Cocoxib

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

Composition:

Active substance: etoricoxib;

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

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

Tablet coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), glycerol monostearate (E 471), aluminium indigo carmine (E 132)*, yellow iron oxide (E 172)*, talc (E 553b), sodium lauryl sulfate.

*Not present in the 90 mg dosage strength.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets of 30 mg: biconvex, oval-shaped, film-coated tablets, blue-green in color, imprinted with "30" on one side and smooth on the other. Tablets of 60 mg: biconvex, oval-shaped, film-coated tablets, dark green in color, imprinted with "60" on one side and smooth on the other. Tablets of 90 mg: biconvex, oval-shaped, film-coated tablets, white in color, imprinted with "90" on one side and smooth on the other. Tablets of 120 mg: biconvex, oval-shaped, film-coated tablets, pale green in color, imprinted 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 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 have been identified – COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme, induced by pro-inflammatory stimuli, and is considered the primary factor responsible for the synthesis of prostanoic mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the arterial duct, regulation of kidney function and the central nervous system (fever induction, pain perception, cognitive function), and may also participate in ulcer healing. COX-2 has been identified in tissue surrounding gastric ulcers 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. These positive effects were observed as early as the second day of treatment and persisted throughout the period up to 52 weeks. In studies using etoricoxib at a dose of 30 mg once daily, the drug's efficacy exceeded that of placebo over a 12-week treatment period (using the same assessments as in other studies). In a dose-finding study, etoricoxib at a dose of 60 mg showed significantly greater improvement compared to 30 mg on 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 mobility. In studies evaluating the 60 mg and 90 mg doses, positive effects were maintained throughout the 12-week treatment period. In a study comparing the 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 more effective than the 60 mg dose according to the Patient's Global Assessment of Pain (0–100 mm visual analogue scale), with a mean improvement of -2.71 (95% CI: -4.98; -0.45).

In patients with 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 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 at a dose of 90 mg once daily provided significant improvement in back pain, inflammation, restricted mobility, and improved functional capacity. Clinical benefits of etoricoxib were observed on the second day 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 at doses of 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 the 60 mg daily dose over 6 weeks, increasing the dose to 90 mg daily improved assessment of back pain intensity (0–100 mm visual analogue scale) compared to continuing 60 mg daily, with a mean improvement of -2.70 (95% CI: -4.88; -0.52).

In a clinical study of postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722) and superior to that of paracetamol/codeine 600 mg/60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001), as measured by the Total Pain Relief over 6 hours (TOTPAR6). 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, 46.7% in the paracetamol/codeine 600 mg/60 mg every 6 hours group, and 76.2% in the placebo group. In this study, the onset of analgesic effect (perceptible pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after administration.

Safety.

Medication for the Evaluation of the Long-term safety of Etoricoxib and Diclofenac 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-controlled comparison studies (MEDAL, EDGE II, and EDGE).

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

The EDGE and EDGE II studies compared gastrointestinal tolerability of etoricoxib and diclofenac. In the EDGE study, 7,111 patients with OA received etoricoxib 90 mg daily (1.5 times higher than the recommended OA dose) or diclofenac 150 mg daily for a mean duration of 9.1 months (maximum 16.6 months, median 11.4 months). In the EDGE II study, 4,086 patients with RA 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 OA and RA treated for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients were treated for over 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 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). Adverse reactions from the gastrointestinal tract and liver 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 serious thrombotic cardiovascular 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 considered separately, the relative risk of confirmed serious thrombotic cardiovascular adverse events with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Table 1

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

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 adverse events of cardiovascular origin
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 complications during the study treatment or within 14 days after its discontinuation (excluding patients who took < 75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs (NSAIDs) for > 10% of the total period). Intention-to-treat: all confirmed complications until the end of the study (including patients who may have received interventions unrelated to the study, followed by discontinuation of the study drug). Total number of randomized patients: 17412 in the etoricoxib group and 17289 in the diclofenac group.

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

Cardiorenal 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 of congestive heart failure (treatment discontinuation and serious events) was similar with etoricoxib 60 mg and diclofenac 150 mg, but higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg versus diclofenac 150 mg in the OA MEDAL group). 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).

Cardiorenal outcomes from the EDGE and EDGE II studies were consistent with the data 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 a higher discontinuation rate observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability outcomes in the MEDAL program.

A significantly lower rate of drug discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib compared to diclofenac in each of the three MEDAL studies. The rates of drug 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 outcomes in the MEDAL program.

Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup 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 events such as upper gastrointestinal bleeding (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 concurrently taking low-dose acetylsalicylic acid (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper gastrointestinal 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 frequency of confirmed upper gastrointestinal 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).

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 in the MEDAL program.

