Coxikea

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KOXIKEA (KOXIKEA)

Composition:

Active substance: etoricoxib;

1 tablet contains 60 mg, 90 mg, or 120 mg of etoricoxib;

Excipients: microcrystalline cellulose (E 460), calcium hydrogen phosphate, sodium croscarmellose, magnesium stearate (E 470b);

Film coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), glycerol monostearate (E 471), indigo carmine (E 132) (for 60 mg and 120 mg tablets), iron oxide yellow (E 172) (for 60 mg and 120 mg tablets), talc (E 553b), sodium lauryl sulfate.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: film-coated tablets, dark green in color, apple-shaped, with a biconvex surface, embossed with "60" on one side and smooth on the other;

90 mg tablets: film-coated tablets, white in color, apple-shaped, with a biconvex surface, embossed with "90" on one side and smooth on the other;

120 mg tablets: film-coated tablets, light green in color, apple-shaped, with a biconvex surface, embossed with "120" on one side and smooth on the other.

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.

In clinical pharmacological studies, etoricoxib dose-dependently inhibited COX-2 without inhibiting cyclooxygenase-1 (COX-1) when administered at doses up to 150 mg daily. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms have been identified – COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme, upregulated by inflammatory stimuli, and is considered the primary mediator 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 renal and central nervous system functions (fever induction, pain perception, cognitive function). It may also participate in ulcer healing processes. COX-2 has been identified in perilesional gastric tissue in humans, although its role in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis, etoricoxib 60 mg once daily significantly improved pain symptoms and patient assessment of disease status. These positive effects were observed as early as day 2 of treatment and persisted throughout the 52-week treatment period. In studies using etoricoxib 30 mg once daily, the efficacy of this agent exceeded that of placebo over a 12-week treatment period (using endpoints applied in other studies). In a dose-finding study, etoricoxib 60 mg demonstrated significantly greater improvement compared to 30 mg across 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 intensity, inflammation, and joint mobility. Positive effects were maintained throughout the 12-week treatment period in dose-evaluation studies. In a study comparing 60 mg and 90 mg doses, both etoricoxib regimens – 60 mg once daily and 90 mg once daily – were more effective than placebo. The 90 mg dose was superior to the 60 mg dose according to the Patient's Global Assessment of Pain (0–100 mm visual analog scale), with a mean improvement of -2.71 mm (95% CI: -4.98 mm, -0.45 mm).

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

In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant improvement in spinal pain, inflammation, restricted mobility, and enhanced functional capacity. Clinical benefits of etoricoxib were observed on day 2 after initiation of therapy and persisted throughout the 52-week treatment period. In a second dose-comparison study evaluating 60 mg versus 90 mg, etoricoxib 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response to 60 mg daily after 6 weeks, dose escalation to 90 mg daily improved assessment of spinal pain intensity (0–100 mm visual analog scale) compared to continuing 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

In a clinical study of postoperative dental pain, etoricoxib 90 mg once daily was administered for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated analgesic efficacy comparable to ibuprofen 600 mg (16.11 vs. 16.39; P=0.722) and superior to acetaminophen/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001), as measured by total pain relief at 6 hours (TOPAR6). The proportion of patients reporting use of rescue analgesic medication within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% in the placebo group. In this study, onset of analgesic action (meaningful pain relief) with 90 mg etoricoxib occurred as early as 28 minutes after dosing.

Safety

International Multicenter Etoricoxib and Diclofenac Outcome Study in Arthritis (MEDAL) Program

The MEDAL program was a prospectively designed safety outcomes program evaluating cardiovascular safety based on pooled data from three randomized, double-blind, active-comparator-controlled trials (the MEDAL, EDGE II, and EDGE studies).

In the MEDAL study, designed to assess cardiovascular effects, 17,804 patients with osteoarthritis and 5,700 with rheumatoid arthritis received etoricoxib 60 mg (osteoarthritis) or 90 mg (osteoarthritis and rheumatoid arthritis) or diclofenac 150 mg daily, for a mean duration of 20.3 months (maximum 42.3 months, median 21.3 months). In this study, only serious adverse reactions and discontinuations due to any adverse reactions were recorded.

