Etoriax pills 60mg 14pcs

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

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

Film shell: Opadray 85F28751 II white* (polyvinyl alcohol, titanium dioxide (E 171), macrogol-3000, talc), iron oxide yellow (E 172) dye (for 60 mg dosage), iron oxide red (E 172) dye (for 90 mg and 120 mg dosages)

* Opadray 85F28751 II white is a ready-to-use dry mixture of polyvinyl alcohol, titanium dioxide (E 171), macrogol-3000 and talc.

Pharmacological action

Pharmacotherapy group:

nonsteroidal anti-inflammatory drugs

ATX Code:

M 01 AN 05

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 with a daily dose of up to 150 mg. The drug does not inhibit prostaglandin synthesis 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 identified. COX-2 is an isoenzyme that is induced by various pro-inflammatory 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 ductus arteriosus, regulation of kidney and central nervous system function (fever induction, pain sensation, cognitive function), and may also play a role in the healing of ulcers. COX-2 has been found in the tissues surrounding gastric ulcers in humans, but its significance for ulcer healing has not been established.

Efficiency

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

In patients with rheumatoid arthritis (RA), etoricoxib, when administered at a dose of 90 mg once a day, significantly reduced pain and inflammation and improved mobility. These beneficial effects persisted during the 12-week treatment period.

In patients with acute gouty arthritis, etoricoxib, when administered at a dose of 120 mg once a day for the entire eight-day treatment period, reduced moderate to severe joint pain and inflammation. The efficacy was comparable to that of Indometacin when administered at 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, when administered at a dose of 90 mg once a day, significantly reduced back pain, inflammation, rigidity, and improved functions. Clinical efficacy of etoricoxib was observed as early as the second day of treatment and was maintained throughout the entire 52-week treatment period.

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

Security

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

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

The MEDAL study was a study whose duration was determined by the achievement of endpoints (SS events), which included 17,804 patients with OA and 5,700 patients with RA who received etoricoxib at a dose of 60 mg (OA) or 90 mg (OA and RA) or diclofenac at a dose of 150 mg per day for an average of 20.3 months (maximum 42.5 months, median 21.3 months). In this study, only serious adverse events and cases of withdrawal from the study 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 7,111 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 4,086 patients with RA who received either 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 received treatment for an average of 17.9 months (maximum 42.3 months, median 16.3 months), and about 12,800 patients received treatment for more than 24 months. A wide range of SS and gastrointestinal risk factors were registered in patients enrolled in the MEDAL Program at the initial assessment. Patients with a recent myocardial infarction, as well as those with coronary artery bypass grafting or percutaneous coronary intervention for 6 months prior to inclusion in the study were excluded. Studies allowed the use of gastroprotectors and low-dose aspirin.

General security

There were no significant differences between etoricoxib and diclofenac in the frequency of thrombotic SS events. Cardiorenal adverse events were more frequently observed 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 with the appointment of diclofenac than with the appointment of etoricoxib. The incidence of adverse events in the EDGE and EDGE II trials, as well as adverse events considered serious or requiring discontinuation of treatment, in the MEDAL study was higher with etoricoxib than with diclofenac.

Results of the cardiovascular safety assessment

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

Table ” Frequency of confirmed SS thrombotic events (MEDAL Program)”

	Etoricoxib(N=16,819) 25,836 patient-years	Diclofenac(N=16483) 24766 patient-years	Comparison between treatment
	types Frequency 1 (95% CI)	Frequency 1 (95% CI)	Relative risk(95% CI)
Confirmed thrombotic SS 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
If the protocol requirements	are met 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
If the protocol requirements	are met 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 population of patients who met the protocol requirements. If the protocol requirements are met, all events that developed during the study therapy within 14 days after its discontinuation (excluding patients who received <75% of the study drug, and patients who took non – steroidal anti-inflammatory drugs (NSAIDs) >10% of the time) that were not included in the study. Depending on the prescribed treatment – all confirmed events that developed before the end of the study (including patients who may have been exposed to non – included interventions after discontinuation of the study drug). Total number of randomized patients: n=17,412 for etoricoxib and n=17,289 for diclofenac.