Etoricoxib was associated with a statistically significantly lower frequency of drug 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 the drug 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 versus diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic complications. In clinical trials, excluding the MEDAL program studies, approximately 3100 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 taking etoricoxib at doses ≥ 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 certain 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 formation 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 incidence of ulcers was higher with etoricoxib than with placebo.

Kidney function study in elderly patients.

In a randomized, double-blind, placebo-controlled parallel-group study, the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on sodium excretion, blood pressure, and other renal function parameters were evaluated in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on sodium excretion after 2 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, the maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is reached at approximately 1 hour (Tmax) after dosing in fasting adults at steady state. The geometric mean AUC0–24hr is 37.8 µg×hr/mL. Within the clinical dosing range, the pharmacokinetics of etoricoxib are linear.

Administration of etoricoxib 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% reduction 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 the 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 primary metabolites are either inactive or weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

Elimination.

After a single intravenous dose of 25 mg radiolabeled etoricoxib administered to healthy volunteers, 70% of the radioactive drug 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 achieved within 7 days with a daily dose of 120 mg, with a cumulative index of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg of the drug 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.

Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh score 5–6), administration of etoricoxib 60 mg once daily resulted in a mean area under the plasma concentration-time curve (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; administration of 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 to severe renal impairment, as well as in patients with end-stage renal disease undergoing hemodialysis, do not differ significantly from those in healthy volunteers. During hemodialysis, etoricoxib is not substantially removed (dialysis clearance approximately 50 mL/min).

Pediatric population. The pharmacokinetics of etoricoxib in children (under 12 years of age) have not been studied. In a pharmacokinetic study (N=16) involving adolescents (12 to 17 years of age), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight over 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 pediatric patients have not been established.

Clinical characteristics.

Indications.

Symptomatic therapy in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as in pain and inflammatory signs 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 an assessment of all individual patient risks.

Contraindications.

The medicinal product is contraindicated:

• in hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• 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 and breastfeeding;
• in severe hepatic impairment (serum albumin < 25 g/L or ≥ 10 points on the Child-Pugh scale);
• if the 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 consistently above 140/90 mm Hg and are poorly 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 by 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) of prothrombin time. Therefore, in patients receiving oral anticoagulants, INR values should be monitored frequently, especially during the first days of etoricoxib treatment or when changing its dosage.

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

Acetylsalicylic acid. In a study involving healthy volunteers at steady state, administration of etoricoxib at a dose of 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib may be administered concomitantly with low-dose acetylsalicylic acid used for cardiovascular disease prevention. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to 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 the interaction between etoricoxib and these medicinal products has 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 medicinal products.

Pharmacokinetic interactions.

Effect of etoricoxib on the pharmacokinetics of other medicinal products.

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 medicinal products, as well as after discontinuation of NSAID therapy.

Methotrexate. The effects of etoricoxib at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days were evaluated in two studies in patients receiving weekly methotrexate at doses of 7.5–20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg did not affect plasma concentration or renal clearance of methotrexate. In one study, administration of etoricoxib at 120 mg did not affect methotrexate plasma concentration or renal clearance, whereas in another study, etoricoxib at 120 mg increased methotrexate plasma concentration by 28% and decreased 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 at a dose of 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 at a dose of 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 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 (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 from 0.625 mg to 1.25 mg during monotherapy with Premarin™, the effect of etoricoxib 120 mg on the exposure (AUC0–24hr) of estrogenic components of Premarin™ was less than half. The clinical significance of this increase is unknown, and the concomitant use of high-dose Premarin™ with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal medicinal product for postmenopausal use concomitantly 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 a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. Administration of etoricoxib at a dose of 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 medicinal products 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 limited and the clinical effects of many medicinal products are still under investigation, etoricoxib should be prescribed with caution when used concomitantly with other medicinal products primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on medicinal products metabolized by CYP isoenzymes. Based on in vitro data, inhibition of cytochrome P450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. In studies involving healthy volunteers, daily administration of etoricoxib at 120 mg did not affect hepatic CYP3A4 activity, as determined by the erythromycin breath test.

Effect of other medicinal products 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, but their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at a dose of 400 mg once daily for 11 days to healthy volunteers, ketoconazole did not have a clinically significant effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (increase in AUC by 43%).

Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole oral gel (both 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 inducer of CYP enzymes) resulted in a 65% decrease in etoricoxib plasma concentration. This may be associated with recurrence of symptoms when used concomitantly with etoricoxib. Since 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 medicinal products 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 taking etoricoxib. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be prescribed with caution to patients at increased risk of GI complications; including elderly patients, patients concurrently using any other NSAID or acetylsalicylic acid, or patients with a history of gastrointestinal disorders, specifically peptic ulcers or gastrointestinal bleeding.