The EDGE and EDGE II studies compared gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7,111 patients with osteoarthritis who received etoricoxib 90 mg daily (1.5 times the recommended dose for osteoarthritis treatment) or diclofenac 150 mg daily for a mean duration of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4,086 patients with rheumatoid arthritis who received etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean duration of 19.2 months (maximum 33.1 months, median 24 months).

The combined MEDAL program included 34,701 patients with osteoarthritis and rheumatoid arthritis who were treated for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients received treatment for more than 24 months. Patients enrolled in this program had varying baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study enrollment were excluded. Concomitant use of gastroprotective agents and low-dose acetylsalicylic acid was permitted in the studies.

Overall safety

There were no significant differences in the frequency of thrombotic cardiovascular adverse events between etoricoxib and diclofenac. Cardiorenal adverse reactions occurred more frequently with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular safety

The incidence of confirmed thrombotic cardiovascular serious adverse events (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the rates of thrombotic complications between etoricoxib and diclofenac across all analyzed subgroups, including patients with cardiovascular risk. When analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse events with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Incidence of confirmed thrombotic cardiovascular complications
(Combined MEDAL program)
Table 1

Complications	Etoricoxib (N=16819) 25836 patient-years	Diclofenac (N=16483) 24766 patient-years	Comparison between treatment groups
	Incidence† (95% CI)	Incidence† (95% CI)	Relative risk (95% CI)
Confirmed serious thrombotic cardiovascular adverse reactions
Per protocol	1.24 (1.11; 1.38)	1.30 (1.17; 1.45)	0.95 (0.81; 1.11)
Intention-to-treat	1.25 (1.14; 1.36)	1.19 (1.08; 1.30)	1.05 (0.93; 1.19)
Confirmed cardiac complications
Per protocol	0.71 (0.61; 0.82)	0.78 (0.68; 0.90)	0.90 (0.74; 1.10)
Intention-to-treat	0.69 (0.61; 0.78)	0.70 (0.62; 0.79)	0.99 (0.84; 1.17)
Confirmed cerebrovascular complications
Per protocol	0.34 (0.28; 0.42)	0.32 (0.25; 0.40)	1.08 (0.80; 1.46)
Intention-to-treat	0.33 (0.28; 0.39)	0.29 (0.24; 0.35)	1.12 (0.87; 1.44)
Confirmed peripheral vascular complications
Per protocol	0.20 (0.15; 0.27)	0.22 (0.17; 0.29)	0.92 (0.63; 1.35)
Intention-to-treat	0.24 (0.20; 0.30)	0.23 (0.18; 0.28)	1.08 (0.81; 1.44)

†Events per 100 patient-years; CI – confidence interval.

N – total number of patients in the per-protocol population.

Per protocol: all events during study therapy or within 14 days after discontinuation (except for patients who took <75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs (NSAIDs) for >10% of the total period).

As treated: all confirmed events up to study completion (including in patients who may have received non-study interventions leading to discontinuation of the study drug). Total number of randomized patients in the etoricoxib group – 17,412, in the diclofenac group – 17,289.

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

Cardio-renal complications

Approximately 50% of patients enrolled in the MEDAL study had a history of arterial hypertension at baseline. In this study, the rate of treatment discontinuation due to adverse reactions related to arterial hypertension was statistically significantly higher in the etoricoxib group compared to the diclofenac group. The frequency of the adverse reaction "heart failure" (treatment discontinuation and serious events) was similar with etoricoxib 60 mg and diclofenac 150 mg; however, the frequency of these events was higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg vs. diclofenac 150 mg in the OA MEDAL subgroup). The frequency of confirmed adverse reactions related to congestive heart failure (events that were serious and required hospitalization or emergency care) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The rate of treatment discontinuation due to adverse reactions related to edema was significantly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference with etoricoxib 90 mg, but not with etoricoxib 60 mg).

