Arcoxia® [Etoricoxib]

Pharmacological properties

mechanism of action. etoricoxib is an oral selective cog-2 inhibitor within the clinical dose range. in clinical pharmacological studies, the drug aroxia dose-dependently inhibited cog-2 without inhibition of cog-1 when used in doses up to 150 mg / day. etoricoxib does not inhibit the synthesis of prostaglandins of the stomach and does not affect platelet function. The enzyme cog is responsible for the formation of prostaglandins. two isoforms were identified - cog-1 and cog-2. cog-2 is an enzyme isoform that is induced by various pro-inflammatory mediators and is considered as the main factor responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. TSOG-2 is also involved in the processes of ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and central nervous system (induction of fever, sensation of pain, cognitive function); may also be involved in the healing process of ulcers. cog-2 has been identified in the tissue around a human stomach ulcer, but no significance has been established for ulcer healing.

Efficiency. In patients with osteoarthritis, etoricoxib at a dose of 60 mg once a day significantly improves the condition for pain and the patients assessment of the condition of the disease. In studies using etoricoxib at a dose of 30 mg once a day, the effectiveness of this drug exceeded that of placebo for 12 weeks of treatment (estimates used in other studies were used). During the dose selection study, etoricoxib at a dose of 60 mg showed a significantly more pronounced improvement than at a dose of 30 mg, relative to all 3 major endpoints after 6 weeks of treatment. The use of a dose of 30 mg for osteoarthritis of the hand has not been studied.

In patients with rheumatoid arthritis, etoricoxib at a dose of 60 and 90 mg 1 time per day significantly improved the condition with respect to the severity of pain, inflammation, as well as mobility. In studies evaluating the doses of 60 and 90 mg, the beneficial effects persisted over the 12-week treatment period. In a comparative study of etoricoxib at a dose of 60 mg 1 time per day and 90 mg 1 time per day, both dosing regimens were more effective than placebo. A dose of 90 mg once a day was effective in accordance with the method of the Universal Patient Pain Assessment (0–100 mm on a visual analogue scale), with an average improvement of –2.71 mm (95% CI: –4.98 mm, –0, 45 mm).

In patients with attacks of acute gouty arthritis, etoricoxib at a dose of 120 mg once a day for 8 days reduced the severity of pain in the joints of moderate and severe degree and inflammation compared with indomethacin at a dose of 50 mg 3 times a day. A decrease in the severity of pain is noted 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once a day provides a significant improvement in pain in the spine, inflammation, restriction of movement, and also increases functional ability. The clinical benefits of etoricoxib were observed on the 2nd day after initiation of therapy and persisted for a 52-week treatment period. In a second study evaluating a dose of 60 mg compared to 90 mg, etoricoxib at a dose of 60 mg daily and 90 mg daily showed similar efficacy compared to naproxen 1000 mg daily. In patients who did not demonstrate an adequate response when applying a dose of 60 mg daily for 6 weeks, increasing the dose to 90 mg daily improved the assessment of back pain intensity (0-100 mm, visual analogue scale) compared with continued administration of 60 mg daily, with an average improvement of –2.70 mm (95% CI: –4.88 mm, –0.52 mm)

During the study of postoperative toothache, etoricoxib, which was used at a dose of 90 mg once a day for up to 3 days, had a more pronounced analgesic effect than placebo.In a subgroup of patients with moderate initial pain, etoricoxib at a dose of 90 mg showed an analgesic effect similar to ibuprofen 600 mg (16.11 versus 16.39; p = 0.722) and exceeded the effect of paracetamol / codeine 600 mg / 60 mg (11, 00; p0.001) and placebo (6.84; p0.001), which was determined by the indicator of complete relief of pain after 6 hours. The number of patients who reported the use of emergency pain medication within 24 hours was 40.8% for etoricoxiba 90 mg, 25.5% for ibuprofen 600 mg every 6 hours and 46.7% for paracetamol / codeine 600 mg / 60 mg every 6 hours compared with 76.2% for placebo. In this study, the onset of an analgesic effect (a noticeable decrease in the severity of pain) of 90 mg of etoricoxib was noted 28 minutes after taking the drug.

Safety

International Research Program for the Prolonged Use of Etoricoxib and Diclofenac for Arthritis (MEDAL). The MEDAL program was a prospectively designed program for cardiovascular safety results obtained from the pooled data of three randomized, double-blind, active drug-controlled study comparisons (MEDAL, EDGE II, and EDGE studies).

In the MEDAL study to determine the endpoint of the effect on the cardiovascular system, in which 17 804 patients with osteoarthritis and 5700 with rheumatoid arthritis participated, etoricoxib was used at a dose of 60 mg (group of patients with osteoarthritis) or 90 mg (groups with osteoarthritis and rheumatoid arthritis), or diclofenac at a dose of 150 mg / day for an average of 20.3 months (maximum 42.3 months, median 21.3 months). In this study, only serious adverse reactions and cases of drug discontinuation due to the occurrence of any adverse reactions were recorded.