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

Cardiorenal phenomena

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

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

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

In individual MEDAL studies, the absolute dropout rate for either 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 chronic heart failure. Patients treated with 90 mg of etoricoxib had a higher dropout rate than patients treated with 60 mg of etoricoxib.

Results of evaluation of gastrointestinal tolerance in the MEDAL Program

In each of the three trials included in the MEDAL Program, the dropout rate for any clinical gastrointestinal adverse event (e. g., dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared to diclofenac. The rate of withdrawal from the study due to gastrointestinal adverse events per 100 patient-years over the entire study period was as follows: 3.23 for etoricoxib and 4.96 for diclofenac in the MEDAL study; 9.12 for etoricoxib and 12.28 for diclofenac in the EDGE study; and 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Results of the GIT safety assessment in the MEDAL Program

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

The frequency of confirmed complicated and uncomplicated clinical adverse events from the upper gastrointestinal tract per 100 patient-years (perforation, ulcers and bleeding) was 0.67 (95% CI 0.57 percent, to 0.77) for etoricoxib and 0.97 (95% CI of 0.85 to 1.10) for diclofenac, based on which the relative risk was 0.69 (95% CI of 0.57,0,83).

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

The incidence of confirmed lower gastrointestinal adverse events (perforation of the small or large intestine, obstruction or bleeding) did not significantly differ between the groups receiving etoricoxib and diclofenac.

Results of the liver safety assessment in the MEDAL Program

Etoricoxib was characterized by a statistically significantly lower rate of withdrawal from the study due to adverse liver events compared to diclofenac. In the combined MEDAL Program,0.3% of patients treated with etoricoxib and 2.7% of patients treated with 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 Most of the liver adverse events in the MEDAL Program were not serious.

Additional safety data related to thrombotic SS events

In clinical trials, with the exception of the MEDAL Program, approximately 3,100 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 SS thrombotic events in patients treated with etoricoxib ≥60 mg, placebo, or non-Naproxen-containing NSAIDs. However, compared to patients treated with Naproxen 500 mg twice daily, the incidence of these events was higher in patients treated with etoricoxib. The difference in antiplatelet activity between some NSAIDs that inhibit COX-1 and selective COX-2 inhibitors may have clinical significance in patients at risk of developing thromboembolic events. Selective COX-2 inhibitors inhibit the formation of systemic (and possibly endothelial) prostacyclin without affecting platelet-derived thromboxane. The clinical significance of these observations has not been established.

Additional information on gastrointestinal safety

In two double-blind endoscopic studies lasting 12 weeks, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients treated with etoricoxib at a dose of 120 mg 1 time per day than in patients treated with Naproxen at a dose of 500 mg 2 times a day or ibuprofen at a dose of 800 mg 3 times a day. The incidence of ulcers with etoricoxib was higher than with placebo.

Study of renal function in elderly patients

A randomized, double-blind, placebo-controlled study in parallel groups evaluated the effects of 15-day 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 parameters of renal function in patients aged 60 to 85 years who received a 200 meq/day sodium diet. Etoricoxib, celecoxib, and Naproxen had similar effects on renal sodium excretion after 2 weeks of treatment. All active comparison drugs resulted in an increase in systolic blood pressure relative to placebo, but etoricoxib therapy resulted in a statistically significant increase in systolic blood pressure on day 14 compared to celecoxib and naproxen (mean change for systolic blood pressure compared to baseline: etoricoxib-7.7 mm Hg, celecoxib-2.4 mm Hg, Naproxen-3.6 mm Hg).

