the body, area of application, spectrum of adverse events and category of cyclooxygenase (COX) inhibition - the main mechanism of action of these pharmacological agents. Based on the nature of COX blocking, NSAIDs are divided into selective COX inhibitors and selective COX-2 inhibitors [2]. It is believed that NSAIDs differ more in their tolerability than in their effectiveness.
The main mechanism of action of NSAIDs is inhibition of the synthesis of prostaglandins, including PGE2, suppression of the expression of COX-1 and COX-2, inhibition of the release of intracellular arachidonic acid, suppression of COX-2 expression in the dorsal horn of the spinal cord and the central nervous system, inhibition of leukotriene synthesis [3]. In addition, they inhibit IL-1β, IL-6, TNF-α, suppress the release of lysosomal enzymes, reduce the expression of adhesion molecules (L-selectin, VCAM-1), suppress the production of nitric oxide, demonstrate antioxidant properties, act on free radicals, inhibit the proliferation of synoviocytes. Some NSAIDs stimulate the synthesis of proteoglycans and hyaluronic acid, eliminate the inhibition of IL-1 glycosaminoglycan synthesis, and inhibit the expression of metalloproteinases (MMP-1, MMP-3), which is of particular importance in the treatment of osteoarthritis.
The diverse direction of the biological action of NSAIDs explains not only their anti-inflammatory effect, but also a wide range of possible adverse events (AEs) that develop during their use. The most common gastrointestinal disorders are observed, which can manifest as dyspepsia, the development of erosive gastritis and duodenitis, the formation of ulcers and their perforation, and gastric bleeding. The frequency of gastrointestinal AEs correlates with the age of patients, concomitant diseases, and the nature of the therapy taken. The mortality rate from NSAID-associated ulcers of the upper gastrointestinal tract in persons under 40 years of age is 0.5%, from 70 to 75 years of age - 3.5%, and after 80 years of age - 5.6%. In addition, NSAIDs have nephro- and hepatotoxicity, promote fluid retention in the body and the development of heart failure, arterial hypertension, have a dystrophogenic effect on the myocardium, and affect the metabolism of brain cells. Hematological disorders including severe cytopenias, inhibition of platelet aggregation, allergic reactions and broncho-obstructive syndrome (“aspirin” asthma) are possible, which is associated with the effect of NSAIDs on the production of leukotrienes. In this regard, it seems extremely important to search for an NSAID that, along with a pronounced anti-inflammatory and analgesic effect, would be well tolerated both with short-term and long-term use. The drug Arcoxia (etoricoxib), a specific inhibitor of COX-2, which has a much more selective effect and, therefore, has less effect on normal physiological processes, deserves attention. The use of selective COX-2 inhibitors in clinical practice can significantly reduce the number of gastrointestinal adverse events and, therefore, significantly expand the possibilities of providing effective medical care to patients with rheumatic diseases, since, according to Lanas, the risk of developing complications in the upper gastrointestinal tract while taking NSAIDs increases on average 4 times, ulcers - 5 times, and mortality is 15.3 per 100,000 treated patients [4].
Etoricoxib has high anti-inflammatory and analgesic activity. It is well absorbed from the gastrointestinal tract, while its oral bioavailability is about 100%, and the maximum plasma concentration (Cmax) is achieved 1 hour after administration. Compared to other NSAIDs, it acts faster (for diclofenac sodium, Cmax is from 2 to 6 hours, for ibuprofen and meloxicam - from 1 to 6 hours, and for naproxen and nimesulide - from 2 to 4 hours). The half-life of etoricoxib is about 22 hours, which ensures its pharmacological action for 24 hours and allows it to be used once a day [5, 6]. Due to its low gastrotoxicity and pharmacokinetics, etoricoxib, unlike many other NSAIDs, can be taken regardless of food intake.
Etoricoxib is a dipyridinyl derivative containing a (4-methylsulfonyl)phenyl group associated with the central ring and interacting with COX-2 [7], which leads to a decrease in the production of substances that mediate the development and maintenance of the activity of this isoenzyme. The secretion of compounds that support normal physiological processes generally remains at a sufficient level. In human whole blood studies, etoricoxib has been shown to be approximately 106 times more potent on COX-2 than on COX-1 and has greater COX-2 selectivity than other NSAIDs (Table 1).
