Etoriax, 90 mg 7 pcs.

Pharmacology

Mechanism of action

Etoricoxib is an oral, selective COX-2 inhibitor in the therapeutic dose range.

In clinical trials, etoricoxib caused dose-dependent inhibition of COX-2 without inhibiting COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit GH synthesis in the stomach and did not affect platelet function.

The COX is responsible for PG production. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the enzyme isoform that has been shown to be induced by proinflammatory stimuli and is thought to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is also involved in ovulation, implantation and closure of the arterial duct, regulation of renal function and CNS functions (fever induction, pain perception and cognitive functions), and may play a role in ulcer healing. COX-2 has been detected in tissues around gastric ulcers in humans, but its importance in ulcer healing has not been established.

Pharmacokinetics

Absorption

Orally taken etoricoxib is well absorbed. Absolute bioavailability is approximately 100%. Against a single daily dose of 120 mg to equilibrium Cmax in plasma (geometric mean – 3.6 µg/ml) was observed approximately 1 h after an adult fasting dose. The geometric mean AUC0-24 was 37.8 μg/h/ml. The pharmacokinetics of etoricoxib are linear over the therapeutic dose range.

A meal (high-calorie meal) had no effect on the degree of absorption of etoricoxib after a dose of 120 mg. The rate of absorption was impaired, resulting in a 36% decrease in Cmax and an increase in Tmax by 2 h. These data are not considered clinically significant. In clinical trials, etoricoxib was administered without regard to food intake.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 to 5 µg/mL. Vss in humans was approximately 120L. Etoricoxib penetrates through the placenta in rats and rabbits, as well as the GEB in rats.

Biotransformation

Etoricoxib is extensively metabolized, with 1% of the ingested dose excreted in the urine as an initial drug. The main metabolic pathway to form the 6′-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to be involved in the metabolism of etoricoxib in vivo. In vitro studies show that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 can also catalyze the major metabolic pathway, but their quantitative role in vivo has not been studied.

Five metabolites have been identified in humans. The major metabolite is the 6′-carboxylic acid derivative of etoricoxib, formed by further oxidation of its 6′-hydroxymethyl derivative. These major metabolites either exhibit no measurable activity or only weak activity as COX-2 inhibitors. None of these metabolites inhibits COX-1.

Excretion

After intravenous administration of radioactively labeled etoricoxib to healthy volunteers at a single dose of 25 mg, 70% of the radioactivity was excreted in the urine and 20% in the feces, mostly as metabolites. Less than 2% was excreted as unchanged etoricoxib.

The elimination of etoricoxib occurs almost exclusively by metabolism followed by renal excretion. Stable concentrations of etoricoxib are achieved within seven days of a single daily dose of 120 mg, with an accumulation rate of approximately 2, corresponding to a T1/2 of approximately 22 h. Plasma clearance after intravenous administration of 25 mg is estimated to be approximately 50 ml/min.

Particular patient groups

Children. The pharmacokinetics of etoricoxib in pediatric patients (<12 years) have not been studied.

In a study (n=16) conducted with adolescents (12 to 17 years old) weighing 40 to 60 kg taking etoricoxib at a dose of 60 mg once daily and weighing >60 kg taking etoricoxib at a dose of 90 mg once daily, pharmacokinetic parameters were similar to those of adults taking etoricoxib at a dose of 90 mg once daily. The safety and efficacy of etoricoxib in pediatric patients have not been established.

Elderly age (>65 years). Pharmacokinetics in the elderly (65 years and older) are similar to those in the young.

Gender. The pharmacokinetics of etoricoxib are similar in men and women.

Hepatic impairment. In patients with mild hepatic impairment (5-6 Child-Pugh scores) taking etoricoxib at a dose of 60 mg once daily, mean AUC was approximately 16% higher compared to healthy subjects taking etoricoxib on the same regimen. In patients with moderate hepatic impairment (7-9 Child-Pugh scores) taking etoricoxib 60 mg every other day, the mean AUC was the same as in healthy subjects taking etoricoxib 60 mg once daily; etoricoxib in the 30 mg once daily dose has not been studied in this population. Clinical and pharmacokinetic data in patients with severe hepatic dysfunction (≥10 Child-Pugh score) are not available (see Contraindications).

Renal insufficiency. Pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate to severe renal failure and patients with end-stage chronic renal disease under hemodialysis were not significantly different from those in healthy subjects. Hemodialysis had no significant effect on elimination (dialysis clearance is approximately 50 ml/min) (see Contraindications and Precautions).