Pharmacokinetics

Suction

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

When etoricoxib was administered at a dose of 120 mg during a meal (food with a high fat content), there was no clinically significant effect on the degree of absorption. The rate of absorption changed, which led to a decrease in Cmax by 36% and an increase in TCmax by 2 hours. These results are not considered clinically significant. In clinical trials, etoricoxib was used regardless of meal timing.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 mcg / ml. The volume of distribution (Vdss) at steady 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 pathway of metabolism is the formation of 6 ‘ – hydroxymethylethoricoxib, which is catalyzed by enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes etoricoxib metabolism in vivo. In vitro studies indicate that the isoenzymes CYP2D6, CYP2C9, CYP1A2, and CYP2C19 can also catalyze the main pathway of metabolism, but their quantitative effect in vivo has not been studied.

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

Deduction

In a single intravenous dose of 25 mg of labeled radioactive etoricoxib,70% of etoricoxib was excreted by the kidneys,20% – through the intestine, mainly in the form of metabolites. Less than 2% were found unchanged.

Elimination of etoricoxib occurs mainly through metabolism, followed by elimination by the kidneys.

Steady-state concentration is achieved with a daily intake of 120 mg of etoricoxib after 7 days with a cumulative coefficient of about 2, which corresponds to a half-life of about 22 hours. Plasma clearance after intravenous use of 25 mg is approximately 50 ml / min

. Pharmacokinetics in special groups of patients

Elderly patients

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

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 once a day was accompanied by an increase in AUC by 16% compared to healthy individuals taking the drug at the same dose.

In patients with moderate hepatic impairment (Child-Pugh score 7-9) who took etoricoxib at a dose of 60 mg every other day, the average AUC value was the same as in healthy individuals who took etoricoxib daily at the same dose. 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 points on the Child-Pugh scale) are not available.

Renal insufficiency

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

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

In a pharmacokinetic study (n=16) conducted in adolescents aged 12 to 17 years, the pharmacokinetics in adolescents with a body weight of 40 to 60 kg when taking etoricoxib at a dose of 60 mg once a day and in adolescents with a body weight of more than 60 kg when taking etoricoxib at a dose of 90 mg once a day were similar to the pharmacokinetics in adults when taking etoricoxib at a dose of 90 mg once a day. The safety and efficacy of etoricoxib in children has 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.

Use during pregnancy and lactation

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Toxic effects on the reproductive system have been observed in animal studies. The potential risk in women during pregnancy is unknown. The use of etoricoxib, as well as 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.

Breast-feeding period

In lactating rats, etoricoxib is excreted in milk. Studies confirming the release of etoricoxib in breast milk in women have not been conducted. Women taking etoricoxib should stop breastfeeding (see section “Contraindications”).

Fertility

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

Contraindications

• Hypersensitivity to any component of the drug.
• Peptic ulcer of the stomach and duodenum 12 in the acute stage, active gastrointestinal bleeding.
• Complete or incomplete combination of bronchial asthma, recurrent nasal and paranasal sinus polyposis, and intolerance to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (including in the anamnesis).
• Pregnancy, breast-feeding period.
• Severe hepatic impairment (serum albumin <25 g / l or >10 points on the Child-Pugh scale).
• Severe renal insufficiency (creatinine clearance < 30 ml / min).
• Children under 16 years of age.
• Inflammatory bowel diseases.
• Chronic heart failure (NYHA functional class II-IV).
• Uncontrolled arterial hypertension, in which blood pressure consistently exceeds 140/90 mm Hg.
• Confirmed coronary artery disease, peripheral artery 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 a high risk of complications from the gastrointestinal tract due to ingestion of NSAIDs, elderly patients simultaneously receiving other NSAIDs, including acetylsalicylic acid, or patients with diseases of the gastrointestinal tract in history, such as peptic ulcer disease or gastrointestinal bleeding.
• patients with a history of risk factors for cardiovascular complications such as dyslipidemia/hyperlipidemia, diabetes mellitus, hypertension, Smoking, heart failure, impaired left ventricular function, swelling, and fluid retention;
• patients with impaired liver function of mild severity (5-6 points on a scale child-Pugh) should not exceed 60 mg 1 time per day, patients with impaired liver function moderate (7-9 points on a scale child-Pugh) – 30 mg 1 time per day;
• patients with dehydration;
• patients with impaired renal function, at the same time using ACE inhibitors, diuretics, antagonists of receptors of angiotensin II, especially in elderly patients;
• patients with CC <60 ml/min;
• patients with previous significant decrease in renal function, with impaired renal function, decompensated heart failure or cirrhosis, are at risk with long-term use of NSAIDs.