Cardio-renal outcomes from the EDGE and EDGE II studies were consistent with those reported in the MEDAL study.

In individual studies of the MEDAL program, the absolute rate of treatment discontinuation in any etoricoxib treatment group (60 mg or 90 mg) was up to 2.6% for arterial hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, with higher discontinuation rates observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability results in the MEDAL program

A significantly lower rate of treatment discontinuation due to any gastrointestinal (GI) clinical event (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib compared to diclofenac in each of the three MEDAL program studies. The rates of treatment discontinuation due to GI clinical events per 100 patient-years over the entire study period were: 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; 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Gastrointestinal safety results from the MEDAL program

Upper GI events were defined as perforations, ulcers, and bleeding. A subgroup of upper GI events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of upper GI events considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of overall upper GI 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 events such as upper GI bleeding (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper GI effects was not statistically significant in patients who were also taking low-dose acetylsalicylic acid (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper GI events (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57; 0.77) with etoricoxib and 0.97 (95% CI 0.85; 1.10) with diclofenac, with a relative risk of 0.69 (95% CI 0.57; 0.83).

The rate of confirmed upper GI events in elderly patients was assessed; the greatest reduction was observed in patients aged ≥75 years (1.35 [95% CI 0.94; 1.87] events per 100 patient-years with etoricoxib compared to 2.78 [95% CI 2.14; 3.56] with diclofenac).

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

Hepatic safety results from the MEDAL program

Etoricoxib was associated with a statistically significantly lower rate of treatment discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac discontinued treatment due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 with etoricoxib and 1.84 with diclofenac (p-value < 0.001 for etoricoxib vs. diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic complications

During clinical trials, excluding the MEDAL program studies, approximately 3,100 patients received etoricoxib at doses ≥60 mg daily for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular complications between patients receiving etoricoxib ≥60 mg, placebo, or other 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 systemic (and thus possibly endothelial) prostacyclin production without affecting platelet thromboxane. The clinical significance of these data is unknown.

Additional gastrointestinal safety data

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

Renal function study in elderly patients

A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effect of 15-day treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after two weeks of 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 (mean change in systolic blood pressure from baseline: etoricoxib 7.7 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).

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 AUC0–24hr is 37.8 µg×hr/mL. Within the clinical dose range, the pharmacokinetics of etoricoxib are linear.

Administration of 120 mg with food (high-fat meal) did not affect the extent of etoricoxib absorption. The rate of absorption was altered, characterized by a 36% decrease in Cmax and a 2-hour increase in Tmax. These findings are not considered clinically significant. In clinical studies, etoricoxib was administered regardless of food intake.

Distribution.

Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.

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 unchanged in urine. The primary metabolic pathway is formation of the 6'-hydroxymethyl derivative catalyzed by cytochrome 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, 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 major metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination.

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

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days with 120 mg once daily, with a cumulative index 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 males and females.

Hepatic 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 receiving 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 etoricoxib 60 mg once daily; etoricoxib 30 mg once daily 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 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 not substantially removed by hemodialysis (dialysis clearance approximately 50 mL/min).

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

In pharmacokinetic studies (n=16) involving adolescents (aged 12 to 17 years), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight >60 kg receiving etoricoxib 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 treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and inflammatory signs associated with acute gouty arthritis.

Short-term treatment of moderate postoperative dental pain.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of all individual patient risks.

Contraindications.

Coxikea is contraindicated:

• in patients with hypersensitivity to the active substance or to any of the excipients;
• 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 or NSAIDs, including COX-2 inhibitors;
• during pregnancy or breastfeeding;
• in severe hepatic impairment (serum albumin <25 g/L or ≥10 points on the Child–Pugh scale);
• when the calculated creatinine clearance is <30 mL/min;
• in children under 16 years of age;
• in inflammatory bowel disease;
• in congestive heart failure (NYHA II–IV);
• in patients with arterial hypertension whose blood pressure values consistently exceed 140/90 mm Hg and are insufficiently controlled;
• in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Oral anticoagulants. In patients whose condition is stabilized on long-term 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) prothrombin time. Therefore, patients receiving oral anticoagulants should be monitored frequently for INR prothrombin time, especially during the first days of etoricoxib treatment or when its dosage is changed.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may reduce the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonists with drugs that inhibit cyclooxygenase may lead to further deterioration in renal function, including 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 with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter.