Preclinical safety data

Preclinical studies have shown that etoricoxib is not genotoxic. Etoricoxib was not carcinogenic in mice. Rats developed hepatocellular and follicular-cell thyroid adenomas at a dose twice the daily dose for humans (90 mg), with systemic exposure to daily administration for about two years. The hepatocellular and follicular-cellular thyroid adenomas observed in rats are thought to result from a rat-specific mechanism involving induction of hepatic CYP450 enzymes. Etoricoxib has not been shown to cause induction of hepatic CYP3A enzymes in humans.

In rats, gastrointestinal toxicity of etoricoxib increased with increasing dose and time of exposure. In a 14-week toxicity study, etoricoxib caused GI ulcers at doses greater than the human therapeutic dose. In the 53- and 106-week toxicity studies, GI ulcers were also observed at exposures comparable to the human therapeutic dose. Renal and gastrointestinal abnormalities were observed in dogs when exposed to high doses.

Etoricoxib was not teratogenic in reproductive toxicity studies conducted in rats at a dose of 15 mg/kg/day (this is approximately 1.5 times the human daily dose (90 mg) for systemic exposure). In rabbits, there was an injection-related increase in cardiovascular malformations at exposures below clinical exposure at the human daily dose (90 mg). However, no treatment-associated external or skeletal fetal malformations were observed. In rats and rabbits, there was a dose-dependent increase in postimplantation loss at exposures greater than or equal to 1.5 times human exposure (see Contraindications and Use in Pregnancy and Lactation).

Etoricoxib is excreted in the milk of lactating rats at concentrations approximately twice as high as plasma concentrations. A decrease in body weight has been observed in infants whose mothers were administered etoricoxib during lactation.

Clinical Studies

Efficacy

In patients with osteoarthritis (OA), etoricoxib at a dose of 60 mg once daily provided significant pain relief and improved patients’ assessment of their condition. These positive effects were observed on the second day of therapy and persisted for 52 weeks. Studies using etoricoxib at a dose of 30 mg once daily demonstrated efficacy superior to placebo over a 12-week treatment period (using the same estimates as in the above studies). In the dose-matching study, etoricoxib at a dose of 60 mg demonstrated significantly greater improvement compared with the 30 mg dose on all 3 primary endpoints during the 6-week treatment period. The 30 mg dose has not been studied in hand OA.

In patients with rheumatoid arthritis (RA), etoricoxib doses of 60 and 90 mg once daily provided significant relief of pain, inflammation and increased mobility. In studies evaluating the 60 and 90 mg doses, these beneficial effects persisted over a 12-week treatment period. In a study evaluating a 60-mg dose versus a 90-mg dose, etoricoxib at 60 mg once daily and at 90 mg once daily was more effective than placebo. The 90 mg dose outperformed the 60 mg dose on patients’ overall pain scores (visual analog scale 0-100 mm), with a mean improvement of -2.71 mm (95% CI: -4.98; -0.45 mm).

In patients experiencing attacks of acute gouty arthritis, etoricoxib at a dose of 120 mg once daily over an eight-day treatment period relieved moderate to severe joint pain and inflammation to a degree comparable to using indomethacin at a dose of 50 mg 3 times daily. Pain relief was observed as early as 4 h after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at 90 mg once daily provided significant improvement in pain, inflammation, stiffness and spinal function. The clinical benefit of etoricoxib was observed as early as the second day after initiation of treatment and was sustained throughout the 52-week treatment period. In a second study evaluating a 60-mg dose compared with a 90-mg dose, etoricoxib at 60 mg daily and 90 mg daily demonstrated similar efficacy compared with naproxen at a dose of 1,000 mg daily. Among patients who responded inadequately to the 60 mg daily dose for 6 weeks, increasing the dose to 90 mg daily improved spinal pain intensity scores (0-100 mm on a visual analog scale) compared with continuing to take 60 mg daily, with an average improvement of -2.70 mm (95% CI: -4.88; -0.52 mm).

