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pharmachologic effect

Etoricoxib, when administered orally at therapeutic concentrations, is a selective inhibitor of cyclooxygenase-2 (COX-2). In clinical pharmacological studies, etoricoxib inhibited dose-dependent COX-2 without affecting COX-1 with a daily dose of up to 150 mg. The drug does not inhibit the synthesis of prostaglandins in the gastric mucosa and does not affect the function of platelets.

Cyclo-oxygenase is responsible for the formation of prostaglandins. Two cyclo-oxygenase isoforms, COX-1 and COX-2, were isolated. COX-2 is an isoenzyme that is induced by various pro-inflammatory mediators and is regarded as the main enzyme responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is involved in the processes of ovulation, implantation and closure of the arterial duct, regulation of kidney function and the central nervous system (induction of fever, pain, cognitive function), and may also play a role in the healing process of ulcers. COX-2 was found in the tissues surrounding stomach ulcers in humans, but its significance for ulcer healing has not been established.

Efficiency

In patients with osteoarthrosis (OA) etoricoxib when used at a dose of 60 mg 1 time / day provided a significant reduction in pain and an improvement in the assessment of their condition by patients. These beneficial effects were observed on the second day of treatment and persisted for 52 weeks. Studies of etoricoxib when administered at a dose of 30 mg 1 time / day (using similar methods of evaluation) demonstrated efficacy compared with placebo for a 12-week treatment period. In a study conducted to determine the optimal dose, etoricoxib, when administered at a dose of 60 mg, showed a significantly more pronounced improvement than at a dose of 30 mg for all three primary endpoints after 6 weeks of treatment. A dose of 30 mg has not been studied with osteoarthritis of the joints of the hands.

In patients with rheumatoid arthritis (RA), etoricoxib when administered at a dose of 90 mg 1 time / day provided a significant reduction in pain and inflammation and an improvement in mobility. These beneficial effects persisted over a 12-week treatment period.

In patients with acute gouty arthritis, etoricoxib when administered at a dose of 120 mg 1 time / day during the entire treatment period of 8 days reduced moderate and severe joint pain and inflammation. Efficacy was comparable to that of Indomethacin when it was applied in a dose of 50 mg 3 times / day. A decrease in pain was noted already 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib when used at a dose of 90 mg 1 time / day provided a significant reduction in back pain, inflammation, stiffness, as well as improved functions. The clinical efficacy of etoricoxib was observed on the second day of treatment and was maintained for the entire period of treatment with a duration of 52 weeks.

In a clinical study of pain after dental surgery, etoricoxib at a dose of 90 mg was administered 1 time / day for 3 days. In the subgroup of patients with moderate pain (at baseline), etoricoxib, when administered at a dose of 90 mg, had the same analgesic effect as Ibuprofen at a dose of 600 mg (16.11 versus 16.39; P = 0.722), and Paracetamol / codeine at a dose of 600 mg / 60 mg (11, P <0.001) and placebo (6.84, P <0.001) according to a general estimate of pain reduction during the first 6 hours (TOPAR6). The proportion of patients who required quick-acting painkillers during the first 24 hours after taking the study drugs was 40.8% with etoricoxib at a dose of 90 mg, 25.5% with ibuprofen at a dose of 600 mg every 6 hours and 46.7% with a combination of paracetamol / codeine 600 mg / 60 mg every 6 hours compared with 76.2% in the placebo group. In this study, the median onset of action (a perceptible reduction in pain) with the use of etoricoxib at a dose of 90 mg was 28 minutes after taking the drug.

Security

MEDAL Program (Multinational Program for the Evaluation of Etoricoxib and Diclofenac for Arthritis)

The MEDAL program was a prospective safety assessment program based on cardiovascular (CC) events from the combined data from three randomized, double-blind, actively-controlled studies: MEDAL, EDGE II and EDGE.

The MEDAL study was a study whose duration was determined by reaching the end points (SS of events), which included 17804 patients with OA and 5700 patients with RA who received Etoricoxib at a dose of 60 mg (OA) or 90 mg (OA and RA) or diclofenac at a dose of 150 mg / day on average for 20.3 months (maximum 42.3 months, median 21.3 months).In this study, only serious adverse events and dropouts from the study due to any adverse events were recorded.