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

Cardiovascular effects.

Clinical studies indicate that use of drugs in the class of selective COX-2 inhibitors may be associated with a 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 use, 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 reviewed, 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 assessment of the risk of complications. Selective COX-2 inhibitors do not replace acetylsalicylic acid 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 production and, consequently, 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 receiving 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 lead to 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. Particular attention should be paid to monitoring blood pressure during treatment. Blood pressure should be monitored within the first 2 weeks after starting treatment 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) (approximately 3 times or more above the upper limit of normal (ULN)) have been observed in approximately 1% of patients participating in clinical trials who received etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily over periods up to 1 year. All patients with symptoms of impaired liver function or with abnormal liver function tests should be closely monitored. Etoricoxib should be discontinued if signs of liver dysfunction occur or if persistent abnormal liver function test results (≥3 times ULN) are observed.

General instructions.

If deterioration in the function of any of the organ systems mentioned above occurs during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. Appropriate medical monitoring should be ensured when etoricoxib is used in elderly patients and in patients with impaired renal, hepatic, or cardiac function.

Etoricoxib therapy should be initiated 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 with 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 (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 symptoms of fever and other signs of inflammation.

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

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

Important information about excipients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, 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 result in 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 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 upon discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib must be discontinued.

Breastfeeding 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 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 medicinal product Kokoksib is taken orally. The medicinal product can be taken regardless of food intake. The onset of effect occurs faster when taken before meals. This should be considered when rapid symptom relief is required. Since the risk of cardiovascular adverse events associated with the use of etoricoxib increases with higher doses and longer duration of exposure, the shortest possible treatment courses at the lowest effective daily doses should be used. The need for symptom relief and response to treatment 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 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. 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.

There is no need for dose adjustment in elderly patients. However, as with other medicinal products, etoricoxib should be prescribed with caution in elderly patients.

Hepatic Impairment.

Regardless of the indication, 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 a dose of 30 mg once daily, regardless of indication.

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

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 result in significant toxic effects. Acute overdosage with etoricoxib has been reported, although in most cases no adverse reactions were reported.

Symptoms. The most commonly observed adverse reactions were consistent with the safety profile of etoricoxib (gastrointestinal, cardiac, and renal reactions).

Treatment. In case of overdose, standard supportive measures are recommended, 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 clinical studies involving 9,295 patients, including 6,757 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 reaction 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 reaction 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 comparing 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 reaction 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 etoricoxib 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	anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia	uncommon
Immune system disorders	hypersensitivity‡ ß	uncommon
	angioedema, anaphylactic/anaphylactoid reactions, including shock‡	rare
Metabolism and nutrition disorders	edema/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, paresthesia/hypoesthesia, 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	arterial hypertension	common
	flushing, cerebrovascular disorder§, transient ischemic attack, hypertensive crisis‡, vasculitis‡	uncommon
Respiratory, thoracic and mediastinal disorders	bronchospasm‡	common
	cough, dyspnea, epistaxis	uncommon
Gastrointestinal disorders	abdominal pain	very common
	constipation, flatulence, gastritis, heartburn/acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, oral ulcers	common
	abdominal distension, change in bowel motility, dry mouth, gastroduodenal ulcers, peptic ulcers including gastrointestinal perforation and hemorrhage, irritable bowel syndrome, pancreatitis‡	uncommon
Hepatobiliary disorders	elevated ALT, elevated AST	common
	hepatitis‡	rare
	hepatic failure‡, jaundice‡	rare†
Skin and subcutaneous tissue disorders	ecchymosis	common
	facial edema, pruritus, rash, erythema‡, urticaria‡	uncommon
	Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, drug-induced fixed erythema‡	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 and warnings”)	uncommon
General disorders and administration site conditions	asthenia/fatigue, influenza-like symptoms	common
	chest pain	uncommon
Investigations	increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid	uncommon
	decreased blood sodium	rare

* The frequency category is defined for each adverse reaction term according to its frequency in the clinical trial database: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000).

‡ Adverse reaction identified during post-marketing surveillance. Frequency was determined based on the highest frequency observed in clinical studies (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 etoricoxib in the phase III pooled 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 etoricoxib-controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious arterial thrombotic events, including myocardial infarction and stroke. According to 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, such as interstitial nephritis and nephrotic syndrome; therefore, occurrence of these events cannot be excluded with etoricoxib use.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via 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 the reach and sight of children.

Packaging.

7 tablets per blister; 1 or 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

RONDIS HELLAS MEDICAL AND PHARMACEUTICAL PRODUCTS S.A.

Manufacturer's address and place of business.

P.O. BOX 3012 Larissa Industrial Area, Larissa, 41004, Greece.