In a clinical study evaluating postoperative pain in dental interventions, etoricoxib at a dose of 90 mg was administered once daily for three days. In patients with moderate pain at baseline, etoricoxib in a 90-mg dose demonstrated an analgesic effect similar to that of ibuprofen in a 600-mg dose (16.11 vs. 16.39 p=0.722), and greater than the combination of paracetamol + codeine 600/60 mg (11, p<0.001) and placebo (6.84, p<0.001) on the index of total pain relief during the first 6 h (TOPARE). The proportion of patients reporting use of analgesic drugs within the first 24 h after administration was 40.8% for etoricoxib at 90 mg, 25.5% for ibuprofen at 600 mg every 6 h, and 46.7% for the combination of paracetamol + codeine 600/60 mg every 6 h, compared with 76.2% for placebo. In this study, the median onset of action (perceived pain relief) of etoricoxib at a dose of 90 mg was 28 minutes after administration.

Safety

The Multinational Long-Term Arthritis Treatment Program with etoricoxib and diclofenac (MEDAL). The MEDAL program is a prospectively designed program to evaluate safety outcomes in terms of CCC interventions, including pooled data from three randomized double-blind active comparative controlled trials – MEDAL, EDGE II and EDGE.

The MEDAL study, a study whose duration was defined by achievement of a CCC endpoint, enrolled 17,804 patients with OA and 5,700 patients with RA who received etoricoxib at a dose of 60 (OA) or 90 mg (OA and RA) or diclofenac at a dose of 150 mg daily for a mean period of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse reactions and discontinuation of the drug due to any adverse reactions 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 daily (1.5 times the dose recommended for OA) or diclofenac at a dose of 150 mg daily for a mean period of 9.1 months (maximum 16.6 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 a mean period 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 a mean period of 17.9 months (maximum 42.3 months, median 16.3 months), with about 12800 patients treated for more than 24 months. Patients enrolled in the program had a wide range of cardiovascular and gastrointestinal risk factors at baseline. Patients with a recent history of myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to inclusion were excluded. Studies allowed the use of gastroprotective agents and low-dose acetylsalicylic acid.

General safety. There was no significant difference in the incidence of cardiovascular thrombotic events between etoricoxib and diclofenac. Cardiorenal adverse reactions were observed more frequently with etoricoxib than with diclofenac, and this effect was dose-dependent (see specific results below). Gastrointestinal and hepatic adverse reactions were significantly more frequent with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as adverse reactions that were considered serious or resulted in discontinuation of the drug in the MEDAL study, were higher with etoricoxib than with diclofenac.

Safety with respect to CCC. The incidence of confirmed thrombotic cardiovascular serious adverse reactions (including cardiac, cerebrovascular, and peripheral vascular events) was comparable between etoricoxib and diclofenac; the data are summarized in Table 1. No statistically significant differences were found in the incidence of thrombotic events between etoricoxib and diclofenac in all analyzed subgroups, including patients with different baseline cardiovascular risk. When considered separately, the relative risks of confirmed thrombotic cardiovascular serious adverse reactions were similar with etoricoxib at a dose of 60 or 90 mg compared with diclofenac at a dose of 150 mg.

Table 1

Percentage of confirmed thrombotic cardiovascular events (pooled MEDAL program)

/p>

1 Events per 100 patient-years.

2 n is the total number of patients included in the “per protocol” population.

3 By-protocol – all events on therapy or within 14 days of discontinuation (excludes patients who took <75% of study drugs or who took non-study NSAIDs >10% of the time).

4 On assigned treatment, all confirmed events until the end of the study (including patients potentially subjected to a non-study intervention after discontinuation of study medication). Total number of randomized patients, n=17412 for etoricoxib and 17289 for diclofenac.

Cardiovascular mortality was similar between the etoricoxib and diclofenac treatment groups, as was overall mortality.

Cardiorenal events. Approximately 50% of patients included in the MEDAL study had hypertension at baseline. During the study, the frequency of discontinuation of the drug due to adverse events related to hypertension was statistically significantly higher for etoricoxib than for diclofenac. The frequency of adverse events related to congestive heart failure (discontinuation and serious events) was similar for etoricoxib in the 60 mg dose compared to diclofenac in the 150 mg dose, but was higher for etoricoxib in the 90 mg dose compared to diclofenac in the 150 mg dose (statistically significant for etoricoxib 90 mg compared to diclofenac 150 mg in the MEDAL OA cohort). The frequency of confirmed adverse events of congestive heart failure (serious events that led to hospitalization or emergency department visits) was slightly higher with etoricoxib compared to diclofenac in the 150 mg dose, and this effect was dose-dependent. The frequency of discontinuation of drugs due to adverse reactions associated with edema was higher with etoricoxib compared with diclofenac at a dose of 150 mg, and this effect was dose-dependent (statistically significant for etoricoxib 90 mg, but not for etoricoxib 60 mg).

