Etoricoxib-zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETOCOXIB-ZDOROVYE (ETORICOXIB-ZDOROVYE)

Composition:

Active substance: etoricoxib;

One tablet contains etoricoxib 30 mg, 60 mg, 90 mg, or 120 mg;

Excipients: microcrystalline cellulose; calcium hydrogen phosphate; sodium croscarmellose; magnesium stearate; dry mixture "Opadry white" containing titanium dioxide (E 171), hypromellose, triacetin (E 1518).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white or almost white, round-shaped, with a biconvex surface.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic drugs. Coxibs. ATC code M01A H05.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Etoricoxib is an oral selective inhibitor of cyclooxygenase-2 (COX-2) within the clinical dose range.

Data are available showing dose-dependent inhibition of COX-2 by etoricoxib without inhibition of cyclooxygenase-1 (COX-1) when administered at doses up to 150 mg per day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase (COX) have been identified: COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme triggered by inflammatory stimuli and is considered the primary factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, as well as in the regulation of kidney and central nervous system function (fever induction, pain perception, cognitive function). It may also participate in the process of ulcer healing. COX-2 has been identified in gastric ulcer tissue in humans, but its significance in ulcer healing has not been established.

Efficacy. In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improves pain symptoms and patient assessment of disease status. It is known that etoricoxib at a dose of 30 mg once daily demonstrated efficacy superior to placebo over a 12-week treatment period. During dose titration, etoricoxib at a dose of 60 mg showed significantly greater improvement compared to 30 mg in 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, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain severity, inflammation, and joint mobility. Positive effects were maintained over a 12-week treatment period. Data indicate that etoricoxib at doses of 60 mg once daily and 90 mg once daily was more effective than placebo.

In patients experiencing acute gouty arthritis attacks, etoricoxib at a dose of 120 mg once daily for 8 days reduced moderate to severe joint pain and inflammation compared to indomethacin at a dose of 50 mg three times daily. Reduction in pain intensity was observed within 4 hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provides significant improvement in back pain, inflammation, and mobility limitations, as well as improved functional capacity. Clinical benefits of etoricoxib were observed on day 2 after initiation of therapy and were maintained throughout a 52-week treatment period. Etoricoxib at doses of 60 mg and 90 mg daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response during 6 weeks of treatment with 60 mg daily, increasing the dose to 90 mg daily improved assessment of back pain intensity compared to continuing treatment with 60 mg daily.

It is known that in postoperative dental pain, etoricoxib administered at a dose of 90 mg once daily for up to three days exerted a more pronounced analgesic effect than placebo. In patients with moderate baseline pain, etoricoxib 90 mg demonstrated analgesic efficacy similar to ibuprofen 600 mg and superior to paracetamol/codeine 600 mg/60 mg and placebo, as determined by the proportion of patients achieving complete pain relief at 6 hours. The proportion of patients requiring rescue analgesics within 24 hours was 40.8% for etoricoxib 90 mg, 25.5% for ibuprofen 600 mg every 6 hours, and 46.7% for paracetamol/codeine 600 mg/60 mg every 6 hours, compared to 76.2% for placebo. The onset of analgesic action (perceptible pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after administration.

Safety.

General safety. There were no significant differences in the frequency of thrombotic cardiovascular complications between etoricoxib and diclofenac. Cardio-renal adverse reactions were more frequently observed with etoricoxib than with diclofenac; this effect was dose-dependent. Gastrointestinal (GI) and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions considered serious or leading to drug discontinuation was higher with etoricoxib than with diclofenac.

Cardiovascular safety outcomes. The frequency of confirmed serious thrombotic cardiovascular adverse reactions (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac. There were no significant differences in the frequency of thrombotic complications between etoricoxib and diclofenac in all analyzed subgroups, including patients with cardiovascular risk. When considered separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions was similar with etoricoxib 60 mg or 90 mg compared to diclofenac 150 mg.

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

Cardio-renal complications. The frequency of treatment discontinuation due to adverse reactions associated with hypertension was statistically higher with etoricoxib than with diclofenac. The frequency of adverse reactions related to congestive heart failure (discontinuation events and serious reactions) was similar with etoricoxib 60 mg and diclofenac 150 mg, but higher with etoricoxib 90 mg compared to diclofenac 150 mg. The frequency of confirmed adverse reactions related to congestive heart failure (events that were serious and led to hospitalization or emergency department visits) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The frequency of treatment discontinuation due to adverse reactions associated with edema was significantly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference for etoricoxib 90 mg, but not for etoricoxib 60 mg).

