Etorelex, 90 mg 28 pcs.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drugs (NSAIDs).

TATX code: M01AN05

Pharmacological properties

Pharmacodynamics

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

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase, COX-1 and COX-2, have been isolated. COX-2 is an isoenzyme that is induced by various proinflammatory mediators and is considered the main enzyme responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is involved in the processes of ovulation, implantation and closure of the arterial duct, regulation of renal and CNS function (induction of fever, sensation of pain, cognitive function), and may also play a role in the process of ulcer healing. COX-2 has been detected in the tissues surrounding gastric ulcers in humans, but its importance in ulcer healing has not been established.

Efficacy

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

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

In patients with acute gouty arthritis, etoricoxib, administered at a dose of 120 mg once daily for the entire treatment period of 8 days, reduced moderate to severe joint pain and inflammation. The efficacy was comparable to that of indomethacin when used in a dose of 50 mg 3 times/day. Decrease in pain was noted as early as 4 hours after the start of treatment.

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

In a clinical study of pain after dental surgery, etoricoxib at a dose of 90 mg was administered once daily for 3 days. In a subgroup of patients with moderate pain (at baseline assessment), etoricoxib had the same analgesic effect as ibuprofen at a dose of 90 mg (16.11 vs. 16.39 P=0.722), and was superior to the paracetamol/codeine combination at a dose of 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001) according to the overall pain reduction score, within the first 6 h (TOPAR6). The proportion of patients who required rapid-acting pain medication within the first 24 h after taking the study drugs was 40.8% with etoricoxib at 90 mg, 25.5% with ibuprofen at 600 mg every 6 h, and 46.7% with the paracetamol/codein combination at 600 mg/60 mg every 6 h, compared with 76.2% in the placebo group. In this study, the median onset of action (perceived pain reduction) with etoricoxib at a dose of 90 mg was 28 minutes after administration.

Pharmacokinetics

Absorption

Etoricoxib is rapidly absorbed when taken orally. Absolute bioavailability when taken orally is about 100%. After the drug is taken by adults on an empty stomach in a dose of 120 mg once a day the maximum concentration (Cmax) is 3.6 mcg/ml, time to reach Cmax – 1 hour after intake. Geometric mean AUC0-24h is 37.8 µg×h/ml. Pharmacokinetics of etoricoxib within therapeutic doses is linear.

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

Distribution

Tericoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 µg/mL. The volume of distribution (Vdss) in the equilibrium state is about 120 l. Etoricoxib penetrates through the placental barrier and the blood-brain barrier.

Metabolism

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

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

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

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

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

Particular patient groups

Elderly

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

Per sex

The pharmacokinetics of etoricoxib are similar in men and women.

Hepatic impairment

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

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

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

Renal Impairment

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

Children

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

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

Indications

Symptomatic therapy of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis.

The short-term therapy of moderate acute pain after dental surgery.

Active ingredient

Composition

Active substance:

Etoricoxib 90.0 mg;

Auxiliary substances:

Core: E15 hypromellose, 3.00 mg; calcium hydrophosphate dihydrate, 90.00 mg; croscarmellose sodium, 6.00 mg; colloidal silicon dioxide, 1.50 mg; sodium stearyl fumarate, 4.50 mg; microcrystalline cellulose 200, 105.00 mg.

The film coating: hypromellose E15 – 7.20 mg; copovidone (Collidon VA64) – 0.96 mg; macrogol 6000 – 1.44 mg; talc – 0.48 mg; titanium dioxide – 1.92 mg.

How to take, the dosage

Overly, regardless of meals, with a small amount of water.

The drug Etorelexâ 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 a dose of 90 mg once daily may increase the therapeutic effect.

In conditions accompanied by acute pain, etoricoxib 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. When treating acute pain, etoricoxib should only be used for an acute period of not more than 3 days.

Doses in excess of those recommended for each indication either have no additional efficacy or have not been studied. Thus:

– the daily dose for osteoarthritis should not exceed 60 mg;

– the daily dose for rheumatoid arthritis should not exceed 90 mg;

– the daily dose for ankylosing spondylitis should not exceed 90 mg;

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

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

Special patient groups

Elderly

Dose adjustment in elderly patients is not required. As with the use of other drugs in elderly patients, caution should be exercised when using etoricoxib (see section “Cautionary Note”).

Patients with impaired liver function.

