Etoriax, 60 mg 14 pcs

Pharmacotherapeutic group:

Non-steroidal anti-inflammatory drugs

ATX code:

M01AN05

Pharmacological properties

Pharmacodynamics

Tericoxib is a selective cyclooxygenase-2 (COX-2) inhibitor when taken orally in therapeutic concentrations. In clinical pharmacological studies, etoricoxib inhibited COX-2 in a dose-dependent manner, with no effect on COX-1 at a daily dose up to 150 mg. The drug does not inhibit the synthesis of prostaglandins in the gastric mucosa and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase, COX-1 and COX-2, have been isolated. COX-2 is an isoenzyme that is induced by various proinflammatory mediators and is considered 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 renal and central nervous system function (induction of fever, sensation of pain, cognitive function), and may also play a role in the process of ulcer healing. COX-2 has been found in tissues surrounding gastric ulcers in humans, but its importance in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis (OA), etoricoxib, when administered at a dose of 60 mg once daily, provided a significant reduction in pain and improvement in patients’ assessment of their condition. These favorable effects were observed on the second day of treatment and persisted for 52 weeks. Studies of etoricoxib at a dose of 30 mg once a day (using similar evaluation methods) demonstrated efficacy compared to placebo during the treatment period of 12 weeks. In a study conducted to determine the optimal dose, etoricoxib, when used at a dose of 60 mg, demonstrated significantly greater improvement than the 30 mg dose for all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in hand osteoarthritis.

In patients with rheumatoid arthritis (RA), etoricoxib at a dose of 90 mg once daily provided a significant reduction in pain and inflammation and improved mobility. These favorable effects persisted over a treatment period of 12 weeks.

In patients with acute gouty arthritis, etoricoxib, administered at a dose of 120 mg once daily for an eight-day treatment period, reduced moderate to severe joint pain and inflammation. The efficacy was comparable to that of indomethacin when used in a dose of 50 mg 3 times a day. Pain reduction was noted as early as 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided a significant reduction in back pain, inflammation, stiffness, and improved function. The clinical efficacy of etoricoxib was observed as early as the second day of treatment and was maintained throughout the entire treatment period of 52 weeks.

In a clinical study of pain after dental surgery, etoricoxib at a dose of 90 mg was administered once daily for three days. In a subgroup of patients with moderate pain (at baseline assessment), etoricoxib had the same analgesic effect as ibuprofen at a dose of 600 mg when administered in a 90-mg dose (16.11 vs. 16.39 P=0.722), and was superior to the paracetamol/codeine combination at a dose of 600 mg/60 mg (11.00; P <0.001) and placebo (6.84; P <0.001) according to the overall first 6-hour pain reduction assessment (TOPAR6). The proportion of patients who required rapid-acting pain medication within the first 24 hours of taking the study drugs was 40.8% with etoricoxib at 90 mg, 25.5% with ibuprofen at 600 mg every 6 hours, and 46.7% with the paracetamol/codein combination at 600 mg/60 mg every 6 hours, compared with 76.2% in the placebo group. In this study, the median onset of action (perceived pain reduction) with etoricoxib at a dose of 90 mg was 28 minutes after administration.

Safety

The MEDAL (Multinational Evaluation of Long-Term Prescribing of Etoricoxib and Diclofenac in Arthritis) Program

The MEDAL Program. The MEDAL program was a prospective safety assessment program based on cardiovascular (CV) events from pooled data from three randomized, double-blind, active-controlled trials: MEDAL, EDGE II and EDGE.

The MEDAL study was a trial, the duration of which was determined by the achievement of endpoints (CC events), that included 17,804 patients with OA and 5,700 patients with RA receiving etoricoxib at a dose of 60 mg (OA) or 90 mg (OA and RA) or diclofenac at a dose of 150 mg daily for an average of 20.3 months (maximum 42.5 months, median 21.3 months). Only serious adverse events and dropouts due to any adverse events were reported in this study.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7111 patients with OA who received etoricoxib at a dose of 90 mg per day (1.5 times the recommended dose for OA) or diclofenac at a dose of 150 mg per day for an average of 9.1 months (maximum 16.5 months, median 11.4 months). The EDGE II study included 4,086 patients with RA who received etoricoxib at a dose of 90 mg daily or diclofenac at a dose of 150 mg daily for an average of 19.2 months (maximum 33.1 months, median 24 months).

In the combined MEDAL Program, 34,701 patients with OA or RA were treated for an average of 17.9 months (maximum 42.3 months, median 16.3 months); about 1,800 patients were treated for more than 24 months. Patients included in the MEDAL Program had a wide range of CV and gastrointestinal risk factors at baseline assessment. Patients with recent myocardial infarction and with aortocoronary bypass or percutaneous coronary intervention within 6 months before study inclusion were excluded. Gastroprotectants and low-dose aspirin were allowed in the studies.

The cardiovascular safety results

The incidence of confirmed serious thrombotic SS adverse events (which included cardiac, cerebrovascular, and peripheral vascular events) was comparable between the groups receiving etoricoxib or diclofenac (data are shown in the table below). There were no statistically significant differences in the incidence of thrombotic events between etoricoxib and diclofenac in all subgroups analyzed, including patient categories in the baseline CC risk range. The relative risk for confirmed serious thrombotic CC adverse events was similar for etoricoxib (when administered at 60 mg or 90 mg) and diclofenac (when administered at 150 mg).

Table “Frequency of Confirmed Thrombotic CC Events (MEDAL Program).”

CC mortality and overall mortality were comparable between the etoricoxib and diclofenac treatment groups.

Cardiorenal events

About 50% of patients included in the MEDAL study had a history of arterial hypertension at baseline assessment. The dropout rate due to adverse events associated with arterial hypertension was statistically significantly higher for etoricoxib than for diclofenac. The frequency of adverse events related to chronic heart failure (dropouts and serious events) was similar for etoricoxib in the 60 mg dose and diclofenac in the 150 mg dose, but was higher for etoricoxib in the 90 mg dose compared to diclofenac in the 150 mg dose (and statistically significantly higher for etoricoxib in the 90 mg dose compared to diclofenac in the 150 mg dose in the MEDAL OA group).