Caution should be exercised when concomitant therapy with the following medications::

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

Side effects

The safety of etoricoxib was evaluated in clinical trials involving 9295 participants, including 6757 patients with OA, RA, chronic lower back pain, and ankylosing spondylitis (approximately 600 patients with OA or RA were treated for 1 year or longer).

In clinical trials, the adverse effect profile was similar in patients with OA or RA who had been taking etoricoxib for 1 year or longer.

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

In the Safety Assessment Program for the SS system, which included data from three active-controlled trials,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 at a dose of 90 mg or 120 mg, the adverse effect profile was generally similar to that in the combined studies of OA, RA, and chronic lower back pain.

The following adverse reactions were reported more frequently with etoricoxib than with placebo, in clinical trials involving patients with OA, RA, chronic lower back pain, or ankylosing spondylitis who took etoricoxib at a dose of 30 mg,60 mg, or 90 mg with an increase in the recommended dose for 12 weeks, in MEDAL studies lasting up to 3.5 years, in short-term acute pain studies, and in post-marketing use.

System / organ class	Undesirable event	Frequency 1
Infectious and parasitic diseases	alveolar ostitis	often
	gastroenteritis, upper respiratory tract infections, urinary tract	infections infrequently
Disorders of the blood and lymphatic system	anemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia	infrequently
Immune system disorders	hypersensitivity reactions 2,4	infrequently
	angioedema, anaphylactic / anaphylactoid reactions, including shock 2	infrequently
Metabolic and nutritional	disorders Edema / fluid retention	often
	decreased or increased appetite, weight gain	infrequently
Mental disorders	anxiety, depression, concentration disorders, hallucinations 2	infrequently
	confusion 2, anxiety 2	rarely
Nervous system disorders	dizziness, headache	often
	taste disorders, insomnia, paresthesia/hypesthesia, drowsiness	infrequently
Visual disturbances	blurred vision, conjunctivitis	infrequently
Hearing disorders and labyrinthine disorders	tinnitus, vertigo	infrequently
Cardiac disorders palpitation	sensation, arrhythmia 2	frequently
	atrial fibrillation, tachycardia 2, chronic heart failure, non-specific changes on the electrocardiogram (ECG), angina 2, myocardial infarction 5	infrequently
Vascular disorders	arterial hypertension	often
	“hot flashes”, cerebrovascular accident 5, transient ischemic attack, hypertensive crisis 2, vasculitis 2	infrequently
Respiratory, thoracic and mediastinal	disorders bronchospasm 2	often
	coughing, shortness of breath, and nosebleeds	infrequently
Violations of the digestive system	abdominal pain	, very often
	constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/discomfort in the epigastric region, nausea, vomiting, esophagitis, ulcers of the mucous membrane of the oral cavity	often,
	bloating, changes in motility, dryness of the mucous membrane of the oral cavity, gastro-duodenal ulcer, gastric ulcer, including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis 2	rarely
Liver and biliary tract	disorders increased activity of alanine aminotransferase (ALT), increased activity of aspartate aminotransferase (AST)	common
	hepatitis 2	rare
	liver failure 2, jaundice 2	rare 3
Skin and subcutaneous tissue disorders	ecchymosis	often
	facial swelling, pruritus, skin rash, erythema 2, urticaria 2	infrequently
	Stevens-Johnson syndrome 2, toxic epidermal necrolysis 2, fixed drug erythema 2	rarely 3

Interaction

Pharmacodynamic interaction

Oral anticoagulants (warfarin)

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

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

NSAIDs may weaken 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), the simultaneous use of an ACE inhibitor or ARA II and drugs that inhibit COX may lead to additional deterioration of renal function, including the possible development of acute renal failure, which is usually reversible. Patients taking etoricoxib concomitantly with ACE inhibitors or with ARA II should be aware of the possibility of such interactions. This combination should be used 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 monitoring of renal function should be considered.