Gastrointestinal tolerability outcomes. A significantly lower rate of drug discontinuation due to any clinical gastrointestinal complications (e.g., dyspepsia, abdominal pain, ulcers) was observed with etoricoxib compared to diclofenac.

Gastrointestinal safety outcomes. Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. The subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding. The subgroup of upper gastrointestinal events considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower frequency of overall upper gastrointestinal events was observed with etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and diclofenac in the rate of complicated events. For the subgroup of upper gastrointestinal bleeding events (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper gastrointestinal effects was not statistically significant in patients who were concurrently taking low-dose acetylsalicylic acid (ASA) (approximately 33% of patients).

The rates of confirmed clinical lower gastrointestinal events (perforation of the small or large intestine, obstruction, or bleeding) did not differ statistically between etoricoxib and diclofenac.

Hepatic safety outcomes. Etoricoxib was associated with a statistically significantly lower frequency of drug discontinuation due to hepatic adverse reactions compared to diclofenac. Most hepatic adverse reactions were mild.

Additional cardiovascular safety data regarding thrombotic complications. There was no significant difference in the rate of confirmed serious thrombotic cardiovascular events in patients taking etoricoxib ≥60 mg, placebo, or other nonsteroidal anti-inflammatory drugs (NSAIDs), except naproxen. However, the frequency of such events was higher in patients receiving etoricoxib compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between some COX-1-inhibiting NSAIDs and selective COX-2 inhibitors may be clinically significant in patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce the formation of systemic (and thus possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these data is unknown.

Additional gastrointestinal safety data. It is known that the frequency of gastroduodenal ulcers was significantly lower in patients taking etoricoxib 120 mg once daily compared to those taking naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The frequency of ulcers was higher with etoricoxib than with placebo.

Kidney function study in elderly patients. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion during 2-week treatment. All active comparator drugs showed an increase in systolic blood pressure compared to placebo, but etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen.

Pharmacokinetics.

Absorption. Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is reached approximately 1 hour (Tmax) after dosing in fasting adults. The geometric mean AUC0–24 is 37.8 µg×h/mL. Within the clinical dose range, the pharmacokinetics of etoricoxib are linear.

Administration of the 120 mg dose with food (high-fat meal) did not result in a clinically significant effect on the extent of absorption. The rate of absorption was altered, characterized by a 36% reduction in Cmax and a 2-hour increase in Tmax. These data are not considered clinically significant. It is known that etoricoxib was administered independent of food intake during clinical studies.

Distribution. Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 µg/mL to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans. Data indicate that etoricoxib crosses the placental barrier in rats and rabbits and crosses the blood-brain barrier in rats.

Metabolism. Etoricoxib is extensively metabolized, with less than 1% of the dose excreted in urine as unchanged drug. The primary metabolic pathway is the formation of the 6'-hydroxymethyl derivative via cytochrome-catalyzed reactions. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway, but their quantitative contributions have not been studied in vivo.

Five metabolites of etoricoxib have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, formed by further oxidation of the 6'-hydroxymethyl derivative. These primary metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Excretion. After a single intravenous dose of 25 mg radiolabeled etoricoxib administered to healthy volunteers, approximately 70% of the radioactive drug was excreted in urine and 20% in feces, primarily as metabolites. Less than 2% was excreted as unchanged drug.

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are achieved within 7 days with a dose of 120 mg once daily, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient populations

Elderly patients. Pharmacokinetics in elderly patients (aged 65 years and older) are similar to those in younger patients.

Gender. Pharmacokinetics of etoricoxib are similar in men and women.

<Liver function impairment. In patients with mild hepatic impairment (Child-Pugh score 5–6), administration of etoricoxib 60 mg once daily resulted in a mean AUC approximately 16% higher than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (Child-Pugh score 7–9), administration of etoricoxib 60 mg every other day resulted in a mean AUC similar to that in healthy volunteers receiving 60 mg once daily; administration of etoricoxib 30 mg has not been studied in this patient group. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh score ≥10).