The incidence of confirmed adverse events associated with chronic heart failure (events that were serious and resulted in hospitalization or emergency department visits) was marginally higher for etoricoxib compared to diclofenac at the 150 mg dose; this effect was dose-dependent. Study dropout rates due to edema-related adverse events were higher for etoricoxib compared with 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 EDGE and EDGE II studies are consistent with the results in the MEDAL study. In individual MEDAL studies, the absolute dropout rate in any treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% for arterial hypertension, up to 1.9% for edema, and up to 1.1% for chronic heart failure. Patients taking etoricoxib at a dose of 90 mg had a higher dropout rate than patients taking etoricoxib at a dose of 60 mg.

The results of the MEDAL gastrointestinal tolerability assessment

In each of the three MEDAL studies, the dropout rate for any clinical GI adverse event (e.g., dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared to diclofenac. The dropout rate due to GI adverse clinical events per 100 patient-years for 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.

The MEDAL Gastrointestinal Safety Assessment Results

In general, upper GI adverse events were defined as perforations, ulcers, and bleeding. Complicated upper GI adverse events included perforations, obstruction and complicated bleeding; uncomplicated upper GI adverse events included uncomplicated bleeding and uncomplicated ulcers. The overall incidence of upper gastrointestinal adverse events was significantly lower for etoricoxib compared with diclofenac. No significant differences between etoricoxib and diclofenac were found in the frequency of complications. No significant differences between etoricoxib and diclofenac were found for hemorrhagic adverse events from the upper gastrointestinal tract (complicated and uncomplicated in the aggregate). The upper GI benefit of etoricoxib compared with diclofenac in patients concomitantly taking low-dose acetylsalicylic acid (approximately 33% of patients) was not statistically significant.

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

The incidence of confirmed upper gastrointestinal adverse events in elderly patients was examined; the maximum reduction 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 incidence of confirmed lower GI adverse events (small or large bowel perforation, obstruction, or bleeding) did not differ significantly between the groups receiving etoricoxib and diclofenac.

The MEDAL liver safety results

Etoricoxib had a statistically significantly lower dropout rate due to liver adverse events compared to 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 liver adverse events. 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 not serious.

Additional safety data related to thrombotic CC events

In clinical trials other than the MEDAL Program trials, approximately 3,100 patients received etoricoxib at a dose of ≥60 mg daily for 12 weeks or longer. There were no notable differences in the incidence of confirmed serious thrombotic CC events in patients receiving etoricoxib at a dose of ≥60 mg, placebo, or Naproxen-free NSAIDs. However, compared with patients receiving Naproxen at a dose of 500 mg twice daily, the incidence of these events was higher in patients receiving etoricoxib. The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk for thromboembolic events. Selective COX-2 inhibitors inhibit systemic (and possibly endothelial) prostacyclin formation without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional Gastrointestinal Safety Data

. In two double-blind, 12-week endoscopic studies, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving etoricoxib at a dose of 120 mg once daily than in patients receiving naproxen at a dose of 500 mg twice daily or ibuprofen at a dose of 800 mg three times daily. The incidence of ulcers was higher with etoricoxib administration compared to placebo.

The study of renal function in elderly patients

. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days of therapy with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily) and placebo on renal sodium excretion, blood pressure (BP) and other measures of renal function in patients aged 60 to 85 years who received a sodium diet of 200 mEq/day. Etoricoxib, celecoxib, and Naproxen had similar effects on renal sodium excretion after 2 weeks of treatment. All active comparison drugs increased systolic BP relative to placebo, but etoricoxib therapy resulted in a statistically significant increase in systolic BP at day 14 compared with celecoxib and naproxen (mean change for systolic BP compared with baseline: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, Naproxen 3.6 mmHg).

Pharmacokinetics

Intake

Etoricoxib is rapidly absorbed when taken orally. Absolute bioavailability when taken orally is about 100%. When administered in adult patients on an empty stomach at a dose of 120 mg once daily until equilibrium is reached, the maximum concentration (Cmax) is 3.6 mcg/ml. Time of reaching maximum concentration (TSmax) in blood plasma is 1 hour after drug administration. Geometric mean area under the curve “concentration-time” (AUC0-24h) is 37.8 µg h/ml. Pharmacokinetics of etoricoxib within therapeutic doses is linear.

When taking etoricoxib at a dose of 120 mg with a meal (high-fat food) there was no clinically significant effect on the degree of absorption. The rate of absorption was altered, resulting in a 36% decrease in Cmax and a 2-hour increase in TCmax. These results are not considered clinically significant. In clinical trials, etoricoxib was used regardless of the time of ingestion.

Distribution

Tericoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 µg/mL. The volume of distribution (Vdss) in the equilibrium state is about 120 liters.

Etoricoxib penetrates the placental barrier and the blood-brain barrier.

Metabolism

Etoricoxib is extensively metabolized. Less than 1% of etoricoxib is excreted unchanged by the kidneys. The main route of metabolism is the formation of 6′-hydroxymethylethoricoxib, catalyzed by enzymes of the cytochrome system. CYP3A4 isoenzyme contributes to the metabolism of etoricoxib under in vivo conditions. In vitro studies indicate that the CYP2D6, CYP2C9, CYP1A2 and CYP2C19 isoenzymes can also catalyze the major metabolic pathway, but their quantitative effects under in vivo conditions have not been studied.

In humans, 5 metabolites of etoricoxib have been identified. The main metabolite is 6′-carboxyacetyl etoricoxib, which is formed by additional oxidation of 6′-hydroxymethyl etoricoxib. These major metabolites have no appreciable activity or are weak COX-2 inhibitors. None of these metabolites inhibits COX-1.

On single intravenous administration of labeled radioactive etoricoxib to healthy volunteers at a dose of 25 mg, 70% of etoricoxib was excreted by the kidneys, 20% – through the intestine, mostly as metabolites. Less than 2% was found unchanged.

The excretion of etoricoxib is mainly by metabolism with subsequent excretion by the kidneys.

The equilibrium concentration is reached when 120 mg of etoricoxib is taken daily after 7 days with a cumulation coefficient of about 2, which corresponds to a half-life of about 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 ml/min.

Pharmacokinetics in special patient groups

Patients in the elderly

Pharmacokinetics in elderly patients (65 years and older) is comparable to that in younger patients.

Performance

The pharmacokinetics of etoricoxib are similar in men and women.

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh score of 5-6) the dosage of etoricoxib 60 mg once daily was associated with an increase in AUC by 16% compared to healthy subjects taking the drug in the same dose.

In patients with moderate hepatic dysfunction (Child-Pugh score 7-9) taking etoricoxib 60 mg once daily, the average AUC was the same as in healthy subjects taking etoricoxib daily at the same dose. Etoricoxib at a dose of 30 mg once daily has not been studied in this population.