Acetylsalicylic Acid

In a study involving 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 SS diseases. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulceration and other complications compared to etoricoxib alone. Concomitant use of etoricoxib with acetylsalicylic acid in doses exceeding those recommended for the prevention of SS complications, as well as with other NSAIDs, is not recommended (see the section “Pharmacological properties”, subsection “Pharmacodynamics”, and section “Special Instructions”).

Cyclosporine and tacrolimus

The interaction of etoricoxib with these drugs has not been studied, but the simultaneous use of NSAIDs with cyclosporine and tacrolimus may increase the nephrotoxic effect of these drugs. Renal function should be monitored when etoricoxib is co-administered with any of these medications.

Pharmacokinetic interaction

Effect of etoricoxib on other medications

Lithium

NSAIDs reduce the excretion of lithium by the kidneys and, consequently, increase the concentration of lithium in the blood plasma. If necessary, frequent monitoring of blood lithium concentrations is performed and the dose of lithium is adjusted during concomitant 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 7.5 mg to 20 mg methotrexate once weekly for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg had no effect on the plasma concentration and renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on the pharmacokinetic parameters of methotrexate. In another study, the concentration of methotrexate in plasma increased by 28%, and the renal clearance of methotrexate decreased by 13%. Concomitant use of etoricoxib and methotrexate should be monitored for possible toxic effects of methotrexate.

Oral contraceptives

Taking etoricoxib for 21 days at a dose of 60 mg with oral contraceptives containing 35 mcg of ethinyl estradiol (EE) and 0.5 mg to 1 mg of norethindrone increases the AUC_{of 0-24 hours} for EE by 37%. Taking etoricoxib at a dose of 120 mg with the above oral contraceptives (simultaneously or at 12-hour intervals) increases the steady-state AUC_{of 0-24 hours} for EE by 50-60%. This increase in EE concentration should be taken into account when selecting an 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 simultaneously with hormone replacement therapy containing conjugated estrogens at a dose of 0.625 mg for 28 days increases the average steady-state AUC_{of 0-24 hours} of unconjugated estrone (41%), equilin (76%) and 17-β-estradiol (22%). The effect of the recommended long-term doses of etoricoxib (30 mg,60 mg, and 90 mg) has not been studied. Etoricoxib at a dose of 120 mg changed the exposure (AUC_{0-24 h}) of these estrogenic components by less than half compared to monotherapy with a drug containing conjugated estrogens, with an increase in the dose of the latter 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. Increased estrogen concentrations should be taken into account when choosing a hormone preparation for use in the postmenopausal period when administered concomitantly with etoricoxib, since increased estrogen exposure may increase the risk of HRT-related adverse events.

Prednisone/Prednisone

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

Digoxin

When using etoricoxib at a dose of 120 mg once a day for 10 days in healthy volunteers, there was no change in the AUC_{of 0-24 hours} at steady state or an effect on the excretion of digoxin by the kidneys. An increase in the_cmax of digoxin (approximately 33%) was observed. Such an increase, as a rule, is not significant in most patients. However, patients at high risk of developing digoxin toxicity should be monitored when etoricoxib and digoxin are co-administered.

Effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase (in particular SULT1E1) and can increase serum EE concentrations. Due to the fact that there is currently insufficient data on the effect of various sulfotransferases, and their clinical significance for the use of many drugs is still being studied, it is advisable to prescribe etoricoxib with caution simultaneously with other drugs that are mainly metabolized by human sulfotransferases (for example, salbutamol for oral use and minoxidil).

Effect of etoricoxib on drugs metabolized by cytochrome isoenzymes

Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P 450 isoenzymes 1A2,2C9,2C19,2D6,2E1, and 3A4. In a study involving healthy volunteers, daily use of etoricoxib at a dose of 120 mg did not affect the activity of the CYP3A4 isoenzyme in the liver, according to the results of an erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism depends on enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes etoricoxib metabolism in vivo. In vitro studies suggest that the isoenzymes CYP2D6, CYP2C9, CYP1A2, and CYP2C19 can also catalyze the main pathway of metabolism, 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 a day for 11 days, it did not have a clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (an increase in AUC by 43%).