Renal function impairment. The pharmacokinetics of a single 120 mg dose of etoricoxib in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease undergoing hemodialysis, do not differ significantly from those in healthy volunteers. Etoricoxib is minimally removed during hemodialysis (dialysis clearance approximately 50 mL/min).

Children. The pharmacokinetics of etoricoxib in children (under 12 years of age) have not been studied.

It is known that the pharmacokinetics of etoricoxib in adolescents aged 12 to 17 years with body weight 40–60 kg receiving etoricoxib 60 mg once daily and those with body weight over 60 kg receiving 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in children have not been established.

Clinical characteristics.

Indications. Symptomatic therapy in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as in pain and signs of inflammation associated with acute gouty arthritis. Short-term treatment of moderate postoperative pain associated with dental surgery. The decision to prescribe a selective COX-2 inhibitor should be based on assessment of all individual patient risks.

Contraindications. The drug is contraindicated:

• in hypersensitivity to the active substance or to any excipient of the drug;
• in active peptic ulcer or active gastrointestinal bleeding;
• in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after taking acetylsalicylic acid (ASA) or NSAIDs, including COX-2 inhibitors;
• during pregnancy and breastfeeding;
• in severe hepatic impairment (serum albumin < 25 g/L or ≥ 10 points on the Child-Pugh scale);
• if calculated creatinine clearance is < 30 mL/min;
• in children under 16 years of age;
• in inflammatory bowel diseases;
• in congestive heart failure (NYHA II–IV);
• in patients with arterial hypertension whose blood pressure values are persistently above 140/90 mmHg and are insufficiently controlled;
• in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other types of interactions.

Pharmacodynamic interactions

Oral anticoagulants. In patients whose condition is stabilized on chronic warfarin therapy, administration of etoricoxib at a dose of 120 mg daily is associated with an approximately 13% increase in the international normalized ratio (INR) of prothrombin time. Therefore, in patients receiving oral anticoagulants, INR values should be monitored frequently, especially during the first days of etoricoxib administration or when changing its dosage.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with COX-inhibiting drugs may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed cautiously, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the initiation of combination therapy and periodically thereafter.

Acetylsalicylic acid (ASA). Administration of etoricoxib at a dose of 120 mg once daily did not affect the antiplatelet activity of ASA (81 mg once daily). Etoricoxib may be prescribed concomitantly with ASA at doses used for cardiovascular disease prevention (low-dose ASA). However, concomitant use of low-dose ASA and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to etoricoxib monotherapy. Concomitant use of etoricoxib with ASA doses higher than those established for prophylaxis, as well as with other NSAIDs, is not recommended.

Cyclosporine and tacrolimus. Although the interaction of etoricoxib with these drugs has not been studied, concomitant use of NSAIDs with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with either of these drugs.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs reduce renal excretion of lithium, thereby increasing plasma lithium levels. Careful monitoring of blood lithium levels and dose adjustment of lithium may be necessary during concomitant use of these drugs, as well as upon discontinuation of NSAIDs.

Methotrexate. Etoricoxib at doses of 60 mg and 90 mg in rheumatoid arthritis did not affect plasma concentrations or renal clearance of methotrexate. Conflicting data exist: one study showed no effect of etoricoxib 120 mg on plasma concentration or renal clearance of methotrexate, while another study showed a 28% increase in plasma methotrexate concentration and a 13% decrease in renal clearance with etoricoxib 120 mg. Appropriate monitoring for signs of methotrexate toxicity should be performed when etoricoxib and methotrexate are used concomitantly.

Oral contraceptives. Etoricoxib at a dose of 60 mg, when administered concomitantly with oral contraceptives containing 35 mcg ethinylestradiol and 0.5–1 mg norethindrone for 21 days, increased the AUC_0–24 of ethinylestradiol by 37%. Etoricoxib at a dose of 120 mg, when administered concomitantly with or 12 hours apart from the above-mentioned oral contraceptives, increased the steady-state AUC_0–24 of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with varying ethinylestradiol content for concomitant use with etoricoxib. Increased ethinylestradiol exposure may increase the frequency of adverse reactions associated with oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of 120 mg etoricoxib with hormone replacement therapy containing conjugated estrogens for 28 days increased the mean steady-state AUC_0–24 of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) has not been studied. Compared to the increase seen with monotherapy using conjugated estrogens increasing from 0.625 mg to 1.25 mg, the effect of etoricoxib 120 mg on exposure (AUC_0–24) of estrogenic components was less than half. The clinical significance of these increases is unknown, and the use of high-dose conjugated estrogens concomitantly with etoricoxib has not been studied. Such increases in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use during concomitant use with etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone. Etoricoxib did not show a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days did not affect the steady-state AUC_0–24 or renal excretion of digoxin. An increase in digoxin C_max (by approximately 33%) was observed. This increase is generally not clinically significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are used concomitantly.