The cardiorenal results in the EDGE and EDGE II trials were consistent with those described in the MEDAL trial. In individual MEDAL studies using etoricoxib (60 or 90 mg), the absolute discontinuation rate in either group was up to 2.6% for hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, with a higher discontinuation rate observed with etoricoxib at the 90 mg dose than with etoricoxib at the 60 mg dose.

Gastrointestinal tolerability in the MEDAL program. Significantly lower rates of discontinuation due to any (e.g., dyspepsia, abdominal pain, ulcers) gastrointestinal side effect were observed with etoricoxib compared to diclofenac in each of the three MEDAL studies. The rates of drug discontinuation due to GI adverse reactions per 100 patient-years over the entire study period were 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.

Gastrointestinal safety in the MEDAL program. In general, upper GI reactions were defined as perforations, ulcers and bleeding. Upper GI reactions considered a complication included perforations, obstructions, and complicated bleeding; reactions that were not considered a complication included uncomplicated bleeding and uncomplicated ulcers. A significantly lower incidence of general upper gastrointestinal reactions was observed with etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and diclofenac in the incidence of complicated reactions. There was no significant difference between etoricoxib and diclofenac for upper gastrointestinal bleeding (complicated and uncomplicated, combined). The advantage of etoricoxib over diclofenac for the upper gastrointestinal tract was not statistically significant in patients who simultaneously took low-dose acetylsalicylic acid (about 33% of patients).

A per 100 patient-years, confirmed complicated and uncomplicated upper GI reactions (perforations, ulcers, and bleeding) were 0.67 (95% CI: 0.57; 0.77) for etoricoxib and 0.97 (95% CI: 0.85; 1.1) for diclofenac, giving a risk ratio of 0.69 (95% CI: 0.57; 0.83).

The evaluation of the incidence of confirmed upper GI events in older patients showed that the greatest reduction was seen in patients aged ≥75 years, 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 GI reactions (small or large bowel perforation, obstruction, or bleeding) was not significantly different between etoricoxib and diclofenac.

Safety with respect to the development of hepatitis in the MEDAL program. The use of etoricoxib was associated with a statistically significantly lower rate of discontinuation due to adverse reactions related to hepatic failure than the use of diclofenac. In the combined MEDAL program, 0.3% of patients taking etoricoxib and 2.7% of patients taking diclofenac discontinued due to adverse events related to hepatic impairment. The rate per 100 patient-years was 0.22 for etoricoxib and 1.84 for diclofenac (p<0.001 for etoricoxib and diclofenac). However, most of the hepatic side effects in the MEDAL program were not serious.

Additional data on thrombotic cardiovascular safety. In clinical trials excluding the MEDAL study, approximately 3,100 patients took etoricoxib at doses ≥60 mg daily for 12 weeks or longer. There were no notable differences in the incidence of confirmed serious thrombotic cardiovascular events between patients receiving etoricoxib, placebo, or nonnaproxen NSAIDs. However, the incidence of these events was higher in patients receiving etoricoxib compared with patients receiving naproxen 500 mg twice daily. 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 reduce systemic (and therefore possibly endothelial) prostacyclin formation without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional data on GI safety. In two 12-week double-blind endoscopic studies, the cumulative incidence of gastroduodenal ulceration was significantly lower in patients taking etoricoxib at a dose of 120 mg once daily than in patients taking naproxen at 500 mg twice daily or ibuprofen at 800 mg three times daily. Etoricoxib had a higher incidence of ulcers compared with placebo.

A study of renal function in the elderly. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg/day), naproxen (500 mg/day) and placebo on urinary sodium excretion, BP and other renal function parameters in patients aged 60 to 85 years following a sodium diet of 200 mEq/day. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion during 2 weeks of treatment. All active comparators showed an increase in BP compared with placebo, but etoricoxib use was associated with a statistically significant increase on day 14 compared with celecoxib and naproxen (mean change in BP compared with baseline: etoricoxib, 7.7 mmHg; celecoxib, 2.4; naproxen, 3.6 mmHg).

Indications

Symptomatic relief of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and pain and signs of inflammation associated with acute gouty arthritis in adults and adolescents 16 years and older.

The short-term treatment of moderate pain associated with dental surgery in adults and adolescents 16 years of age and older.