Etoricoxib does not affect the synthesis of the gastroprotector prostaglandin E2 (PGE2) and is no different from placebo in this respect, which explains its low gastrotoxicity. A randomized, placebo-controlled, multiple-dose dual-therapy study with placebo examined the effects of etoricoxib 120 mg/day and naproxen 1000 mg/day on ex vivo synthesis of the gastroprotective agent PGE2 in gastric biopsies. Naproxen reduced gastric PGE2 synthesis by approximately 78% (p
The clinical effectiveness of etoricoxib was traced using the example of the main nosological forms that are in the field of view of a rheumatologist. A pronounced anti-inflammatory effect of this NSAID was noted in patients with rheumatoid arthritis (RA). Etoricoxib was compared with naproxen in two large randomized, placebo-controlled clinical trials involving 1,700 patients. Patients were assigned to etoricoxib 60 and 90 mg/day, naproxen 1000 mg/day, or placebo. The duration of therapy was 12 weeks. Differences in the effectiveness of treatment were determined by changing the degree of pain sensitivity in the joints, the severity of exudative phenomena and the overall assessment of effectiveness by patients and the researcher [10]. The results of these studies showed that in the etoricoxib group the effectiveness of therapy was 52.6% and was almost 1.5 times higher than in the naproxen group and 2.5 times higher than in patients taking placebo. Moreover, it has been proven that when taking a high dose of etoricoxib, there is a significant decrease in the number of swollen joints, that is, an indicator that largely reflects the anti-inflammatory effect of the drug used [11].
In a long-term study to determine the optimal dose range of etoricoxib in patients with RA, a daily dose of 90 mg was found to provide significantly higher treatment efficacy compared with 60 mg. As for diclofenac 150 mg/day, it was more effective than 60 mg etoricoxib, but inferior in its effect to etoricoxib 90 mg/day (Fig. 2) [10]. The resulting positive effect of etoricoxib, which developed in the first 12 weeks. therapy, persisted throughout the 52-week observation period. In this study, a dose of etoricoxib 90 mg once daily was determined as the recommended dose for the treatment of RA.
Etoricoxib showed an even more significant therapeutic effect in ankylosing spondylitis (AS). It is known that NSAIDs are first-line drugs and an obligate component of combination therapy for AS. They quickly reduce the intensity of pain, as well as the duration and severity of morning rigidity, and the positive effect in the first 48 hours of their use is considered one of the diagnostic criteria for this disease. It was previously believed that if a patient does not respond to NSAID therapy, then the probability of being diagnosed with AS is only 3%. According to A. Wanders et al., NSAIDs, when used regularly, help reduce the rate of radiological progression of AS by 4 times compared to placebo [12]. These data are of great importance, since there are currently no basic anti-inflammatory drugs aimed at reducing the progression of AS, except for sulfasalazine, which acts only on manifestations of peripheral arthritis, but not spondylitis. Etoricoxib in this disease promotes a good clinical response in 70% of patients [13]. The effectiveness of etoricoxib 90 and 120 mg/day in reducing the intensity of back pain was the same and was significantly higher than taking 1000 mg of naproxen both in the first 6 weeks and in the next 52 weeks. therapy.
The effectiveness of etoricoxib in osteoarthritis (OA) has been studied in numerous controlled studies involving more than 4400 patients with gonarthrosis, coxarthrosis and OA of the hand joints [14]. In particular, etoricoxib 30 mg/day was no less effective than ibuprofen 2400 mg/day in reducing pain on the WOMAC scale. Etoricoxib 60 mg once daily and diclofenac 50 mg three times daily provided effective and sustained reduction in WOMAC OA pain scores over 6 weeks. study, and its decrease was observed with the use of both drugs already in the 2nd week. and persisted throughout the entire treatment period (Fig. 3). The maximum effect was observed at the 6th week. By the end of the study, the VAS value decreased compared to the baseline by 31.3 mm in the etoricoxib group and by 30.9 mm in the diclofenac group [15]. In the treatment of osteoarthritis, an important circumstance is the fact that in elderly patients (65 years and older), the pharmacokinetics of etoricoxib are similar to those in young people.