Effect of etoricoxib on drugs metabolized by sulfotransferases. Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may increase serum ethinylestradiol concentrations. Since data on the effects of numerous sulfotransferases are limited and the clinical effects of many drugs are under investigation, it is advisable to use etoricoxib cautiously when coadministered with other drugs primarily metabolized by human sulfotransferases (such as oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by CYP isoenzymes. Based on in vitro studies, inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. Daily administration of etoricoxib 120 mg did not affect hepatic CYP3A4 activity, as determined by the erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

The primary metabolic pathway of etoricoxib depends on CYP enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, but their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole, a potent inhibitor of CYP3A4, at doses of 400 mg once daily for 11 days, had no clinically significant effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (43% increase in AUC).

Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole as an oral gel for local use (potent inhibitors of CYP3A4) with etoricoxib resulted in a slight increase in etoricoxib exposure, which, however, was not considered clinically significant according to published data.

Rifampicin. Concomitant use of etoricoxib and rifampicin (a potent inducer of CYP enzymes) resulted in a 65% reduction in plasma concentration of etoricoxib. This may be associated with recurrence of symptoms. Since such data may suggest a need for dose adjustment, etoricoxib should not be used at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.

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

Special precautions for use.

Gastrointestinal effects. Complications of the upper gastrointestinal tract (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients taking etoricoxib.

The drug should be prescribed with caution to patients at increased risk of gastrointestinal complications, elderly patients, patients taking any other NSAID or ASA concurrently, or patients with a history of gastrointestinal disorders (ulcers and gastrointestinal bleeding).

There is an additional risk of gastrointestinal adverse reactions (gastrointestinal ulcer or other gastrointestinal complications) when etoricoxib is used concomitantly with ASA (even at low doses). No significant difference in gastrointestinal safety has been observed between the use of a selective COX-2 inhibitor + ASA and NSAID + ASA.

Cardiovascular effects. The use of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (particularly myocardial infarction and stroke) compared to placebo and some NSAIDs. Since the risk of cardiovascular complications may increase with higher doses and longer duration of etoricoxib treatment, the drug should be prescribed for the shortest possible duration and at the lowest effective daily dose. The need for symptomatic pain relief and the response to treatment should be periodically reassessed, especially in patients with osteoarthritis.

Etoricoxib should be prescribed to patients with significant risk factors for cardiovascular complications (arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful evaluation of the risk of complications.

Selective COX-2 inhibitors do not replace the use of ASA for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet activity; therefore, antiplatelet agents should not be discontinued.

Renal effects. Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions associated with impaired renal perfusion, the use of etoricoxib may lead to reduced prostaglandin synthesis and, consequently, to decreased renal blood flow, thereby worsening renal function. Patients with pre-existing severe renal impairment, uncompensated heart failure, or cirrhosis are at high risk of such reactions. Renal function should be monitored in these patients.

Fluid retention, edema, and arterial hypertension. As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent reaction information is provided in the "Pharmacodynamics" section.

The drug should be prescribed with caution to patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as to patients with edema due to any other cause. If clinical signs of worsening condition occur in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

Etoricoxib, especially at high doses, may lead to more frequent and severe arterial hypertension compared to some other NSAIDs and selective COX-2 inhibitors. Therefore, arterial hypertension should be controlled before initiating etoricoxib therapy, and special attention should be paid to monitoring blood pressure during treatment. Blood pressure should be monitored within the first 2 weeks of treatment initiation and then periodically thereafter. If blood pressure increases significantly, alternative therapy should be considered.

Hepatic effects. Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels (approximately 3 times or more above the upper limit of normal (ULN)) have been observed in approximately 1% of patients treated with etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily.