There are no clinical or pharmacokinetic studies in patients with severe hepatic impairment (≥10 Child-Pugh score).

Renal failure

The pharmacokinetic parameters of a single dose of etoricoxib 120 mg in patients with moderate to severe renal impairment and with end-stage chronic renal failure (CKF) under hemodialysis were not significantly different from those in healthy subjects. Hemodialysis had little effect on excretion (dialysis clearance was about 50 ml/min).

Children

The pharmacokinetic parameters of etoricoxib in children younger than 12 years have not been studied.

. In a pharmacokinetic study (n=16) conducted in adolescents aged 12 to 17 years, the pharmacokinetics in adolescents weighing 40 to 60 kg when taking etoricoxib at a dose of 60 mg once daily and in those weighing more than 60 kg when taking etoricoxib at a dose of 90 mg once daily were similar to the pharmacokinetics in adults when taking etoricoxib at a dose of 90 mg once daily. The safety and efficacy of etoricoxib in children have not been established.

Indications

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis.
Short-term treatment of moderate acute pain after dental surgery.

Pharmacological effect

Pharmacotherapeutic group:

non-steroidal anti-inflammatory drugs

ATX Code:

M01AN05

Pharmacological properties

Pharmacodynamics

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

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase have been isolated: COX-1 and COX-2. COX-2 is an isoenzyme that is induced by various proinflammatory mediators and is considered 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 ductus arteriosus, regulation of kidney and central nervous system function (induction of fever, pain sensation, cognitive function), and may also play a role in the healing process of ulcers. COX-2 has been found in tissue surrounding human gastric ulcers, but its importance in ulcer healing has not been established.

Efficiency

In patients with osteoarthritis (OA), etoricoxib, when used at a dose of 60 mg 1 time per day, provided a significant reduction in pain and improved patient assessment of their condition. These beneficial effects were observed as early as the second day of treatment and persisted for 52 weeks. Studies of etoricoxib at a dose of 30 mg once daily (using similar assessment methods) demonstrated efficacy compared with placebo over a treatment period of 12 weeks. In an optimal dose determination study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg for all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of the hand joints.

In patients with rheumatoid arthritis (RA), etoricoxib, administered at a dose of 90 mg once daily, provided significant reductions in pain and inflammation and improved mobility. These beneficial effects were maintained over a 12-week treatment period.

In patients with acute gouty arthritis, etoricoxib 120 mg once daily for an eight-day treatment period reduced moderate to severe joint pain and inflammation. The effectiveness was comparable to that of indomethacin when administered at a dose of 50 mg 3 times a day. A decrease in pain was noted within 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib, administered at a dose of 90 mg once daily, provided significant reductions in back pain, inflammation, stiffness, and improvement in function. Clinical efficacy of etoricoxib was observed as early as the second day of treatment and was maintained throughout the 52-week treatment period.

In a clinical study examining pain after dental surgery, etoricoxib 90 mg was administered once daily for three days. In the subgroup of patients with moderate pain (at baseline), etoricoxib 90 mg had the same analgesic effect as ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722) and was superior to paracetamol/codeine 600 mg/60 mg (11.00; P < 0.722). 0.001) and placebo (6.84; P < 0.001) according to the total pain reduction score during the first 6 hours (TOPAR6). The proportion of patients who required rapid-acting pain medications within the first 24 hours of study drug use was 40.8% with etoricoxib 90 mg, 25.5% with ibuprofen 600 mg every 6 hours, and 46.7% with paracetamol/codeine 600 mg/60 mg every 6 hours, compared with 76.2% in placebo group. In this study, the median onset of action (perceived pain relief) with etoricoxib 90 mg was 28 minutes after dosing.

Safety

MEDAL Program (Multinational Evaluation Program for Long-Term Administration of Etoricoxib and Diclofenac in Arthritis)

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

The MEDAL study was a duration-to-endpoint (SS) study that included 17,804 patients with OA and 5,700 patients with RA who received etoricoxib 60 mg (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for an average of 20.3 months (maximum 42.5 months, median 21.3 months). In this study, only serious adverse events and dropouts due to any adverse events were recorded.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7111 patients with OA who received etoricoxib 90 mg daily (1.5 times the recommended dose for OA) or diclofenac 150 mg daily for an average of 9.1 months (maximum 16.5 months, median 11.4 months). The EDGE II study included 4086 patients with RA who received etoricoxib 90 mg daily or diclofenac 150 mg daily for an average of 19.2 months (maximum 33.1 months, median 24 months).

In the combined MEDAL Program, 34,701 patients with OA or RA were treated for an average of 17.9 months (maximum 42.3 months, median 16.3 months), and approximately 12,800 patients were treated for more than 24 months. Patients enrolled in the MEDAL Program had a wide range of CV and gastrointestinal risk factors at baseline assessment. Patients with a recent myocardial infarction, as well as coronary artery bypass grafting or percutaneous coronary intervention within 6 months before inclusion in the study were excluded. The studies allowed the use of gastroprotectors and low-dose aspirin.

General security

No significant differences were found between etoricoxib and diclofenac in the incidence of thrombotic CV events. Cardiorenal adverse events were observed more frequently with etoricoxib than with diclofenac; this effect was dose-dependent (selected results are presented below). Adverse events from the gastrointestinal tract (GIT) and liver were significantly more often observed when prescribing diclofenac than when prescribing etoricoxib. The incidence of adverse events in the EDGE and EDGE II studies, as well as adverse events considered serious or requiring treatment discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular safety results

The incidence of confirmed serious thrombotic CV adverse events (including cardiac, cerebrovascular and peripheral vascular events) was comparable between the groups receiving etoricoxib or diclofenac (data are shown in the table below). There were no statistically significant differences in the incidence of thrombotic events between etoricoxib and diclofenac in all analyzed subgroups, including categories of patients in the range of baseline CV risk. The relative risk for confirmed serious thrombotic CV adverse events was similar for etoricoxib (at a dose of 60 mg or 90 mg) and diclofenac (at a dose of 150 mg).