Etoricoxib is used to relieve acute and chronic pain. Its rapid (after 20 minutes) onset of action and maximum concentration in inflamed tissue allow this drug to be used to provide immediate assistance with the highest frequency of analgesic effect on the first try. The advantages of etoricoxib as a drug for the treatment of chronic pain include the absence of addiction during long-term use, maintaining effectiveness throughout the entire treatment period, a safe profile and the ability to calibrate an individual dose.
This selective NSAID has shown high effectiveness in acute attacks of gout, which, as a rule, are characterized by pronounced pain and a significant inflammatory reaction. In a study of 150 patients with impaired purine metabolism and an acute attack of gouty arthritis, the patients were divided into two groups. The main group was treated with etoricoxib 120 mg/day, patients in the control group received indomethacin 150 mg/day. The effectiveness of the two drugs in terms of relieving acute pain was the same [16]. However, indomethacin is known to have a particularly wide range of AEs, which is why it is currently used extremely rarely in clinical practice.
The analgesic effect of etoricoxib is also used in dentistry. After tooth extraction, a significant decrease in pain intensity 8 hours after taking etoricoxib was observed in 20.9% of patients, while after taking other drugs that are widely used in the treatment of pain of various origins, this percentage was lower: for naproxen it was 21.3% , for codeine with paracetamol - only in 11.5% (total number of patients 201) [17].
Etoricoxib is characterized by high safety. It has both common tolerability features with other coxibs, which primarily relates to gastrointestinal toxicity, and distinctive features. The latter concerns primarily its cardiovascular safety.
Etoricoxib statistically significantly reduced the rate of treatment discontinuation due to gastrointestinal AEs. The incidence of serious complications (perforations, ulcers and bleeding) was analyzed in patients receiving etoricoxib at doses of 60, 90 or 120 mg / day (total number of patients 3142) or non-selective NSAIDs, in particular, naproxen 1000 mg / day, diclofenac 150 mg /day or ibuprofen 2400 mg/day (total number of patients 1828), as part of a pooled analysis of 10 clinical trials in patients with OA, RA and chronic low back pain. Serious AEs that occurred during therapy or within 14 days after the end of treatment were included in the analysis. The incidence of confirmed events was 1.16/100 patient-years in patients receiving etoricoxib and 3.05/100 patient-years in patients receiving non-selective NSAIDs (Fig. 4) [9]. Etoricoxib at a dose ≥ 60 mg reduced the risk of gastrointestinal perforations, ulcers, and bleeding by approximately 55% compared with non-selective NSAIDs (p
Etoricoxib therapy was associated with statistically significant lower occult blood loss compared with ibuprofen, lower incidence of GI ulcers and erosions compared with naproxen and ibuprofen, and a lower relative incidence of concomitant medications with GI effects and discontinuation of therapy due to gastrointestinal symptoms and adverse events.
Like other specific COX-2 inhibitors, etoricoxib does not affect platelet function. A meta-analysis of randomized controlled trials involving 4585 patients compared etoricoxib with placebo. The risk of thrombotic cardiovascular complications in the two study groups was almost equal and amounted to 1.11% in the etoricoxib group and 1.0% in the placebo group [18]. However, these data suggest that etoricoxib should be avoided in patients with unstable angina or focal myocardial dystrophy. It should also be used with caution in patients with arterial hypertension. Thus, in 10 placebo-controlled studies lasting from 6 to 12 weeks. from the clinical development program, one or more AEs related to arterial hypertension were identified in 3.9, 4.2 and 4.7% of patients receiving etoricoxib in doses of 60, 90 and 120 mg 1 time / day, respectively. The incidence of such events was 2.6% in the placebo group, 3.5% in the naproxen 1000 mg/day group, and 7.1% in the ibuprofen 2400 mg/day group [7, 8]. Like other drugs that inhibit prostaglandin synthesis, etoricoxib can lead to fluid retention, edema, and, consequently, hypertension in some patients.