All patients with symptoms of hepatic dysfunction or with abnormal liver function tests should be monitored. Etoricoxib should be discontinued if signs of hepatic dysfunction occur or if persistent abnormal liver function test results (3 times above ULN) are observed.

General instructions. If during treatment a patient develops impairment of any of the organ systems listed above, appropriate measures should be taken and discontinuation of etoricoxib should be considered. Appropriate medical monitoring is required when etoricoxib is administered to elderly patients and patients with renal, hepatic, or cardiac impairment.

Initiation of etoricoxib therapy should be done with caution in dehydrated patients. Rehydration is recommended before starting etoricoxib.

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with the use of NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs at the beginning of therapy, with onset of symptoms usually within the first month of treatment. Serious hypersensitivity reactions (anaphylaxis, angioedema) have been observed in patients taking etoricoxib. Some selective COX-2 inhibitors may increase the risk of skin reactions in patients with a history of allergic reaction to any drug. Etoricoxib should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

Etoricoxib may mask symptoms of fever and other signs of inflammation.

Concomitant use of etoricoxib and warfarin or other oral anticoagulants should be prescribed with caution.

The use of etoricoxib, as with other drugs that inhibit COX/prostaglandin synthesis, is not recommended for women planning pregnancy.

Use during pregnancy or breastfeeding.

Pregnancy. There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk to pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may lead to uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking NSAIDs from the 20th week of pregnancy onward. In some cases, this may lead to impaired renal function in newborns. These effects may occur soon after initiation of NSAID therapy; oligohydramnios is usually reversible after discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while taking etoricoxib, the drug should be discontinued immediately.

Period of breastfeeding. It is unknown whether etoricoxib passes into breast milk. It is known that in animals etoricoxib is excreted in milk. Women taking etoricoxib should not breastfeed.

Fertility. The use of etoricoxib, as with other drugs that inhibit COX-2, is not recommended for women planning pregnancy.

Ability to influence reaction speed when driving or operating machinery. Patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should not drive or operate machinery.

Method of Administration and Dosage.

The drug is administered orally. The drug can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken on an empty stomach. This should be taken into account when rapid symptom relief is required.

Since the risk of cardiovascular adverse events with etoricoxib increases with higher doses and longer exposure duration, the shortest possible treatment courses should be used at the lowest effective daily doses. The need for symptom relief and response to treatment should be periodically re-evaluated, especially in patients with osteoarthritis.

Osteoarthritis. The recommended dose is 30 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 60 mg once daily may enhance efficacy. If no improvement is observed, alternative treatment options should be considered.

Rheumatoid arthritis. The recommended dose is 60 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 90 mg once daily may improve therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Ankylosing spondylitis. The recommended dose is 60 mg once daily. In some patients, if symptoms are insufficiently relieved, increasing the dose to 90 mg once daily may improve therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Acute pain. In cases of acute pain, etoricoxib should be used only during the acute symptomatic period.

Acute gouty arthritis. The recommended dose is 120 mg once daily. Etioricoxib has been used for up to 8 days.

Postoperative dental pain. The recommended dose is 90 mg once daily for up to 3 days. Some patients may require additional postoperative analgesia.

Doses exceeding those recommended for each indication either have not demonstrated additional efficacy or have not been studied. Therefore:

• the dose in osteoarthritis should not exceed 60 mg per day;
• the dose in rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg per day;
• the dose in acute gout should not exceed 120 mg per day for a maximum treatment duration of 8 days;
• the dose for acute pain following dental surgery should not exceed 90 mg per day for a maximum of 3 days.

Elderly patients. Dose adjustment is not necessary in elderly patients. As with other drugs, however, the drug should be prescribed with caution in elderly patients.

Hepatic impairment. Regardless of the indication, the dose should not exceed 60 mg once daily in patients with mild hepatic impairment (Child-Pugh score 5–6). In patients with moderate hepatic impairment (Child-Pugh score 7–9), the dose should not exceed 30 mg once daily, regardless of indication.

Clinical experience is limited, particularly in patients with moderate hepatic impairment; therefore, the drug should be used with caution. There is no clinical experience with etoricoxib in patients with severe hepatic impairment (Child-Pugh score ≥10); therefore, the drug is contraindicated in these patients.

Renal impairment. Dose adjustment is not required in patients with creatinine clearance ≥30 mL/min. The use of etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min.