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

Cyclosporine and tacrolimus. Although interactions between etoricoxib and these drugs have not been studied, concomitant use of any NSAID 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 agents.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs.

Lithium. NSAIDs reduce renal elimination 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 NSAID therapy.

MTX (Methotrexate). Two studies evaluated the effects of etoricoxib administered at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days in patients receiving weekly methotrexate at doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg had no effect on plasma concentration or renal clearance of methotrexate. In one study, administration of etoricoxib 120 mg had no effect on methotrexate plasma concentration or renal clearance, whereas in another study, etoricoxib 120 mg increased methotrexate plasma concentration by 28% and reduced its renal clearance by 13%. Appropriate monitoring for signs of methotrexate toxicity should be performed when etoricoxib and methotrexate are used concomitantly.

Oral contraceptives. Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 µg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0–24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the same oral contraceptives, either simultaneously or 12 hours apart, increased the steady-state AUC0–24hr 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 incidence 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 (0.625 mg of Premarin™) for 28 days increased the mean steady-state AUC0–24hr 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 increasing the dose of Premarin™ from 0.625 mg to 1.25 mg during monotherapy, the effect of etoricoxib 120 mg on exposure (AUC0–24hr) of estrogenic components of Premarin™ was less than half. The clinical significance of this increase is unknown, and the use of high-dose Premarin™ concomitantly with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use during concomitant administration with etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone. In interaction studies, etoricoxib did not show clinically significant effects on the pharmacokinetics of prednisone/prednisolone.

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect the steady-state AUC0–24hr or renal excretion of digoxin. However, an increase in digoxin Cmax (by approximately 33%) was observed. This increase is generally not clinically significant in most patients. Nevertheless, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are prescribed concomitantly.

Effect of etoricoxib on drugs metabolized by sulfotransferases.

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum ethinylestradiol concentrations. Since data on the effects of numerous sulfotransferases are still limited and the clinical effects of many drugs are under investigation, etoricoxib should be prescribed with caution when used concomitantly with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by CYP isoenzymes.

In vitro data indicate no expected inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. In studies involving healthy volunteers, daily administration of etoricoxib 120 mg did not affect hepatic CYP3A4 activity, as assessed 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 suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, although their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at 400 mg once daily for 11 days to healthy volunteers, ketoconazole 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 oral gel (potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure, which, however, was not considered clinically significant according to published data.

Rifampicin. Concomitant administration of etoricoxib and rifampicin (a potent CYP enzyme inducer) resulted in a 65% reduction in etoricoxib plasma concentration. This may be associated with recurrence of symptoms when used concomitantly with etoricoxib. While such data may suggest the 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 do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Special precautions for use.

Gastrointestinal tract effects.

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

NSAIDs should be prescribed with caution in patients at increased risk of GI complications; elderly patients, patients taking any other NSAID or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disorders, particularly peptic ulcers or gastrointestinal bleeding.

There is an additional risk of developing GI adverse effects (gastrointestinal ulcer or other GI complications) when etoricoxib is used concomitantly with acetylsalicylic acid (even at low doses). In long-term clinical studies, no significant difference in GI safety was observed between selective COX-2 inhibitors + acetylsalicylic acid and traditional NSAIDs + acetylsalicylic acid.

Cardiovascular system effects.

Clinical studies indicate that the use of drugs belonging to the class 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 increases 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 patient's 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 (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful evaluation of the risk of developing complications.