The interaction between etoricoxib and acetylsalicylic acid (ASA) was studied by ex vivo platelet aggregation and TXB2 formation in serum under the influence of 1.6 mM arachidonic acid and 1 μg/ml collagen. In a double-blind, randomized, placebo-controlled, parallel-group study, healthy volunteers received placebo (n = 14) or etoricoxib 120 mg/day (n = 13) for 12 days. From days 1 to 5, etoricoxib or placebo was administered without ASA. From days 6 to 12, all participants took low dose ASA (81 mg once daily). Serum samples taken on day 6 of the study showed no effect of etoricoxib on platelet aggregation. On day 12, there was also no effect of etoricoxib on the ability of ASA 81 mg/day to inhibit platelet aggregation.
The high safety of etoricoxib was monitored in the MEDAL program, based on a study of 34,000 patients with RA and OA. This program was the first clinical program designed to compare the safety with respect to thrombotic cardiovascular events of a selective COX-2 inhibitor (etoricoxib) and a traditional NSAID (diclofenac). Patients had a wide range of cardiovascular risk and received NSAIDs for 3.5 years (mean 18 months). Treatment with etoricoxib and diclofenac showed comparable rates of thrombotic events. In the per-protocol population analysis, the rate of IRB-reviewed and confirmed thrombotic cardiovascular events (primary endpoint) for etoricoxib was the same as for diclofenac [19, 20]. The hazard ratio for etoricoxib compared with diclofenac was 0.95 (95% CI 0.81–1.11). The upper limit of 1.11 was lower than the predetermined limit of 1.3.
The same study assessed gastrointestinal toxicity. The rate of confirmed upper gastrointestinal clinical events was significantly lower in the etoricoxib group (0.67 events per 100 patient-years) than in the diclofenac group (0.97 events per 100 patient-years), with a hazard ratio of 0.69 (95% CI 0.57–0.83) (p = 0.0001). Etoricoxib at doses of 60 and 90 mg showed better gastrointestinal tolerability and safety, determined by the frequency of serious AEs (perforations, ulcers and bleeding), compared with diclofenac at a dose of 150 mg. However, discontinuation rates due to gastrointestinal and hepatic events were significantly lower with etoricoxib 60 and 90 mg than with diclofenac 150 mg.
Thus, etoricoxib (Arcoxia) is a selective COX-2 inhibitor. It is recommended for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and other spondyloarthritis/spondyloarthropathy, low back pain, acute attack of gout and other diseases accompanied by pain and/or inflammation. The daily dose of the drug for osteoarthritis is 60 mg, for rheumatoid arthritis and ankylosing spondylitis - 90 mg, and for acute gouty arthritis - 120 mg. Doses higher than recommended should not be used, as they usually do not lead to an increase in the effectiveness of the drug.
Contraindications to taking etoricoxib are hypersensitivity to the drug, active peptic ulcer or gastrointestinal bleeding, liver failure (more than 9 points on the Child-Pugh scale), renal failure with creatinine clearance less than 30 ml/min, inflammatory bowel disease, severe congestive heart failure. It should not be prescribed to patients with broncho-obstructive syndrome, acute rhinitis, nasal polyposis, angioedema or urticarial rash that developed after taking acetylsalicylic acid or other NSAIDs. The use of this drug should be avoided during pregnancy and lactation, as well as in children and adolescents under 16 years of age.
These data allow us to highly evaluate etoricoxib (the drug Arcoxia) in rheumatic diseases, which is based on the results of numerous carefully controlled clinical studies conducted in a large number of patients. The drug has been proven to be highly effective and well-tolerated for major inflammatory and degenerative diseases of the joints and spine. The positive features of this selective COX-2 inhibitor are its ease of use (once a day) and the possibility of combining it with low doses of aspirin, which increases compliance with therapy. Its analgesic and anti-inflammatory effects are comparable to those of naproxen or ibuprofen, as well as high doses of diclofenac, the “gold standard” NSAID drug. Available data convincingly demonstrate that etoricoxib is an alternative in the treatment of many inflammatory and degenerative rheumatic diseases and significantly expands the physician's ability to individually select NSAIDs. This drug is indicated for patients at risk of gastrointestinal and cardiovascular adverse events.