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

Cautious use of etoricoxib in patients with moderate hepatic impairment is recommended 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 hepatic impairment (≥10 points by Child-Pugh scale) the drug is contraindicated for this group of patients (see section “Pharmacological properties”, subsection “Pharmacokinetics”, as well as sections “Contraindications” and “Special indications”).

Patients with impaired renal function.

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

Children

Etoricoxib is contraindicated in children and adolescents under 16 years of age (see Contraindications).

Interaction

Pharmacodynamic interaction

Orderal anticoagulants (warfarin). In patients receiving warfarin, administration of etoricoxib at a dose of 120 mg/day was accompanied by an increase of approximately 13% in MHO and prothrombin time. In patients receiving warfarin or similar drugs, MHO values should be monitored during initiation of therapy or change of etoricoxib dosing regimen, especially in the first few days.

Diuretics, ACE inhibitors and angiotensin II antagonists. NSAIDs may weaken the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., in patients with dehydration or elderly patients with impaired renal function), the simultaneous use of an ACE inhibitor or angiotensin II antagonist and cyclooxygenase inhibitor drugs may lead to additional deterioration 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 angiotensin II antagonists. Such 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 should be performed and renal function monitoring should be considered.

Acetylsalicylic acid. In a study involving healthy volunteers, etoricoxib at a dose of 120 mg/day at equilibrium did not affect the antiplatelet activity of acetylsalicylic acid (81 mg 1 time/day). Etoricoxib can be used concomitantly with acetylsalicylic acid in low doses designed for the prevention of cardiovascular disease. However, concomitant administration of low doses of acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared with etoricoxib administration alone. Concomitant use of etoricoxib with acetylsalicylic acid in doses higher than those recommended for the prevention of cardiovascular complications, as well as with other NSAIDs is not recommended.

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 concomitant use of etoricoxib with any of these drugs.

Pharmacokinetic interaction

The effect of etoricoxib on other medicinal products

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 dose of lithium is adjusted during concomitant use with NSAIDs, as well as when NSAIDs are withdrawn.

Methotrexate. Two studies examined the effects of etoricoxib in doses of 60, 90, and 120 mg once daily for 7 days in patients receiving once weekly methotrexate at doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 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 etoricoxib and methotrexate are prescribed concomitantly, monitoring should be conducted for possible toxic effects of methotrexate.

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

Hormone replacement therapy (HRT). Administration of etoricoxib at a dose of 120 mg simultaneously with drugs for hormone replacement therapy containing conjugated estrogens at a dose of 0.625 mg for 28 days increased the average equilibrium AUC0-24h of unconjugated estrone (41%), equilin (76%) and 17-P-estradiol (22%). The effects of the doses of etoricoxib recommended for long-term use (30, 60, 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 twofold compared to monotherapy with a drug containing conjugated estrogens when the dose of the latter was increased from 0.625 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 considered when choosing a hormone for use in the postmenopause when concomitantly prescribed with etoricoxib because increased estrogen exposure may increase the risk of adverse events associated with MHT.

Prednisone/prednisolone. In drug interaction studies, etoricoxib had no clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. When administering etoricoxib at a dose of 120 mg once daily for 10 days in healthy volunteers there was no change in equilibrium AUC0-24h or influence on excretion of digoxin by kidneys. There was an increase in digoxin Cmax (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 can increase serum EE concentrations. Due to the fact that there are currently insufficient data on the effects of various sulfotransferases and their clinical relevance for many drugs is still being studied, it is advisable to prescribe etoricoxib with caution simultaneously with other drugs that are metabolized primarily by human sulfotransferases (e.g., oral salbutamol and minoxidil).

The effect of etoricoxib on drugs metabolized by cytochrome system isoenzymes. Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. In a study 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.

The effect of other drugs on the pharmacokinetics of etoricoxib

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

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4 isoenzyme. When ketoconazole was administered in healthy volunteers in dose of 400 mg once per day for 11 days it had no clinically significant effect on pharmacokinetics of one dose of etoricoxib 60 mg (increase AUC by 43%).

Voriconazole and miconazole. Concomitant administration 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. Concomitant administration of etoricoxib and rifampicin (a potent inducer of the cytochrome system) resulted in a 65% decrease in plasma concentration of etoricoxib. 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 higher than those recommended for each indication, since the combined use of rifampicin and etoricoxib at such doses has not been studied.