Voriconazole and miconazole

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

Rifampicin

Concomitant use of etoricoxib and rifampicin (a potent inducer of the cytochrome system) resulted in a 65% reduction in etoricoxib plasma concentrations. This interaction may be accompanied by a relapse of symptoms when etoricoxib is co-administered with rifampicin. These data may indicate the need to increase the dose, but etoricoxib should not be used at doses that exceed the recommended dose for each indication (see section “Dosage and use”), since 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.

How to take it, course of use and dosage

Inside, regardless of the meal time, with a small amount of water.

The drug Etoriax should be used in the minimum effective dose of the shortest possible course.

Osteoarthritis

The recommended dose is 30 mg once a day or 60 mg once a day.

Rheumatoid arthritis and ankylosing spondylitis

The recommended dose is 60 mg or 90 mg once a day. The minimum effective daily dose is 60 mg once a day. In some patients, taking a dose of 90 mg once a day may lead to an increased therapeutic effect.

For conditions accompanied by acute pain, Etoriax should only be used during the acute symptomatic period.

Acute gouty arthritis

The recommended dose in the acute period is 120 mg once a day. The duration of use of the drug in a dose of 120 mg is no more than 8 days.

Acute pain after dental surgery

The recommended dose is 90 mg once a day. In the treatment of acute pain after dental surgery, Etoriax should be used only in the acute period of no more than 3 days.

Doses that exceed the recommended dose for each indication either do not have additional efficacy or have not been studied. Thus:

· daily dose of osteoarthritis should not exceed 60 mg;

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

· daily value in ankylosing spondylitis should not exceed 90 mg;

· daily dosage in acute gouty arthritis should not exceed 120 mg; for a period of not more than 8 days;

· daily dose for relief of pain after dental operations should not exceed 90 mg; for a period of not more than 3 days.

Special patient groups

Elderly patients

No dose adjustment is required in elderly patients. As with other medications used in elderly patients, caution should be exercised when using Etoriax (see section “Special instructions”).

Impaired liver function

Regardless of the indication, patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) should not exceed the dose of 60 mg 1 time per day, patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale) – 30 mg 1 time per day.

Caution is recommended when using Etoriax in patients with moderate hepatic impairment, as the clinical experience of using 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 (≥ 10 points on the Child-Pugh scale), Etoriax is contraindicated in this group of patients (see the section “Pharmacological properties”, subsection “Pharmacokinetics”, as well as the sections” Contraindications “and”Special Instructions”).

Impaired renal function

No dose adjustment is required in patients with creatinine clearance ≥ 30 ml / min (see section “Pharmacological properties”, subsection “Pharmacokinetics”). Use of etoricoxib in patients with CC

Children

Etoricoxib is contraindicated for use in children and adolescents under 16 years of age (see section “Contraindications”).

Overdose

In clinical studies, taking etoricoxib at a single dose of up to 500 mg or multiple doses of up to 150 mg / day for 21 days did not cause significant toxic effects. Acute overdose with etoricoxib has been reported, but no adverse reactions have been reported in most cases.

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

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

Description

Tablets 30 mg:

Round, slightly biconvex tablets, film-coated in white or almost white color, with a chamfer.

View at the break: white or almost white rough mass with a film shell of white or almost white color.

Tablets 60 mg:

Round, biconvex tablets, covered with a film-coated light brownish-yellow color, with a chamfer, with the inscription “60” on one side.

View at the break: white or almost white rough mass with a film shell of light brownish-yellow color.

90 mg tablets:

Round, biconvex tablets, covered with a film-coated pink color, with a chamfer, with the inscription “90” on one side.

View at the break: white or almost white rough mass with a pink film shell.