Table “Frequency of confirmed thrombotic CV events (MEDAL Program)”

Etoricoxib
(N=16819)
25836 patient-years
Diclofenac
(N=16483)
24,766 patient-years
Comparison between
types of treatment
Frequency1 (95% CI)
Frequency1 (95% CI)
Relative risk
(95% CI)
Confirmed thrombotic CV serious adverse events
When meeting protocol requirements
1.24 (1.11, 1.38)
1.30 (1.17, 1.45)
0.95 (0.81, 1.11)
Depending on the prescribed treatment
1.25 (1.14, 1.36)
1.19 (1.08, 1.30)
1.05 (0.93, 1.19)
Confirmed cardiac events
When meeting protocol requirements
0.71 (0.61, 0.82)
0.78 (0.68, 0.90)
0.90 (0.74, 1.10)
Depending on the prescribed treatment
0.69 (0.61, 0.78)
0.70 (0.62, 0.79)
0.99 (0.84, 1.17)
Confirmed cerebrovascular events
When meeting protocol requirements
0.34 (0.28, 0.42)
0.32 (0.25, 0.40)
1.08 (0.80, 1.46)
Depending on the prescribed treatment
0.33 (0.28, 0.39)
0.29 (0.24, 0.35)
1.12 (0.87, 1.44)
Confirmed peripheral vascular events
When meeting protocol requirements
0.20 (0.15, 0.27)
0.22 (0.17, 0.29)
0.92 (0.63, 1.35)
Depending on the prescribed treatment
0.24 (0.20, 0.30)
0.23 (0.18, 0.28)
1.08 (0.81, 1.44)
1 Number of events per 100 patient-years; CI=confidence interval; N=total number of patients included in the protocol-compliant patient population.
If the protocol requirements are met, all events that developed during study therapy within 14 days of its cessation (patients who received 10% of the time are excluded).
Depending on the assigned treatment, all confirmed events that occurred before the end of the study (included patients who may have undergone non-study interventions after discontinuation of the study drug). Total number of patients randomized: n=17412 for etoricoxib and n=17289 for diclofenac.

CV mortality and all-cause mortality were comparable between the etoricoxib and diclofenac treatment groups.

Cardiorenal phenomena

Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension at baseline assessment. The dropout rate due to hypertension-related adverse events was statistically significantly higher for etoricoxib than for diclofenac. The incidence of adverse events associated with chronic heart failure (study dropouts and serious events) was similar for etoricoxib 60 mg and diclofenac 150 mg, but was higher for etoricoxib 90 mg compared with diclofenac 150 mg (and statistically significantly higher for etoricoxib 90 mg compared with diclofenac 150 mg). 150 mg in the OA group of the MEDAL study).

The incidence of confirmed adverse events related to chronic heart failure (events that were serious and resulted in hospitalization or emergency department visit) was not significantly higher for etoricoxib compared with diclofenac 150 mg; this effect was dose-dependent. The rate of withdrawal from the study due to adverse events related to edema was higher for etoricoxib compared with diclofenac 150 mg; this effect was dose-dependent (statistically significant for etoricoxib 90 mg, but not for etoricoxib 60 mg).

Cardiorenal safety results from the EDGE and EDGE II studies are consistent with those from the MEDAL study

In the individual MEDAL Program studies, the absolute rate of study attrition in any treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% due to hypertension, up to 1.9% due to edema, and up to 1.1% due to congestive heart failure. Patients treated with etoricoxib 90 mg had a higher dropout rate than patients treated with etoricoxib 60 mg.

Results of gastrointestinal tolerance assessment in the MEDAL Program

In each of the three studies included in the MEDAL Program, the dropout rate for any clinical GI adverse event (eg, dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared with diclofenac. The rate of withdrawal from the study due to adverse clinical events from the gastrointestinal tract per 100 patient-years for 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.

Results of the gastrointestinal safety assessment in the MEDAL Program

Overall, upper gastrointestinal adverse events were defined as perforation, ulceration, and bleeding. Complicated upper GI adverse events included perforation, obstruction, and complicated bleeding; uncomplicated upper GI adverse events included uncomplicated bleeding and uncomplicated ulcers. The overall incidence of upper gastrointestinal adverse events was significantly lower for etoricoxib compared to diclofenac. No significant differences were found between etoricoxib and diclofenac in the incidence of complicated events. For upper gastrointestinal hemorrhagic adverse events (complicated and uncomplicated combined), no significant differences were found between etoricoxib and diclofenac. The upper gastrointestinal benefit of etoricoxib compared with diclofenac in patients concomitantly taking low-dose acetylsalicylic acid (about 33% of patients) was not statistically significant.

The incidence of confirmed complicated and uncomplicated clinical upper gastrointestinal adverse events per 100 patient-years (perforation, ulceration and bleeding) was 0.67 (95% CI 0.57, 0.77) for etoricoxib and 0.97 (95% CI 0.85, 1.10) for diclofenac, resulting in a relative risk of 0.69 (95% CI 0.57, 0.83).

The incidence of confirmed upper gastrointestinal adverse events in elderly patients was studied; the greatest reduction in incidence was observed in patients aged ≥75 years, with 1.35 (95% CI 0.94, 1.87) versus 2.78 (95% CI 2.14, 3.56) events per 100 patient-years for etoricoxib and diclofenac, respectively.

The incidence of confirmed lower gastrointestinal adverse events (small or large bowel perforation, obstruction, or bleeding) was not significantly different between the etoricoxib and diclofenac groups.

Liver Safety Results from the MEDAL Program

Etoricoxib was characterized by a statistically significantly lower rate of withdrawal from the study due to adverse events from the liver compared with diclofenac. In the pooled MEDAL Program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac withdrew from the study due to liver adverse events. 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 non-serious.

Additional safety data related to thrombotic CV events

In clinical studies excluding the MEDAL Program studies, approximately 3100 patients received etoricoxib at a dose of ≥60 mg per day for 12 weeks or longer. There were no significant differences in the incidence of confirmed serious thrombotic CV events in patients receiving etoricoxib ≥60 mg, placebo, or non-naproxen NSAIDs. However, compared with patients receiving Naproxen 500 mg twice daily, the incidence of these events was higher in patients receiving etoricoxib. The difference in antiplatelet activity between some COX-1 inhibitory NSAIDs and selective COX-2 inhibitors may be of clinical significance in patients at risk for thromboembolic events. Selective COX-2 inhibitors suppress the formation of systemic (and possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional gastrointestinal safety data

In two double-blind endoscopic studies lasting 12 weeks, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving etoricoxib 120 mg once daily than in patients receiving naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The incidence of ulcers was higher with etoricoxib compared with placebo.