In the EDGE and EDGE II studies, the gastrointestinal tolerability of Etoricoxib and Diclofenac was compared. The EDGE study included 7111 patients with OA who received Etoricoxib at a dose of 90 mg / day (1.5 times the dose recommended for OA) or diclofenac at a dose of 150 mg / day on average for 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4086 RA patients who received Etoricoxib 90 mg / day or Diclofenac 150 mg / day on average for 19.2 months (maximum 33.1 months, median 24 months).

In the joint MEDAL program, 34 701 patients with OA or RA received treatment on average for 17.9 months (maximum 42.3 months, median 16.3 months), about 12,800 patients received treatment for more than 24 months. At the initial assessment, a wide range of SS and gastrointestinal risk factors were recorded for the patients included in the MEDAL program. Patients with recent myocardial infarction, as well as coronary artery bypass surgery or percutaneous coronary intervention for 6 months before being included in the study, were excluded. Gastroprotectors and low doses of Aspirin were allowed in the studies.

General safety

Significant differences between etoricoxib and diclofenac regarding the frequency of thrombotic SS events were not found. Cardiorenal adverse events were more frequently observed with the administration of Etoricoxib than with the administration of diclofenac; this effect was dose-dependent (some results are presented below). Adverse events from the gastrointestinal tract and liver were significantly more frequently observed with diclofenac than with etoricoxib. The incidence of adverse events in the EDGE and EDGE II studies, as well as adverse events considered serious or requiring discontinuation of treatment, was higher in the MEDAL study with etoricoxib than with diclofenac.

Cardiovascular safety assessment results

The frequency of confirmed serious thrombotic SS adverse events (including cardiac, cerebrovascular and peripheral vascular events) was comparable between the groups treated with etoricoxib or diclofenac (data are shown in the table below). In terms of the incidence of thrombotic events, there were no statistically significant differences between etoricoxib and diclofenac in all analyzed subgroups, including categories of patients in the range of baseline risk CS.The relative risk for confirmed serious thrombotic SS adverse events was similar for etoricoxib (when taken in a dose of 60 mg or 90 mg) and diclofenac (when taken in a dose of 150 mg).

¹ The number of occurrences per 100 patient-years; CI = confidence interval; N = total number of patients included in the population of patients who fulfilled the protocol requirements.

If the protocol requirements are met, all phenomena that developed on the background of the studied therapy or within 14 days from the moment of its termination (excluded patients who received <75% of the studied drug, and patients who did not take NSAIDs> 10% of the time).

Depending on the prescribed treatment, all confirmed phenomena that developed before the end of the study (included patients who may have undergone non-included interventions after discontinuing the study drug). The total number of randomized patients is n = 17 412 for etoricoxib and n = 17 289 for diclofenac.

SS mortality and total mortality were comparable between the treatment groups of Etoricoxib and Diclofenac.

Cardiorenal phenomena

In approximately 50% of the patients included in the MEDAL study, at baseline, a history of arterial hypertension was recorded. The frequency of elimination due to adverse events associated with arterial hypertension was significantly higher for etoricoxib than for diclofenac. The incidence of adverse events associated with chronic heart failure (dropout cases and serious events) was similar for etoricoxib at a dose of 60 mg and diclofenac at a dose of 150 mg, but was higher for etoricoxib at a dose of 90 mg compared to diclofenac at a dose of 150 mg (and statistically significantly higher for etoricoxib at a dose of 90 mg compared with diclofenac at a dose of 150 mg in the OA group of the MEDAL study).The incidence of confirmed adverse events associated with chronic heart failure (events that were serious and led to hospitalization or a visit to the emergency room) was slightly higher for atoricoxib compared to diclofenac at a dose of 150 mg; this effect was dose-dependent. The incidence of dropouts due to adverse events associated with edema was higher for etoricoxib compared to diclofenac at a dose of 150 mg; this effect was dose-dependent (statistically significant for etoricoxib at a dose of 90 mg, but not for etoricoxib at a dose of 60 mg).

The results of the cardiorenal safety assessment in the EDGE and EDGE II studies are consistent with the results of the MEDAL study.