Active ingredient

Composition

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

Core:

Active substance:

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

Associates: microcrystalline cellulose, type KG-802, microcrystalline cellulose, type PH-200 LM, calcium hydrophosphate, croscarmellose sodium, sodium stearyl fumarate, colloidal silicon dioxide

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

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

How to take, the dosage

Orally, regardless of the time of meals, with a small amount of water.

The drug Etoriax should be used in the lowest effective dose for the shortest possible course.

Osteoarthritis

The recommended dose is 30 mg once daily or 60 mg once daily.

Rheumatoid arthritis and ankylosing spondylitis

The recommended dose is 60 mg or 90 mg once daily. The minimum effective daily dose is 60 mg once daily. In some patients, taking 90 mg once daily may increase the therapeutic effect.

In conditions accompanied by acute pain, Etoriax should be used only in the acute symptomatic period.

Acute gouty arthritis

The recommended dose in the acute period is 120 mg once daily. The duration of use of the drug in a dose of 120 mg is not more than 8 days.

Acute pain after dental surgery

The recommended dose is 90 mg once daily. In the treatment of acute pain after dental surgery, Etoriax should be used only in the acute period for not more than 3 days.

Doses higher than those recommended for each indication either have no additional efficacy or have not been studied. Thus:

– daily dose in osteoarthritis should not exceed 60 mg;

– daily dose in rheumatoid arthritis should not exceed 90 mg;

– daily dose in ankylosing spondylitis should not exceed 90 mg;

– daily dose in acute gouty arthritis should not exceed 120 mg; for a period not to exceed 8 days;

– daily dose for pain relief after dental surgery should not exceed 90 mg; for a period not exceeding 3 days.

Special patient groups

Elderly patients

Dose adjustment in elderly patients is not necessary. As with other drugs in elderly patients, caution should be exercised when using Etoriax (see “Cautionary Note”).

Liver function impairment

Regardless of the indication, patients with mild liver dysfunction (Child-Pugh score 5-6) should not exceed a dose of 60 mg once daily; patients with moderate liver dysfunction (Child-Pugh score 7-9) should not exceed 30 mg once daily.

Caution is recommended when using etoricoxib in patients with moderate hepatic impairment because clinical experience with etoricoxib in this group of patients is limited. Due to the lack of clinical experience with etoricoxib in patients with severe hepatic impairment (≥ 10 points on the Child-Pugh score), etoricoxib is contraindicated for this group of patients (see section “Pharmacological properties”, subsection “Pharmacokinetics” as well as sections “Contraindications” and “Cautions”).

Renal dysfunction

Dose adjustment in patients with CK ≥ 30 ml/min is not required (see section “Pharmacological properties”, subsection “Pharmacokinetics”). The use of etoricoxib in patients with CKR < 30 ml/min is contraindicated (see sections “Contraindications” and “Special Precautions”).

Children

Etoricoxib is contraindicated for use in children and adolescents younger than 16 years (see Contraindications).

Interaction

Pharmacodynamic interaction

Anticoagulants for oral administration (warfarin)

In patients receiving warfarin, administration of etoricoxib at a dose of 120 mg daily was accompanied by an approximately 13% increase in the international normalized ratio (MHO) prothrombin time. In patients receiving oral anticoagulants, prothrombin time and MHO should be monitored at the start of treatment or when treatment with etoricoxib is changed, especially in the first few days.

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

NSAIDs may weaken the effects of diuretics and other hypotensive drugs. In some patients with impaired renal function (e.g., patients with dehydration or elderly patients with impaired renal function) concomitant use of ACE inhibitor or ARA II and COX-inhibiting drugs may lead to additional impairment of renal function including possible development of acute renal failure which is usually reversible. It should be remembered about the possibility of such interactions in patients who take etoricoxib simultaneously with ACE inhibitors or with ARA II. Such a combination should be administered with caution, especially in elderly patients. At the beginning of combined treatment, as well as at certain intervals thereafter, fluid replacement and renal function monitoring should be performed.

Acetylsalicylic acid

In a study involving healthy volunteers, etoricoxib at a dose of 120 mg daily at equilibrium did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid in low doses designed for prevention of CC diseases. However, concomitant administration of low doses of acetylsalicylic acid and etoricoxib may result in an increased incidence of GI ulcers and other complications compared with etoricoxib administration alone. Concomitant use of etoricoxib with acetylsalicylic acid in doses higher than those recommended for prevention of CC complications, as well as with other NSAIDs is not recommended (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as section “Cautions”).