Selective COX-2 inhibitors do not replace acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet (antiaggregant) effects. 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, decompensated 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 treated with etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics." The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in 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, particularly at high doses, may cause more frequent and more 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 blood pressure monitoring during treatment. Blood pressure should be monitored within the first 2 weeks after starting therapy and then periodically thereafter. If blood pressure increases significantly, alternative treatment 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 participating in clinical trials and receiving etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily for up to 1 year.

All patients with symptoms of hepatic dysfunction or with abnormal liver function tests should be closely monitored. Etoricoxib should be discontinued in the presence of signs of liver dysfunction or persistent abnormal liver function test results (≥3 times ULN).

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. Adequate 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 prior to starting etoricoxib.

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance of NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, with most cases beginning within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and 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 appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

Etoricoxib may mask signs of fever and other symptoms 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 cyclooxygenase/prostaglandin synthesis, is not recommended in women planning pregnancy.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

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 gestation onwards. 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 upon discontinuation of treatment. The use of etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while being treated with etoricoxib, the drug should be discontinued immediately.

Lactation period

It is unknown whether etoricoxib is excreted in human breast milk. In rats, 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 in women planning pregnancy.

Ability to influence reaction speed when driving vehicles or operating machinery.

Patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage.

The medicinal product Coxikea is intended for oral administration. The drug can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken before meals. 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 using the lowest effective daily doses should be used. The need for symptom relief and response to therapy should be periodically reassessed, especially in patients with osteoarthritis.

Osteoarthritis.

The recommended dose is 30 mg once daily. In some patients, if symptoms are insufficiently controlled, 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 controlled, 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 controlled, 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. In clinical trials of acute gouty arthritis, etoricoxib was administered for 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 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 required for elderly patients. As with other drugs, the drug should be prescribed with caution in elderly patients.

Hepatic impairment.

Regardless of the indication, patients with mild hepatic impairment (5–6 points on the Child–Pugh scale) should not exceed a dose of 60 mg once daily. Patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale) should not exceed a dose of 30 mg once daily, regardless of indication.

Clinical experience with the drug is limited, particularly in patients with moderate hepatic impairment; therefore, the drug should be used with caution. There is no clinical experience with the use of the drug in patients with severe hepatic impairment (≥10 points on the Child–Pugh scale); therefore, the drug is contraindicated in such 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.

Etoricoxib is contraindicated in children under 16 years of age.

Overdose.

In clinical trials, 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. Cases of acute etoricoxib overdose have been reported, although in most cases no adverse reactions were reported. The most commonly observed adverse reactions were consistent with the safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal reactions).

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

Etoricoxib is not removed by hemodialysis; it is unknown whether the drug is eliminated during peritoneal dialysis.

Adverse reactions

The safety of etoricoxib was evaluated in clinical studies involving 9295 patients, including 6757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis received treatment for 1 year or longer).

During clinical studies, the adverse event profile was consistent in patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

In a clinical study involving patients with acute gouty arthritis, etoricoxib was administered at a dose of 120 mg once daily for 8 days. The adverse event profile in this study was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.

In the cardiovascular safety assessment program, data from three active-controlled studies included 17,412 patients with osteoarthritis or rheumatoid arthritis who received etoricoxib (at doses of 60 mg or 90 mg) for a mean duration of approximately 18 months. Safety data and more detailed information on this program are presented in the section "Pharmacological properties".

In clinical studies involving patients with acute postoperative dental pain, including 614 patients who received etoricoxib (at doses of 90 mg or 120 mg), the adverse event profile was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.

The adverse reactions listed below were reported more frequently with the use of the drug than with placebo in clinical studies involving patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis who received etoricoxib at doses of 30 mg, 60 mg, or 90 mg for 12 weeks (studies within the MEDAL program, short-term acute pain studies, and post-marketing experience).