Children. Etioricoxib is contraindicated in children under 16 years of age.

Overdose. Single doses of etoricoxib up to 500 mg or multiple doses up to 150 mg daily for 21 days did not cause significant toxic effects. Acute overdose of etoricoxib has been reported, although adverse reactions were not reported in most cases. The most commonly observed adverse reactions were consistent with the safety profile of etoricoxib (gastrointestinal, cardiac, and renal events).

In case of overdose, standard supportive measures should be implemented, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and, if necessary, supportive treatment.

Etoricoxib is not eliminated by hemodialysis. It is unknown whether the drug is eliminated by peritoneal dialysis.

Adverse Reactions

The safety of etoricoxib was evaluated in patients with osteoarthritis, rheumatoid arthritis, chronic lower back pain, and ankylosing spondylitis.

The adverse event profile was consistent in patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

Patients with acute gouty arthritis were treated with etoricoxib at a dose of 120 mg once daily for 8 days. The adverse event profile was generally similar to that observed in patients with osteoarthritis, rheumatoid arthritis, and chronic lower back pain.

In patients with acute postoperative pain following dental and abdominal-gynecological surgical procedures, including those who received etoricoxib (at doses of 90 mg or 120 mg), the adverse event profile was generally comparable to that seen in patients with osteoarthritis, rheumatoid arthritis, and chronic lower back pain.

The adverse reactions listed below were reported more frequently with the use of the drug than with placebo.

Frequency categories are defined for each adverse event term based on the frequency observed in the clinical trial database: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000).

Infections and infestations: common – alveolar osteitis; uncommon – gastroenteritis, upper respiratory tract infections, urinary tract infections.

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

Immune system disorders: uncommon – hypersensitivityß; rare – angioedema/anaphylactic/anaphylactoid reactions, including shock.

Metabolism and nutrition disorders: common – edema/fluid retention; uncommon – decreased or increased appetite, weight gain.

Psychiatric disorders: uncommon – anxiety, depression, cognitive impairment, hallucinations; rare – confusion, restlessness.

Nervous system disorders: common – dizziness, headache; uncommon – dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence.

Eye disorders: uncommon – blurred vision, conjunctivitis.

Ear and labyrinth disorders: uncommon – tinnitus, vertigo.

Cardiac disorders: common – palpitations, arrhythmia; uncommon – atrial fibrillation, tachycardia, congestive heart failure, non-specific ECG changes, angina pectoris, myocardial infarction§.

Vascular disorders: common – arterial hypertension; uncommon – flushing, cerebrovascular disorders§, transient ischemic attack, hypertensive crisis, vasculitis.

Respiratory, thoracic and mediastinal disorders: common – bronchospasm; uncommon – cough, dyspnea, epistaxis.

Gastrointestinal disorders: very common – abdominal pain; common – constipation, flatulence, gastritis, heartburn/acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, oral ulcers; uncommon – abdominal distension, changes in intestinal peristalsis, dry mouth, gastroduodenal ulcers, peptic ulcers including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis.

Hepatobiliary disorders: common – increased ALT, increased AST; rare – hepatitis; very rare – hepatic failure, jaundice.

Skin and subcutaneous tissue disorders: common – ecchymosis; uncommon – facial swelling, pruritus, rash, erythema, urticaria; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis, persistent drug eruption.

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms/cramps, musculoskeletal pain/stiffness.

Renal and urinary disorders: uncommon – proteinuria, increased serum creatinine, renal failure/dysfunction.

General disorders and administration site conditions: common – asthenia/fatigue, influenza-like symptoms; uncommon – chest pain.

Investigations: uncommon – increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid; rare – decreased serum sodium.

ßHypersensitivity includes: allergy, drug allergy, drug hypersensitivity, hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction, and unspecified allergy.

§Selective COX-2 inhibitors have been associated with an increased risk of serious arterial thrombotic events, including myocardial infarction and stroke. The absolute risk of such events is unlikely to exceed 1% per year (uncommon).

Serious adverse reactions reported with NSAIDs include nephrotoxicity, such as interstitial nephritis and nephrotic syndrome; therefore, these cannot be excluded during etoricoxib use.

Reporting of adverse reactions. Reporting of adverse reactions after marketing authorization is important for continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Film-coated tablets, 30 tablets (10x3) in a blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business.

22, Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.