Cyclosporine and tacrolimus

The interaction of etoricoxib with these drugs has not been studied, but concomitant use of NSAIDs with cyclosporine and tacrolimus may increase the nephrotoxic effect of these drugs. When concomitant use of etoricoxib with any of these drugs, renal function should be monitored.

Pharmacokinetic interaction

Influence of etoricoxib on other drugs

Lithium

NSAIDs decrease renal excretion of lithium and, therefore, increase plasma lithium concentrations. If necessary, frequent monitoring of lithium concentration in blood is carried out and the lithium dose is adjusted during concomitant use with NSAIDs, as well as when NSAIDs are withdrawn.

Metotrexate

Two studies examined the effects of etoricoxib at doses of 60 mg, 90 mg, and 120 mg once daily for seven days in patients receiving once-weekly methotrexate at doses ranging from 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 at a dose of 120 mg had no effect on the pharmacokinetic parameters of methotrexate. In another study, plasma concentrations of methotrexate were increased by 28% and renal clearance of methotrexate was decreased by 13%. When concomitant use of etoricoxib and methotrexate should be monitored for possible toxic effects of methotrexate.

Contraceptives for oral administration

Taking etoricoxib for 21 days at a dose of 60 mg with oral contraceptives containing 35 µg ethinylestradiol (EE) and 0.5 mg to 1 mg of norethindrone increases the AUC0-24h for EE by 37%. Taking etoricoxib at a dose of 120 mg with the above oral contraceptives (simultaneously or 12 hours apart) increases the equilibrium AUC0-24h for EE by 50-60%. This increase in AE concentration should be taken into account when selecting an appropriate oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increased incidence of adverse events associated with oral contraceptive use (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT)

The use of etoricoxib at a dose of 120 mg concomitantly with hormone replacement therapy containing conjugated estrogens at a dose of 0.625 mg for 28 days increased the mean equilibrium AUC0-24h of unconjugated estrone (41%), equiline (76%), and 17-β-estradiol (22%). The effects of the doses of etoricoxib 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 less than twice as much as monotherapy with a drug containing conjugated estrogens when the latter dose was increased from 0.625 mg to 1.25 mg. The clinical significance of such increases is unknown. The use of a combination of etoricoxib and a drug containing higher doses of conjugated estrogens has not been studied. Elevated estrogen concentrations should be considered when choosing a hormonal drug for use in postmenopause when concomitantly administered with etoricoxib because increased estrogen exposure may increase the risk of OHF-related adverse events.

Prednisone/prednisolone

In drug interaction studies, etoricoxib had no 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 equilibrium or effect on digoxin renal excretion. There was an increase in Cmax of digoxin (approximately 33%). This increase is generally not significant in most patients. However, concomitant use of etoricoxib and digoxin should be monitored in patients at high risk of digoxin toxicity.

The effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase (specifically SULT1E1) and may increase serum EE concentrations. Due to the fact that currently insufficient data on the effects of various sulfotransferases have been obtained and their clinical relevance for the use of many drugs is still under study, it is advisable to prescribe etoricoxib with caution simultaneously with other drugs metabolized mainly by human sulfotransferases (for example, salbutamol for oral administration and minoxidil).

The effect of etoricoxib on drugs metabolized by cytochrome system isoenzymes

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

Effects of other drugs on the pharmacokinetics of etoricoxib

The main metabolic pathway of etoricoxib depends on enzymes of the cytochrome system. The CYP3A4 isoenzyme contributes to the metabolism of etoricoxib under in vivo conditions. Studies in vitro suggest that the CYP2D6, CYP2C9, CYP1A2 and CYP2C19 isoenzymes may also catalyze the main metabolic pathway, but their quantitative characteristics under in vivo conditions have not been studied.

Ketoconazole

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

Voriconazole and myconazole

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

Rifampicin

The concomitant use of etoricoxib and rifampicin (a potent inducer of the cytochrome system) resulted in a 65% decrease in plasma etoricoxib concentrations. This interaction may be accompanied by relapse of symptoms when concomitant use of etoricoxib with rifampicin. These data may indicate the need to increase the dose; however, etoricoxib should not be used in doses that exceed those recommended for each indication (see section “Dosage and administration”), since the combined use of rifampicin and etoricoxib in such doses has not been studied.

Antacids

Antacids have no clinically significant effect on the pharmacokinetics of etoricoxib.