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

Special Instructions

Impact on the gastrointestinal tract

There have been cases of upper gastrointestinal complications (perforations, ulcers or bleeding), sometimes with fatal outcome, in patients who received etoricoxib. It is recommended to exercise caution when treating patients with a high risk of GI complications when using NSAIDs, particularly in the elderly, patients who simultaneously use other NSAIDs, including acetylsalicylic acid, as well as in patients with such GI diseases in the history as ulceration or gastrointestinal bleeding.

There is an additional risk of adverse gastrointestinal reactions (gastrointestinal ulcers or other gastrointestinal complications) when etoricoxib and acetylsalicylic acid are used concomitantly (even at low doses). In long-term clinical trials, no significant differences were observed with respect to GI 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”).

Impact on the cardiovascular system

The results of clinical studies suggest 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 cardiovascular events with selective COX-2 inhibitors may increase with increasing dose and duration of use, the shortest possible duration of use and the lowest effective daily dose should be chosen. 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 cardiovascular complications (such as arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) should only be prescribed etoricoxib after a thorough benefit-risk assessment (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

The selective COX-2 inhibitors are not a substitute for acetylsalicylic acid in the prevention of cardiovascular disease because they have no effect on platelets. Therefore, the use of antiplatelet agents should not be discontinued (see section “Pharmacological properties”, subsection “Pharmacodynamics”, and section “Interaction with other medicinal products”).

Impact on renal function

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. In the presence of conditions that adversely affect renal perfusion, administration of etoricoxib may cause decreased formation of prostaglandins 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 prostaglandin synthesis inhibiting drugs, fluid retention, edema and arterial hypertension have been 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 deterioration 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, 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.

In clinical studies lasting up to one year, approximately 1% of patients treated with etoricoxib at doses of 30 mg, 60 mg, and 90 mg per day experienced increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) activity (approximately 3 or more times the upper limit of normal).

The condition of all patients with symptoms and/or signs of liver dysfunction, as well as patients with abnormal liver function parameters should be monitored. Etoricoxib should be discontinued if persistent abnormal liver function is detected (three times the upper limit of normal).

General Instructions

If a patient experiences deterioration in 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.

With caution, treatment with etoricoxib should be initiated in patients who are dehydrated. Rehydration is recommended before starting etoricoxib.

During postmarketing surveillance, serious skin reactions have very rarely been reported with NSAIDs and some selective COX-2 inhibitors. Some of them (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) were fatal. The risk of developing such reactions is highest at the beginning of therapy, in most cases during the first month of treatment. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported in patients receiving etoricoxib. 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 etoricoxib is used 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, effects on fertility”).

Influence on driving, operating machinery

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

Synopsis

Contraindications

– Hypersensitivity to any component of the drug;

– Acute gastric and duodenal ulcer, active gastrointestinal bleeding;

– Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and sinuses, and intolerance to acetylsalicylic acid or other NSAIDs (including a history of drug abuse).history).

– Pregnancy, period of breastfeeding.

– Severe liver function impairment (serum albumin <25 g/l or ≥10 points on the Child-Pugh scale);

– Severe renal impairment (creatinine clearance less than 30 ml/min);

– Childhood under 16 years of age;

– Inflammatory bowel disease;

– Chronic heart failure (NYHA functional class II-IV);

– Uncontrolled arterial hypertension with persistent BP greater than 140/90 mm Hg.Hg.

– Confirmed coronary heart disease, peripheral arterial disease, and/or cerebrovascular disease;

– Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

– Confirmed hyperkalemia;

– Progressive renal disease.

Caution

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

– patients with an increased risk of gastrointestinal complications due to NSAIDs; the elderly, concomitantly taking other NSAIDs, including. Patients with a history of GI disorders, such as peptic ulcer disease or bleeding;

Patients with a history of GI disorders such as peptic ulcer disease or bleeding 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 (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;

Patients with dehydration;

Patients with impaired renal function concomitantly using ACE inhibitors, angiotensin II diuretics, especially the elderly;

Patients with creatinine clearance <60 ml/min;

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– Patients with a previous significant decrease in renal function, impaired renal function, decompensated heart failure, or cirrhosis of the liver who are at risk for long-term use of NSAIDs.

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

– anticoagulants (e.g., warfarin);

– antiaggregants (e.g., acetylsalicylic acid, clopidogrel);

– drugs metabolized by sulfotransferases.