Renal function testing in elderly patients

A randomized, double-blind, placebo-controlled, parallel group study assessed the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on renal sodium excretion, blood pressure (BP), and other measures of renal function in patients aged 60 to 85 years receiving a 200 sodium diet. mEq/day Etoricoxib, celecoxib, and naproxen had similar effects on renal sodium excretion after 2 weeks of treatment. All active comparators increased systolic BP relative to placebo, but etoricoxib treatment resulted in a statistically significant increase in systolic BP at day 14 compared with celecoxib and naproxen (mean change from baseline for systolic BP: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, Naproxen – 3.6 mmHg).

Pharmacokinetics

Suction

Etoricoxib is rapidly absorbed when taken orally. Absolute bioavailability when taken orally is about 100%. When using the drug in adult patients on an empty stomach at a dose of 120 mg 1 time per day until a steady state is achieved, the maximum concentration (Cmax) is 3.6 mcg/ml. The time to reach maximum concentration (TCmax) in blood plasma is 1 hour after taking the drug. The geometric mean area under the concentration-time curve (AUC0-24h) is 37.8 μg h/ml. The pharmacokinetics of etoricoxib within therapeutic doses is linear.

When etoricoxib was administered at a dose of 120 mg with food (high fat meal), no clinically significant effect on the extent of absorption was observed. The rate of absorption was changed, resulting in a decrease in Cmax by 36% and an increase in TCmax by 2 hours. These results are not considered clinically significant. In clinical studies, etoricoxib was administered regardless of meal timing.

Distribution

Etoricoxib is approximately 92% bound to plasma proteins in humans at concentrations of 0.05-5 mcg/ml. The volume of distribution (Vdss) at equilibrium is approximately 120 l.

Etoricoxib penetrates the placental barrier and the blood-brain barrier.

Metabolism

Etoricoxib is extensively metabolized. Less than 1% of etoricoxib is excreted unchanged by the kidneys. The main route of metabolism is the formation of 6′-hydroxymethyletoricoxib, catalyzed by enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes the metabolism of etoricoxib in vivo. In vitro studies indicate that the isoenzymes CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyze the major metabolic pathway, but their quantitative effects in vivo have not been studied.

Five metabolites of etoricoxib have been detected in humans. The main metabolite is 6′-carboxyacetyletoricoxib, formed by additional oxidation of 6′-hydroxymethylethoricoxib. These main metabolites do not have significant activity or are weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

Removal

With a single intravenous administration of radiolabeled etoricoxib at a dose of 25 mg to healthy volunteers, 70% of etoricoxib was excreted by the kidneys, 20% through the intestines, mainly in the form of metabolites. Less than 2% was found unchanged.

Elimination of etoricoxib occurs primarily through metabolism followed by renal excretion.

Equilibrium concentration is achieved with a daily dose of 120 mg of etoricoxib after 7 days with an accumulation coefficient of about 2, which corresponds to a half-life of about 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 ml/min.

Pharmacokinetics in special groups of patients

Elderly patients

Pharmacokinetics in elderly patients (65 years and older) are comparable to pharmacokinetics in young patients.

Floor

The pharmacokinetics of etoricoxib are similar in men and women.

Liver failure

In patients with mild hepatic impairment (Child-Pugh score 5-6), taking etoricoxib at a dose of 60 mg 1 time per day was accompanied by an increase in AUC by 16% compared with healthy individuals taking the drug at the same dose.

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9) receiving etoricoxib 60 mg every other day, the mean AUC was the same as in healthy subjects receiving etoricoxib at the same dose daily. Etoricoxib 30 mg once daily has not been studied in this population.

Data from clinical and pharmacokinetic studies in patients with severe hepatic impairment (≥10 Child-Pugh points) are not available.

Kidney failure

The pharmacokinetic parameters of a single dose of etoricoxib 120 mg in patients with moderate to severe renal impairment and end-stage chronic renal failure (ESRD) on hemodialysis did not differ significantly from those in healthy individuals. Hemodialysis had little effect on excretion (dialysis clearance – about 50 ml/min).

Children

The pharmacokinetic parameters of etoricoxib have not been studied in children under 12 years of age.

In a pharmacokinetic study (n=16) conducted in adolescents aged 12 to 17 years, the pharmacokinetics in adolescents weighing 40 to 60 kg with etoricoxib 60 mg once daily and in adolescents weighing more than 60 kg with etoricoxib 90 mg once daily were similar to those in adults with etoricoxib. Etoricoxib 90 mg once daily. The safety and effectiveness of etoricoxib in children has not been established.

Special instructions

Caution should be exercised when using the drug in the following groups of patients:

– patients with an increased risk of developing gastrointestinal complications due to taking NSAIDs, elderly patients concomitantly taking other NSAIDs, including acetylsalicylic acid, or patients with a history of gastrointestinal diseases, such as peptic ulcers and gastrointestinal bleeding;

– patients with a history of risk factors for cardiovascular complications, such as dyslipidemia/hyperlipidemia, diabetes mellitus, hypertension, smoking, heart failure, left ventricular dysfunction, edema and fluid retention;

– patients with mild liver dysfunction (5-6 points on the Child-Pugh scale) should not exceed a dose of 60 mg once a day, patients with moderate liver dysfunction (7-9 points on the Child-Pugh scale) – 30 mg once a day;

– patients with dehydration;

– patients with impaired renal function who are simultaneously using ACE inhibitors, diuretics, angiotensin II receptor antagonists, especially elderly patients;

– patients with CC < 60 ml/min;

– patients with a previous significant decrease in renal function, with weakened renal function, decompensated heart failure or cirrhosis, who are at risk with long-term use of NSAIDs.

Caution should be exercised during concomitant therapy with the following drugs:

– anticoagulants (for example, warfarin);

– antiplatelet agents (for example, acetylsalicylic acid, clopidogrel);

– drugs metabolized by sulfotransferases.

Etoricoxib is contraindicated for use in children and adolescents under 16 years of age.

Elderly patients

No dose adjustment is required in elderly patients. As with other drugs in elderly patients, caution should be exercised when using Etoriax.

Liver dysfunction

Regardless of the indication for use of the drug, patients with mild liver dysfunction (5-6 points on the Child-Pugh scale) should not exceed a dose of 60 mg once a day, patients with moderate liver dysfunction (7-9 points on the Child-Pugh scale) should not exceed 30 mg once a day.

Caution is recommended when using Etoriax in patients with moderate hepatic impairment, since clinical experience with etoricoxib in this group of patients is limited. Due to the lack of clinical experience with the use of etoricoxib in patients with severe hepatic impairment (Child-Pugh score ≥ 10), Etoriax is contraindicated in this group of patients.