Special Instructions

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

– patients at increased risk of GI complications due to NSAIDs, elderly patients taking other NSAIDs, including acetylsalicylic acid, simultaneously, or patients with a history of GI disorders such as peptic ulcer disease and gastrointestinal bleeding;

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

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

– dehydration patients;

-patients with impaired renal function concurrently using ACE inhibitors, diuretics, angiotensin II receptor antagonists, especially elderly patients;

– patients with CK < 60 ml/min;

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

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

– anticoagulants (eg, warfarin);

– antiaggregants (eg, acetylsalicylic acid, clopidogrel);

– drugs metabolized by sulfotransferases.

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

Elderly patients

Dose adjustment in elderly patients is not required. As with other drugs in elderly patients, caution should be exercised when using Etriax.

Hepatic dysfunction

Regardless of the indication, patients with mild liver dysfunction (Child-Pugh score 5-6) should not exceed a dose of 60 mg once daily; patients with moderate liver dysfunction (Child-Pugh score 7-9) should not exceed 30 mg once daily.

Caution is recommended when using etoricoxib in patients with moderate hepatic impairment because clinical experience with etoricoxib in this group of patients is limited. Due to the lack of clinical experience of etoricoxib use in patients with severe liver dysfunction (≥ 10 points by Child-Pugh score) the drug etoricoxib is contraindicated for this group of patients.

Renal dysfunction

Dose adjustment in patients with CK ≥ 30 ml/min is not required. The use of etoricoxib in patients with CK < 30 ml/min is contraindicated.

Influence on the gastrointestinal tract

Cases of upper gastrointestinal complications (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients who received etoricoxib.

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

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

Influence on the cardiovascular system

The results of clinical studies suggest that the use of drugs from 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 CC diseases when taking COX-2 selective inhibitors may increase with increasing the dose and duration of use, it is necessary to choose the shortest possible duration of use and the lowest effective daily dose. The patient’s need for symptomatic treatment and response to therapy should be periodically evaluated, especially for patients with osteoarthritis (see section “Pharmacological properties”, subsection “Pharmacodynamics” as well as sections “Contraindications”, “Administration and doses” and “Side effects”).

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

Selective COX-2 inhibitors are not a substitute for acetylsalicylic acid in the prevention of CC diseases because they do not affect platelets. Therefore, the use of antiplatelet agents should not be discontinued (see section “Pharmacological properties”, subsection “Pharmacodynamics” and section “Interaction with other medicinal products”).

Influence on renal 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 decreased prostaglandin formation and decreased renal blood flow, and thereby 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 renal function should be monitored.

Fluid retention, edema, and arterial hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension were observed in patients using etoricoxib. The use of all NSAIDs, including etoricoxib, may be associated with the occurrence or recurrence of chronic heart failure. Information about the dose-dependent effect of etoricoxib is given in section “Pharmacological properties”, subsection “Pharmacodynamics”. Caution should be exercised when prescribing etoricoxib in patients with a history of heart failure, left ventricular dysfunction or arterial hypertension, as well as in patients with pre-existing edema due to any other reason. If there are clinical signs of worsening in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

The use of etoricoxib, especially in high doses, may be associated with more frequent and severe arterial hypertension than with some other NSAIDs and COX-2 selective inhibitors. During treatment with etoricoxib, special attention should be paid to BP 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 BP, alternative treatment should be considered.

Influence on liver function

In clinical trials 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 ACT activity (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 parameters should be monitored.

In case of persistent liver function abnormalities (three times the upper limit of normal), etoricoxib should be discontinued.

General instructions

If the patient experiences a deterioration of any of the organ systems listed above during treatment, appropriate action should be taken and consideration should be given to discontinuing etoricoxib. Appropriate medical monitoring is necessary when using etoricoxib in elderly patients and in patients with impaired renal, hepatic or cardiac function.

Treatment with etoricoxib should be initiated with caution in patients with dehydration. Rehydration is recommended before starting etoricoxib administration.

During post-marketing surveillance during the use of NSAIDs and some selective COX-2 inhibitors, serious skin reactions were very rarely reported. Some of them (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) were fatal (see section “Adverse effects”). The risk of 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 section “Adverse effects”). The use of some selective COX-2 inhibitors was accompanied by an increased risk of skin reactions in patients with a history of any drug allergy. 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 “Interaction with other medicinal products”).