120 mg tablets:

Round, slightly biconvex tablets, covered with a film-coated brownish-red color, with a chamfer, with a risk on one side.

View at the break: white or almost white rough mass with a film shell of brownish-red color.

Special instructions

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

– patients with a high risk of complications from the gastrointestinal tract due to ingestion of NSAIDs, elderly patients simultaneously receiving other NSAIDs, including acetylsalicylic acid, or patients with diseases of the gastrointestinal tract in history, such as peptic ulcer disease and gastrointestinal bleeding;

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

– patients with impaired liver function of mild severity (5-6 points on a scale child-Pugh) should not exceed 60 mg 1 time per day, patients with impaired liver function moderate (7-9 points on a scale child-Pugh) – 30 mg 1 time per day;

– patients with dehydration;

– patients with impaired renal function, at the same time using ACE inhibitors, diuretics, antagonists of receptors of angiotensin II, especially in elderly patients;

– patients with CC < 60 ml/min;

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

Caution should be exercised when concomitant therapy with the following medications::

– 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 medications used in elderly patients, caution should be exercised when using Etoriax.

Impaired liver function

Regardless of the indication, patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) should not exceed the dose of 60 mg 1 time per day, patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale) – 30 mg 1 time per day.

Caution is recommended when using Etoriax in patients with moderate hepatic impairment, as the clinical experience of using 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 scale), Etoriax is contraindicated in this group of patients.

Impaired renal function

No dose adjustment is required in patients with creatinine clearance ≥ 30 ml / min. Use of etoricoxib in patients with CC

Effect on the gastrointestinal tract

Upper gastrointestinal complications (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients treated with etoricoxib.

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

There is an additional risk of gastrointestinal adverse reactions (gastrointestinal ulcers or other gastrointestinal complications) when etoricoxib and acetylsalicylic acid are co-administered (even at 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 NSAIDs in combination with acetylsalicylic acid (see section 4.4).section “Pharmacological properties”, subsection “Pharmacodynamics”).

Impact on the cardiovascular system

The results of clinical studies indicate that the use of drugs of 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 SS 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 assess the patient’s need for symptomatic treatment and response to therapy, especially for patients with osteoarthritis (see the section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as the sections “Contraindications”, “Dosage and use” and “Side effects”).

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

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

Effects on kidney function

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. In the presence of conditions that negatively 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 exists for 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, patients taking etoricoxib experienced fluid retention, edema, and hypertension. The use of all NSAIDs, including etoricoxib, may be associated with the occurrence or recurrence of chronic heart failure. For information on the dose-dependent effect of etoricoxib, see the section “Pharmacological properties”, 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 that has occurred for any other reason. If there are clinical signs of deterioration in these 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 certain 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.

Effects 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 showed an increase in ALT and/or ACT activity (approximately three or more times relative to the upper limit of normal).

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

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

General instructions

If the patient experiences a 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, liver or heart function, appropriate medical supervision is necessary.

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

Serious skin reactions have been reported very rarely during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors. Some of them (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) were fatal (see the 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 treated with etoricoxib (see section “Side effects”). The use of some selective COX-2 inhibitors was associated with an increased risk of skin reactions in patients with a history of 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 etoricoxib is co-administered with warfarin or other oral anticoagulants (see section “Interactions 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 are planning pregnancy (see the section “Pharmacological properties”, subsection “Pharmacodynamics” and the section “Use during pregnancy and lactation”).

Patients who have experienced dizziness, drowsiness or weakness during the use of etoricoxib should refrain from driving vehicles and working with mechanisms.

Form of production

Film-coated tablets,30 mg,60 mg,90 mg,120 mg.

7 or 10 tablets in a blister made of a combined OPA/Al / PVC material-aluminum foil.

1,2,4,8 or 12 blisters of 7 tablets or 1,3,6 or 10 blisters of 10 tablets are placed in a cardboard pack together with the instructions for use.

Storage conditions

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

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Etoricoxib

Conditions of release from pharmacies

By prescription

Dosage form

Tablets