Renal dysfunction

No dose adjustment is required in patients with CC ≥ 30 ml/min. The use of etoricoxib in patients with creatinine clearance <30 ml/min is contraindicated.

Effect on the gastrointestinal tract

Cases of upper gastrointestinal complications (perforation, ulceration or bleeding), sometimes fatal, have been reported in patients receiving etoricoxib.

Caution is recommended when treating patients at high risk of developing gastrointestinal complications when using NSAIDs, particularly in elderly patients, patients who are concomitantly using other NSAIDs, including acetylsalicylic acid, and in patients with a history of gastrointestinal diseases such as ulcers or gastrointestinal bleeding.

There is an additional risk of developing gastrointestinal adverse reactions (gastrointestinal ulcers or other gastrointestinal complications) with concomitant use of etoricoxib and acetylsalicylic acid (even in low doses). In long-term clinical studies, there were no significant differences in gastrointestinal safety when using selective COX-2 inhibitors in combination with acetylsalicylic acid compared with the use of NSAIDs in combination with acetylsalicylic acid (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

Effect on the cardiovascular system

The results of clinical studies indicate that the use of drugs in the class of selective COX-2 inhibitors is associated with an increased risk of thrombotic events (especially myocardial infarction and stroke) relative to placebo and some NSAIDs. Since the risk of developing cardiovascular diseases when taking selective COX-2 inhibitors may increase with increasing dose and duration of use, it is necessary to choose the shortest possible duration of use and the lowest effective daily dose. It is necessary to periodically evaluate the patient’s need for symptomatic treatment and response to therapy, especially for patients with osteoarthritis (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as sections “Contraindications”, “Dosage and Administration” and “Side Effects”).

Patients with known risk factors for the development of cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed etoricoxib only after a careful assessment of benefits and risks (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

Selective COX-2 inhibitors are not a replacement for acetylsalicylic acid in the prevention of cardiovascular diseases, since they do not affect platelets. Therefore, you should not stop using antiplatelet drugs (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as section “Interaction with other drugs”).

Effect on kidney function

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. In the presence of conditions that adversely affect renal perfusion, the use of etoricoxib may cause a decrease in prostaglandin formation and a decrease in renal blood flow, and thus reduce renal function. The greatest risk of developing this reaction is in patients with a significant decrease in renal function, decompensated heart failure, or a history of cirrhosis. In such patients, it is necessary to monitor renal function.

Fluid retention, edema and hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and hypertension have been reported in patients treated with etoricoxib. All NSAIDs, including etoricoxib, may be associated with the onset or recurrence of chronic heart failure. Information on the dose dependence of the effect of etoricoxib is given in the “Pharmacological properties” section, subsection “Pharmacodynamics”. Caution should be exercised when prescribing etoricoxib to patients with a history of heart failure, left ventricular dysfunction or hypertension, as well as to patients with pre-existing edema due to any other cause. If clinical signs of deterioration occur in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

The use of etoricoxib, especially at high doses, may be associated with more frequent and severe hypertension than with some other NSAIDs and selective COX-2 inhibitors. During treatment with etoricoxib, special attention should be paid to blood pressure control (see section “Contraindications”), which should be monitored for 2 weeks after the start of treatment and periodically thereafter. If there is a significant increase in blood pressure, alternative treatment should be considered.

Effect on liver function

In clinical studies lasting up to one year, approximately 1% of patients treated with etoricoxib at doses of 30 mg, 60 mg and 90 mg per day experienced increases in ALT and/or AST (approximately three or more times the upper limit of normal).

All patients with symptoms and/or signs of liver dysfunction, as well as patients with abnormal liver function tests, should be monitored.

If persistent liver function abnormalities (three times the upper limit of normal) are detected, etoricoxib should be discontinued.

General instructions

If the patient experiences deterioration in the function of any of the organ systems listed above during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. When using etoricoxib in elderly patients and in patients with impaired renal, hepatic or cardiac function, appropriate medical supervision is required.

Caution should be exercised when initiating treatment with etoricoxib in patients with dehydration. Rehydration is recommended before starting etoricoxib.

During post-marketing surveillance, serious skin reactions have been reported very rarely with the use of NSAIDs and some selective COX-2 inhibitors. Some of them (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) were fatal (see section “Side effects”). The risk of developing such reactions is highest at the beginning of therapy, in most cases during the first month of treatment. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported in patients receiving etoricoxib (see Adverse Reactions section). The use of some selective COX-2 inhibitors has been associated with an increased risk of skin reactions in patients with a history of any drug allergies. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

The use of etoricoxib may mask fever or other signs of inflammation.

Caution should be exercised when using etoricoxib concomitantly with warfarin or other oral anticoagulants (see section “Interactions with other drugs”).

The use of etoricoxib, like other drugs that inhibit COX and prostaglandin synthesis, is not recommended for women who are planning pregnancy (see section “Pharmacological properties”, subsection “Pharmacodynamics” and section “Use during pregnancy and breastfeeding”).

Patients who experience dizziness, drowsiness, or weakness while taking etoricoxib should avoid driving or operating machinery.

Active ingredient

Etoricoxib

Composition

1 film-coated tablet, 30 mg/60 mg/90 mg/120 mg contains:

Core:

Active ingredient:

Etoricoxib 30.00 mg/60.00 mg/90.00 mg/120.00 mg

Excipients: microcrystalline cellulose, type KG-802, microcrystalline cellulose, type PH-200 LM, calcium hydrogen phosphate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide

Film coating: Opadry 85F28751 II white* (polyvinyl alcohol, titanium dioxide (E171), macrogol-3000, talc), yellow iron oxide dye (E172) (for a dosage of 60 mg), red iron oxide dye (E172) (for dosages of 90 mg and 120 mg)

* Opadry 85F28751 II white – ready-to-use dry mixture of polyvinyl alcohol, titanium dioxide (E171), macrogol-3000 and talc.

Pregnancy

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Reproductive toxicity has been observed in animal studies. The potential risk in women during pregnancy is unknown. The use of etoricoxib, like other drugs that inhibit prostaglandin synthesis, during the last trimester of pregnancy can lead to suppression of uterine contractions and premature closure of the ductus arteriosus. Etoricoxib is contraindicated during pregnancy (see section “Contraindications”). If pregnancy occurs during treatment, etoricoxib should be discontinued.

Breastfeeding period

In lactating rats, etoricoxib is excreted in milk. Studies have not been conducted to confirm the excretion of etoricoxib into breast milk in women. Women taking etoricoxib should stop breastfeeding (see Contraindications section).