Table 2

System organ class	Adverse reactions	Frequency category*
Infections and infestations	alveolar osteitis	common
	gastroenteritis, upper respiratory tract infections, urinary tract infections	uncommon
Blood and lymphatic system disorders	anaemia (mainly due to gastrointestinal bleeding), leucopenia, thrombocytopenia	uncommon
Immune system disorders	hypersensitivity‡ ß	uncommon
	angioneurotic oedema, anaphylactic/anaphylactoid reactions, including shock‡	rare
Metabolism and nutrition disorders	oedema/fluid retention	common
	decreased or increased appetite, weight gain	uncommon
Psychiatric disorders	anxiety, depression, impaired cognition, hallucinations‡	uncommon
	confusion‡, restlessness‡	rare
Nervous system disorders	dizziness, headache	common
	dysgeusia, insomnia, paraesthesia/hypoaesthesia, somnolence	uncommon
Eye disorders	blurred vision, conjunctivitis	uncommon
Ear and labyrinth disorders	tinnitus, dizziness	uncommon
Cardiac disorders	palpitations, arrhythmia‡	common
	atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§	uncommon
Vascular disorders	hypertension	common
	flushing, cerebral ischaemia§, transient ischaemic attack, hypertensive crisis‡, vasculitis‡	uncommon
Respiratory, thoracic and mediastinal disorders	bronchospasm‡	common
	cough, dyspnoea, epistaxis	uncommon
Gastrointestinal disorders	abdominal pain	very common
	constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric discomfort, nausea, vomiting, oesophagitis, mouth ulcers	common
	abdominal distension, altered bowel habit, dry mouth, gastroduodenal ulcers, peptic ulcers, including gastrointestinal perforation and haemorrhage, irritable bowel syndrome, pancreatitis‡	uncommon
Hepatobiliary disorders	increased ALT, increased AST	common
	hepatitis‡	rare
	hepatic failure‡, jaundice‡	rare†
Skin and subcutaneous tissue disorders	ecchymosis	common
	facial oedema, pruritus, rash, erythema‡, urticaria‡	uncommon
	Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, drug-induced erythema multiforme‡	rare†
Musculoskeletal and connective tissue disorders	muscle spasms/cramps, musculoskeletal pain/stiffness	uncommon
Renal and urinary disorders	proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section «Special precautions»)	uncommon
General disorders and administration site conditions	asthenia/fatigue, influenza-like symptoms	common
	chest pain	uncommon
Investigations	increased blood urea nitrogen, increased creatine phosphokinase, hyperkalaemia, increased uric acid	uncommon
	decreased blood sodium	rare

* The frequency category is defined for each adverse reaction term according to the frequency in the clinical trial database: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).

‡ Adverse reaction identified during post-marketing surveillance. Frequency was determined based on the highest frequency observed in clinical trials (data collected for approved indications and doses).

† The frequency category "rare" was defined in accordance with the Guideline on summary of product characteristics (SmPC) (2nd revision, September 2009), based on the calculated upper limit of the 95% CI for 0 events, taking into account the number of participants who received Coxikea in the pooled Phase III analysis by dose and indication (n=15,470).

ß Hypersensitivity includes the following terms: allergy, drug allergy, drug hypersensitivity, hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction, and unspecified allergy.

§ Based on analyses of long-term, placebo- and active comparator-controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk increase for such events exceeds 1% per year (uncommon).

Serious adverse reactions reported with NSAID use include nephrotoxicity, including interstitial nephritis and nephrotic syndrome; therefore, occurrence of these events cannot be excluded with etoricoxib use.

"Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua".

Shelf life.

4 years.

Storage conditions.

Store in the original packaging to protect from moisture. No special storage conditions are required for this medicinal product. Keep out of reach of children.

Packaging.

Tablets 60 mg and 90 mg: 7 tablets per blister; 4 blisters per cardboard box.

Tablets 120 mg: 7 tablets per blister; 1 blister per cardboard box.

Prescription status.

Prescription-only.

Manufacturer.

Rontis Hellas Medical And Pharmaceutical Products S.A. /
Rontis Hellas Medical And Pharmaceutical Products S.A.

Manufacturer's address and location of its business operations.

Larissa Industrial Area, P.O. Box 3012, Larissa, 41500, Greece /
Larissa Industrial Area, P.O. Box 3012, Larissa, 41500, Greece.