In individual studies of the MEDAL program, the absolute frequency of withdrawal from a study in any treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% due to arterial hypertension, up to 1.9% due to edema, and up to 1.1% due to chronic heart failure. In patients who took Etoricoxib at a dose of 90 mg, the frequency of withdrawal from the study was higher than in patients who took Etoricoxib at a dose of 60 mg.

Gastrointestinal Tolerance Evaluation Results in the MEDAL Program

In each of the three studies included in the MEDAL program, the frequency of elimination from the study for any clinical adverse event from the gastrointestinal tract (eg, dyspepsia , abdominal pain, ulcers) was significantly lower for etoricoxib compared with diclofenac. The frequency of elimination from the study due to adverse clinical events in the gastrointestinal tract per 100 patient-years over the entire study period was as follows: 3.23 for etoricoxib and 4.96 for diclofenac in the MEDAL study; 9.12 for etoricoxib and 12.28 for diclofenac in the EDGE study; and 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Outcomes of the GAL safety evaluation in the MEDAL program

In general, adverse events from the upper GI tract were defined as perforations, ulcers and bleeding. Complicated adverse events in the upper GI tract included perforation, obstruction, and complicated bleeding; uncomplicated adverse events from the upper GI tract included uncomplicated bleeding and uncomplicated ulcers.The overall incidence of adverse events in the upper GI tract was significantly lower for etoricoxib compared with diclofenac. Significant differences between etoricoxib and diclofenac in the incidence of complicated events were not found. For hemorrhagic adverse events from the upper gastrointestinal tract (complicated and uncomplicated in the aggregate), no significant differences were found between etoricoxib and diclofenac. The advantage of etoricoxib in relation to the upper gastrointestinal tract compared with diclofenac in patients simultaneously taking aspirin in low doses (about 33% of patients) was not statistically significant.

The frequency of confirmed complicated and uncomplicated clinical adverse events from the upper GI tract per 100 patient-years (perforation, ulcer and bleeding) was 0.67 (95% CI 0.57, 0.77) for etoricoxib and 0.97 (95% CI 0.85, 1.10) for diclofenac, on the basis of which the relative risk was 0.69 (95% CI 0.57, 0.83).

The frequency of confirmed adverse events from the upper GI tract in elderly patients was studied; The maximum decrease in frequency was observed in patients aged ≥75 years - 1.35 (95% CI 0.94, 1.87) compared with 2.78 (95% CI 2.14, 3.56) events per 100 patient-years for Etoricoxib and Diclofenac, respectively. The frequency of confirmed adverse events on the part of the lower GI tract (perforation of the small or large intestine, obstruction or bleeding) did not significantly differ between the groups treated with etoricoxib and diclofenac.

Results of a liver safety assessment in the MEDAL Program

Etoricoxib was characterized by a statistically significantly lower drop-out rate due to adverse events in the liver compared with diclofenac. In the combined MEDAL program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac dropped out of the study due to adverse events in the liver. The incidence of adverse events per 100 patient-years was 0.22 for etoricoxib and 1.84 for diclofenac (p <0.001 for etoricoxib versus diclofenac). Most liver adverse events in the MEDAL program were frivolous.

Additional safety data related to thrombotic SS events

In clinical studies, with the exception of the MEDAL program, approximately 3,100 patients received etoricoxib at a dose of ≥60 mg / day for 12 weeks or longer. There were no noticeable differences in the frequency of confirmed serious thrombotic SS events in patients who received etoricoxib at a dose of ≥60 mg, placebo or NSAIDs that do not contain Naproxen. However, in comparison with patients receiving naproxen at a dose of 500 mg 2 times / day, the frequency of these events was higher in patients treated with etoricoxib. The difference in antiplatelet activity between some NSAIDs inhibiting COX-1 and selective COX-2 inhibitors may be of clinical importance in patients at risk of developing thromboembolic events. Selective COX-2 inhibitors inhibit the formation of systemic (and, possibly, endothelial) prostacyclin, without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional safety data on the gastrointestinal tract

In two double-blind endoscopic studies with a duration of 12 weeks, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients who received etoricoxib 120 mg 1 time / day than patients who received naproxen 500 mg 2 times / day or ibuprofen 800 mg 3 times / day. The incidence of ulcers in the administration of etoricoxib was higher compared with placebo.

Study of kidney function in elderly patients

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