Fertility

The use of etoricoxib, like other drugs that inhibit COX-2 and prostaglandin synthesis, is not recommended for women planning pregnancy.

Contraindications

Hypersensitivity to any component of the drug.
Peptic ulcer of the stomach and duodenum in the acute stage, active gastrointestinal bleeding.
Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including a history).
Pregnancy, breastfeeding period.
Severe liver dysfunction (serum albumin 10 points on the Child-Pugh scale).
Severe renal failure (creatinine clearance (CC) less than 30 ml/min).
Children’s age up to 16 years.
Inflammatory bowel diseases.
Chronic heart failure (NYHA functional class II-IV).
Uncontrolled arterial hypertension, in which blood pressure levels persistently exceed 140/90 mmHg. Art.
Confirmed coronary heart disease, peripheral arterial disease and/or cerebrovascular disease.
Confirmed hyperkalemia.
Progressive kidney diseases.
With caution

Caution should be exercised when using the drug in the following groups of patients:

patients with an increased risk of developing gastrointestinal complications due to the use of NSAIDs, elderly patients concomitantly taking other NSAIDs, including acetylsalicylic acid, or patients with a history of gastrointestinal diseases such as peptic ulcers and gastrointestinal bleeding;
patients with a history of risk factors for cardiovascular complications, such as dyslipidemia/hyperlipidemia, diabetes mellitus, hypertension, smoking, heart failure, left ventricular dysfunction, edema and fluid retention;
patients with mild liver dysfunction (5-6 points on the Child-Pugh scale) should not exceed a dose of 60 mg 1 time per day, patients with moderate liver dysfunction (7-9 points on the Child-Pugh scale) – 30 mg 1 time per day;
patients with dehydration;
patients with impaired renal function who are simultaneously using ACE inhibitors, diuretics, angiotensin II receptor antagonists, especially elderly patients;
patients with CC < 60 ml/min; patients with a previous significant decrease in renal function, with weakened renal function, decompensated heart failure or cirrhosis, who are at risk with long-term use of NSAIDs.

Caution should be exercised during concomitant therapy with the following drugs:

anticoagulants (eg warfarin);
antiplatelet agents (for example, acetylsalicylic acid, clopidogrel);
drugs metabolized by sulfotransferases.

Side Effects

The safety of etoricoxib was assessed in clinical studies that included 9,295 participants, including 6,757 patients with OA, RA, chronic low back pain, and ankylosing spondylitis (approximately 600 patients with OA or RA were treated for 1 year or longer).

In clinical studies, the adverse effect profile was similar in patients with OA or RA who took etoricoxib for 1 year or longer.

In a clinical trial of acute gouty arthritis, patients received etoricoxib 120 mg/day for 8 days. The adverse effect profile in this study was generally the same as in the pooled studies of OA, RA, and chronic low back pain.

In the Safety Assessment Program for the CV System, which included data from three active-controlled studies, 17,412 patients with OA or RA received etoricoxib at a dose of 60 mg or 90 mg for an average of 18 months (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

In clinical studies of acute postoperative pain associated with dental surgery, in which 614 patients received etoricoxib 90 mg or 120 mg, the adverse effect profile was generally similar to that in the combined studies of OA, RA and chronic low back pain.

The following adverse reactions were reported at a higher frequency with etoricoxib than with placebo in clinical studies that included patients with OA, RA, chronic low back pain, or ankylosing spondylitis who received etoricoxib at a dose of 30 mg, 60 mg, or 90 mg, with escalation to the recommended dose over 12 weeks, in MEDAL Program studies of up to 3.5 years, in short-term studies of acute pain, as well as during post-marketing use.

Class system/organ

Adverse event

Frequency1

Infectious and parasitic diseases

alveolar osteitis

often

gastroenteritis, upper respiratory tract infections, urinary tract infections

infrequently

Blood and lymphatic system disorders

anemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia

infrequently

Immune system disorders

hypersensitivity reactions2,4

infrequently

angioedema, anaphylactic/anaphylactoid reactions, including shock2

rarely

Metabolic and nutritional disorders

swelling/fluid retention

often

decreased or increased appetite, weight gain

infrequently

Mental disorders

anxiety, depression, concentration problems, hallucinations2

infrequently

confusion2, anxiety2

rarely

Nervous system disorders

dizziness, headache

often

taste disturbance, insomnia, paresthesia/hypoesthesia, drowsiness

infrequently

Visual disorders

blurred vision, conjunctivitis

infrequently

Hearing and labyrinth disorders

ringing in the ears, vertigo

infrequently

Heart disorders

palpitations, arrhythmia2

often

atrial fibrillation, tachycardia2, chronic heart failure, nonspecific changes on the electrocardiogram (ECG), angina pectoris2, myocardial infarction5

infrequently

Vascular disorders

arterial hypertension

often

“hot flashes”, cerebrovascular accident5, transient ischemic attack, hypertensive crisis2, vasculitis2

infrequently

Respiratory, thoracic and mediastinal disorders

bronchospasm2

often

cough, shortness of breath, nosebleeds

infrequently

Digestive system disorders

stomach pain

very often

constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, ulcers of the oral mucosa

often

bloating, changes in peristalsis, dry oral mucosa, gastroduodenal ulcer, stomach ulcer, including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis2

infrequently

Disorders of the liver and biliary tract

increased activity of alanine aminotransferase (ALT), increased activity of aspartate aminotransferase (AST)

often

hepatitis2

rarely

liver failure2, jaundice2

rarely3

Skin and subcutaneous tissue disorders

ecchymosis

often

swelling of the face, itching, skin rash, erythema2, urticaria2

infrequently

Stevens-Johnson syndrome2, toxic epidermal necrolysis2, fixed drug erythema2

rarely3

Interaction

Pharmacodynamic interaction

Oral anticoagulants (warfarin)

In patients receiving warfarin, etoricoxib 120 mg daily was associated with an approximately 13% increase in international normalized ratio (INR) prothrombin time. In patients receiving oral anticoagulants, prothrombin time and INR should be monitored when starting treatment or when changing etoricoxib treatment, especially in the first few days.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA II)

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (for example, in patients with dehydration or in elderly patients with impaired renal function), concomitant use of an ACE inhibitor or ARB II and drugs that inhibit COX may lead to an additional deterioration of renal function, including the possible development of acute renal failure, which is usually reversible. The possibility of such interactions should be kept in mind in patients taking etoricoxib concomitantly with ACE inhibitors or with ARB II. This combination should be prescribed with caution, especially in elderly patients. At the beginning of combined treatment, as well as at certain intervals in the future, fluid deficiency should be replenished and the issue of monitoring renal function should be considered.