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

Patients who have experienced dizziness, drowsiness or weakness while using etoricoxib should refrain from driving or operating machinery.

Synopsis

Tablets 30 mg:

Round, slightly biconvex tablets, film-coated white or almost white, with bevel.

Breakage appearance: white or almost white rugged mass with white or almost white film coating.

Tablets 60 mg:

Round, biconvex, film-coated tablets, light brownish-yellow, beveled, with “60” engraved on one side.

Breakage appearance: white or almost white rough mass with light brownish-yellow film coating.

Tablets 90 mg:

Round, biconvex, film-coated tablets in pink, beveled, with “90” engraved on one side.

Breakage appearance: white or almost white rough mass with a pink film coating.

Tablets 120 mg:

Round, slightly biconvex, film-coated, brownish-red tablets, beveled, with a bevel on one side.

Breakage appearance: white or almost white rugged mass with brownish-red film coating .

Contraindications

Side effects

Safety Profile Review

The safety of etoricoxib was evaluated in 9,295 people in clinical trials, including 6,757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (about 600 patients with OA or RA were treated for one year or longer).

In clinical trials, the profile of adverse events was similar in patients with OA or RA who received etoricoxib for one year or longer.

In a clinical trial of acute gouty arthritis, patients took etoricoxib 120 mg once daily for eight days. The side effect profile in this study was broadly similar to that reported in the pooled studies of OA, RA, and chronic low back pain.

In the CCC safety evaluation program, which included pooled data from three active comparative controlled trials, 17412 patients with OA or RA took etoricoxib (60 or 90 mg) for about 18 months. For safety data and details of this program, see. “Pharmacology,” Clinical Studies.

In clinical trials involving 614 patients with acute postoperative toothache receiving etoricoxib (90 or 120 mg), the adverse event profile was generally similar to that reported in the pooled studies of OA, RA and chronic low back pain.

. Table 2 summarizes adverse reactions reported with a frequency greater than placebo in clinical trials in patients with OA, RA, chronic low back pain, or ankylosing spondylitis receiving etoricoxib at doses of 30, 60, or 90 mg for 12 weeks, in MEDAL studies over 3.5 years, in short-term acute pain studies over 7 days, or in post-registration follow-ups.

Table 2

1 Frequency Category: Defined for each adverse event term by the frequency reported in the clinical trial database: very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare(< 1/10000).

2 This adverse reaction was identified during post-registration follow-up. Its frequency was estimated based on the highest frequency observed in clinical trials pooled by indication and approved dose.

3 Hypersensitivity includes the terms allergy, drug allergy, drug hypersensitivity, drug hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction, and non-specific allergy.

4 Based on an analysis of data from long-term controlled placebo and active-controlled clinical trials, selective COX-2 inhibitors increased the risk of serious thrombotic arterial events, including myocardial infarction and stroke. According to current data, the absolute increase in the risk of such events is not higher than 1% per year (infrequent).

The following serious adverse reactions have been reported in connection with the use of NSAIDs that cannot be excluded for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Overdose

In clinical trials, administration of etoricoxib at a single dose of up to 500 mg or multiple doses of up to 150 mg/day over 21 days did not cause significant toxic effects. Acute overdose with etoricoxib has been reported, but in most cases adverse reactions have not been reported.

The most frequent adverse reactions were consistent with the safety profile of etoricoxib (e.g., GI disturbances, cardiorenal events).

In case of overdose, the usual supportive measures such as removal of unabsorbed drug from the GI tract, clinical observation and, if necessary, supportive therapy are appropriate. Etoricoxib is not excreted by hemodialysis; excretion of etoricoxib by peritoneal dialysis has not been studied.

Pregnancy use

Etoricoxib is contraindicated in pregnancy (see Contraindications). If a woman becomes pregnant during treatment, etoricoxib should be discontinued.

There are no clinical data on pregnant women exposed to etoricoxib. Animal studies have shown marked reproductive toxicity. The potential risk to women in pregnancy is unknown. Etoricoxib, like other drugs that inhibit PG synthesis, can cause uterine inertia and premature closure of the arterial ductus in the last trimester of pregnancy.

It is not known whether etoricoxib is excreted with milk in women. Etoricoxib is excreted in the milk of lactating rats. Women using etoricoxib should not breastfeed (see Contraindications).

The effect on fertility. The use of etoricoxib, like any other COX-2 inhibitor, is not recommended for women planning to become pregnant.

Similarities