Side effects

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

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

In a clinical trial 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 low back pain studies.

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

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

. The following adverse reactions were reported with greater frequency with the drug than with placebo in clinical trials involving patients with OA, RA, chronic low back pain or ankylosing spondylitis who were taking etoricoxib at doses of 30 mg 60 mg or 90 mg with dose escalation to the recommended dose within 12 weeks, in MEDAL Program trials lasting up to 3.5 years, in short-term acute pain studies, and in postmarketing use (definition of frequency recorded in the clinical trial database: very frequently (≥1/10), frequently (≥1/100 to < 1/10), infrequently (≥1/1000 to < 1/100), rarely (≥1/10 000 to < 1/1000), very rarely (< 1/10 000):

Infectious and parasitic diseases: frequent – alveolar ostitis; infrequent – gastroenteritis, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders: infrequent – anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia.

Immune system disorders: infrequent hypersensitivity reactions 1,3; rarely – angioedema, anaphylactic/anaphylactoid reactions, including shock 1.

Metabolic and nutritional disorders: often – edema/ fluid retention; infrequent – decreased or increased appetite, increased body weight.

Mental disorders: infrequent – anxiety, depression, concentration disorders, hallucinations1; rarely – confusion 1, anxiety 1.

Nervous system disorders: often – dizziness, headache; infrequent – taste disorder, insomnia, paresthesia/hypoesthesia, somnolence.

Visual disorders: infrequent – blurred vision, conjunctivitis.

Hearing and labyrinth disorders: infrequent – tinnitus, vertigo.

Cardiovascular system disorders: Frequent – palpitations, arrhythmia1, arterial hypertension; infrequent – atrial fibrillation, tachycardia1, chronic heart failure, nonspecific changes on ECG, angina1, myocardial infarction4, “hot flashes”, cerebral circulatory disorders4, transient ischemic attack, hypertensive crisis 1, vasculitis 1.

Respiratory system disorders: frequent – bronchospasm1; infrequent – cough, shortness of breath, nasal bleeding.

Gastrointestinal disorders: very common – abdominal pain; common – constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/ epigastric discomfort, nausea, vomiting, esophagitis, oral mucosal ulcers; infrequent – abdominal bloating, changes in peristalsis, dry oral mucosa, gastroduodenal ulcer, peptic ulcer, including gastrointestinal perforations and bleeding, irritable bowel syndrome, pancreatitis1.

Liver and biliary tract disorders: frequent – increased ALT activity, increased ACT activity; rare – hepatitis1; rare2 – liver failure1, jaundice1.

Skin and subcutaneous tissue disorders: Frequent – ecchymosis; infrequent – facial swelling, itching, rash, erythema1, urticaria1; rare2 – Stevens-Johnson syndrome1, toxic epidermal necrolysis1, fixed drug erythema1.

Muscular and connective tissue disorders: infrequent – muscle spasms/ cramps, skeletal muscle pain/scarcity.

Renal and urinary tract disorders: infrequent – proteinuria, increased serum creatinine, renal failure1.

General disorders and disorders at the site of administration: often – asthenia/weakness, flu-like syndrome; infrequently – pain in the chest.

Impact on the results of laboratory and instrumental studies: infrequent – increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid; rarely – decrease of sodium in blood.

1 This adverse reaction has been reported in post-marketing surveillance. The frequency of reports for it is estimated based on the highest frequency observed in clinical trials pooled according to dose and indication.

2 The frequency category “rare” was determined based on the estimated upper limit of the 95% confidence interval for 0 events, given the number of patients who received etoricoxib in the analysis of phase III data pooled by dose and indication (n=15,470).

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

4 An analysis of long-term placebo-controlled and actively controlled clinical studies shows that selective COX-2 inhibitors increase the risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk of these events exceeds 1% per year (infrequent).

The following serious adverse events have been reported in association with NSAID use and 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 etoricoxib overdose has been reported, but in most cases no adverse reactions have been reported.

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

Treatment: in case of overdose, the usual supportive measures such as removal of the drug not absorbed 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

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 the synthesis of prostaglandins, during the last trimester of pregnancy may lead to suppression of uterine contractions and premature closure of the arterial duct. Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during the treatment period, etoricoxib should be discontinued.

Breastfeeding

In lactating rats, etoricoxib is excreted with milk. There have been no studies confirming etoricoxib excretion with breast milk in women. Women who take 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 to become pregnant.

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