Acetylsalicylic acid

In a study in healthy volunteers, etoricoxib 120 mg daily at steady state did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used simultaneously with acetylsalicylic acid in low doses intended for the prevention of cardiovascular diseases. However, simultaneous administration of low doses of acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared to taking etoricoxib alone. The simultaneous use of etoricoxib with acetylsalicylic acid in doses exceeding those recommended for the prevention of cardiovascular complications, as well as with other NSAIDs, is not recommended (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as section “Special instructions”).

Cyclosporine and tacrolimus

The interaction of etoricoxib with these drugs has not been studied, however, the simultaneous use of NSAIDs with cyclosporine and tacrolimus may increase the nephrotoxic effect of these drugs. Monitor renal function when etoricoxib is used concomitantly with any of these drugs.

Pharmacokinetic interaction

Effect of etoricoxib on other drugs

Lithium

NSAIDs reduce the renal excretion of lithium and, therefore, increase the concentration of lithium in the blood plasma. If necessary, frequently monitor the concentration of lithium in the blood and adjust the dose of lithium during simultaneous use with NSAIDs, as well as when NSAIDs are discontinued.

Methotrexate

Two studies examined the effects of etoricoxib 60 mg, 90 mg, and 120 mg once daily for seven days in patients receiving once-weekly methotrexate 7.5 mg to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg had no effect on plasma concentrations and renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on the pharmacokinetics of methotrexate. In another study, plasma methotrexate concentrations increased by 28% and renal clearance of methotrexate decreased by 13%. If etoricoxib is used concomitantly with methotrexate, monitor for possible toxic effects of methotrexate.

Contraceptives for oral administration

Taking etoricoxib 60 mg for 21 days with oral contraceptives containing 35 mcg ethinyl estradiol (EE) and 0.5 mg to 1 mg norethindrone increased the AUC0-24h for EE by 37%. Taking etoricoxib at a dose of 120 mg with the above oral contraceptives (simultaneously or at intervals of 12 hours) increases the steady-state AUC0-24h for EE by 50-60%. This increase in EE concentrations should be taken into account when selecting the appropriate oral contraceptive when used concomitantly with etoricoxib. This fact may lead to an increase in the incidence of adverse events associated with the use of oral contraceptives (for example, venous thromboembolism in women at risk).

Hormone replacement therapy (HRT)

The use of etoricoxib at a dose of 120 mg concurrently with hormone replacement therapy products containing conjugated estrogens at a dose of 0.625 mg for 28 days increased the mean steady-state AUC0-24h of unconjugated estrone (41%), equilin (76%) and 17-β-estradiol (22%). The effects of etoricoxib doses recommended for long-term use (30 mg, 60 mg and 90 mg) have not been studied. Etoricoxib at a dose of 120 mg changed the exposure (AUC0-24h) of these estrogenic components to less than half compared with monotherapy with a drug containing conjugated estrogens, when the dose of the latter was increased from 0.625 mg to 1.25 mg. The clinical significance of such increases is unknown. The combination of etoricoxib and a product containing higher doses of conjugated estrogens has not been studied. Increased estrogen concentrations should be taken into account when choosing a hormonal drug for postmenopausal use when administered concomitantly with etoricoxib, since increased estrogen exposure may increase the risk of HRT-related adverse events.

Prednisone/prednisolone

In drug interaction studies, etoricoxib did not have a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin

When etoricoxib was administered at a dose of 120 mg once daily for 10 days in healthy volunteers, there was no change in AUC0-24h at steady state or an effect on renal excretion of digoxin. An increase in digoxin Cmax was noted (approximately 33%). This increase is usually not significant in most patients. However, when etoricoxib and digoxin are used concomitantly, patients at high risk for digoxin toxicity should be monitored.

Effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferases (specifically SULT1E1) and may increase serum EE concentrations. Due to the fact that there is currently insufficient data on the effects of various sulfotransferases, and their clinical relevance for the use of many drugs is still being studied, it is advisable to use caution when prescribing etoricoxib concomitantly with other drugs that are metabolized primarily by human sulfotransferases (for example, oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by isoenzymes of the cytochrome system

Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. In a study of healthy volunteers, daily administration of etoricoxib 120 mg had no effect on hepatic CYP3A4 activity as measured by the erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

The main pathway of metabolism of etoricoxib depends on enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes the metabolism of etoricoxib in vivo. In vitro studies suggest that the isoenzymes CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyze the main metabolic pathway, but their quantitative characteristics have not been studied in vivo.

Ketoconazole

Ketoconazole is a potent inhibitor of the CYP3A4 isoenzyme. When ketoconazole was administered to healthy volunteers at a dose of 400 mg once daily for 11 days, it had no clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (43% increase in AUC).

Voriconazole and miconazole

Concomitant use of strong CYP3A4 inhibitors (oral voriconazole or topical miconazole oral gel) and etoricoxib caused a slight increase in etoricoxib exposure, which was not considered clinically significant based on published data.

Rifampicin

The simultaneous use of etoricoxib and rifampicin (a powerful inducer of the cytochrome system) led to a decrease in the concentration of etoricoxib in the blood plasma by 65%. This interaction may be accompanied by a relapse of symptoms when etoricoxib is co-administered with rifampicin. These data may indicate a need for dose escalation, but etoricoxib should not be used in doses that exceed those recommended for each indication (see Dosage and Administration) as the combined use of rifampicin and etoricoxib at such doses has not been studied.

Antacids

Antacids do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Overdose

In clinical studies, single doses of etoricoxib up to 500 mg or multiple doses of up to 150 mg/day for 21 days did not cause significant toxic effects. There have been reports of acute overdose with etoricoxib, but in most cases no adverse reactions were reported.

The most common adverse reactions were consistent with the safety profile of etoricoxib (eg, gastrointestinal disorders, cardiorenal events).

In case of overdose, it is advisable to apply the usual supportive measures, such as removal of unabsorbed drug from the gastrointestinal tract, clinical observation and, if necessary, supportive therapy. Etoricoxib is not eliminated by hemodialysis, and the elimination of etoricoxib by peritoneal dialysis has not been studied.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of the reach of children.

Shelf life

3 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA dd Novo Mesto, Slovenia