In studies of EDGE and EDGE II, the gastrointestinal tolerance of etoricoxib and diclofenac was compared. The EDGE study involved 7111 patients with osteoarthritis who received etoricoxib at a dose of 90 mg / day (1.5 times the recommended dose for the treatment of osteoarthritis), or diclofenac at a dose of 150 mg / day for an average of 9.1 months (maximum - 16.6 months, median - 11.4 months). The EDGE II study involved 4,086 patients with rheumatoid arthritis who received treatment with etoricoxib at a dose of 90 mg / day or diclofenac at a dose of 150 mg / day for an average of 19.2 months (maximum 33.1 months, median 24 months).

The combined MEDAL program involved 34,701 patients with osteoarthritis and rheumatoid arthritis who received treatment for an average of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients received treatment for more than 24 months. Patients enrolled in this program had different initial risk factors for the cardiovascular system and gastrointestinal tract. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary angioplasty for 6 months prior to registration in the study were excluded from the study. The studies allowed the use of gastroprotective drugs and acetylsalicylic acid in low doses.

General security. There were no significant differences in the incidence of thrombotic cardiovascular complications with the use of etoricoxib and diclofenac. Cardiorenal adverse reactions more often occurred with the use of etoricoxib than diclofenac; this effect was dose dependent (see detailed results below). Side effects from the gastrointestinal tract and liver developed much more often with diclofenac than etoricoxib. The incidence of adverse reactions in the EDGE and EDGE II studies, as well as adverse events that were considered serious or those that lead to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular safety. The frequency of confirmed thrombotic cardiovascular serious adverse reactions (including cardiac, cerebrovascular, and peripheral vascular reactions) was comparable in etoricoxib and diclofenac (data are summarized in Table 1). There were no significant differences in the rates of thrombotic complications for etoricoxib and diclofenac in all the analyzed subgroups, including patients with cardiovascular risk.On separate examination, the relative risk of confirmed serious thrombotic adverse reactions from the cardiovascular system was the same when using etoricoxib at a dose of 60 or 90 mg and diclofenac at a dose of 150 mg.

^†Complications per 100 patient-years; CI - confidence interval.

N is the total number of patients in the population according to the protocol.

According to the protocol: all complications during the study therapy or within 14 days after its termination (including in patients who took 75% of the study drug or took unexplored NSAIDs for 10% of the entire period).

If desired, to be treated: all confirmed complications before the end of the study (including in patients who may have undergone an intervention that is not related to the study, with subsequent discontinuation of the study drug). The total number of randomized patients: 17 412 - in the group of etoricoxib and 17 289 - in the group of diclofenac.

The cardiovascular mortality rate, as well as the overall mortality rate, was similar in the etoricoxib and diclofenac treatment groups.

Cardiorenal complications. About 50% of patients involved in the MEDAL study had a history of hypertension. In this study, treatment discontinuation due to adverse reactions associated with hypertension was statistically higher for etoricoxib than for diclofenac. The frequency of such an adverse reaction as congestive heart failure (discontinuation of the drug and serious reactions) was similar when taking etoricoxib 60 mg and when taking diclofenac 150 mg, but the incidence of these reactions was higher when taking etoricoxib 90 mg compared with diclofenac 150 mg (statistically significant difference for etoricoxib 90 mg compared to 150 mg diclofenac in the cohort of osteoarthritis of the MEDAL study). The frequency of confirmed adverse reactions associated with congestive heart failure (phenomena that were serious and led to hospitalization or to the emergency department) was slightly higher with etoricoxib compared with diclofenac 150 mg, and this effect was dose-dependent. The discontinuation rate due to adverse reactions associated with edema was significantly higher with etoricoxib compared with diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference for etoricoxib 90 mg, but not for etoricoxib 60 mg).

In terms of cardiorenal complications, the results obtained in the EDGE and EDGE II studies were consistent with the data reported in the MEDAL study.

In individual MEDAL studies, the absolute discontinuation rate in any group for etoricoxib (60 mg or 90 mg) was up to 2.6% for hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, at the same time, a higher frequency of drug withdrawal was noted for etoricoxib 90 mg than for etoricoxib 60 mg.

Results of gastrointestinal tolerance in the MEDAL program. A significantly lower rate of drug withdrawal due to any clinical complication of the gastrointestinal tract (for example, dyspepsia, abdominal pain, ulcers) was recorded with etoricoxib than diclofenac in each of the three MEDAL studies. The drug withdrawal rates due to clinical reactions from the gastrointestinal tract per 100 patient-years for the entire study period were as follows: 3.23 - for etoricoxib and nb