Etoriax

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Etoriax® (Etoriax®)

Composition:

Active substance: etoricoxib;

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

Excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium croscarmellose, sodium stearyl fumarate, colloidal anhydrous silicon dioxide;

Film coating: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3000, talc, yellow iron oxide (E 172) (only in 60 mg tablets), red iron oxide (E 172) (only in 90 mg or 120 mg tablets).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg: white or almost white, round, slightly biconvex film-coated tablets with bevelled edges;

60 mg: slightly brownish-yellow, round, biconvex film-coated tablets with bevelled edges and "60" engraved on one side;

90 mg: pink, round, biconvex film-coated tablets with bevelled edges and "90" engraved on one side;

120 mg: brownish-red, round, slightly biconvex film-coated tablets with bevelled edges and a groove on one side.

The groove is not intended for breaking the tablet.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01AH05.

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 enzyme isoform induced 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 kidney function and the central nervous system (fever induction, pain perception, cognitive function). It may also participate in the process of ulcer healing. COX-2 has been identified in perilesional gastric tissue in humans, but its significance for ulcer healing has not been established.

Clinical efficacy and safety

Efficacy

In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improves pain and patient assessment of disease status. These positive effects were observed as early as the second day of treatment and persisted throughout the 52-week period. In studies using etoricoxib at a dose of 30 mg once daily, the efficacy of this agent exceeded that of placebo over a 12-week treatment period (using assessments employed in other studies). In a dose-finding study, etoricoxib at a dose of 60 mg demonstrated significantly greater improvement compared to 30 mg in all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in hand osteoarthritis.

In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain 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 based on patients' overall assessment of pain (measured using a visual analog scale from 0 to 100 mm), with a mean improvement of -2.71 mm (95% confidence interval (CI): -4.98 mm, -0.45 mm).

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 at 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 enhanced 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-evaluation study comparing 60 mg to 90 mg, etoricoxib at 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 (measured using a visual analog scale from 0 to 100 mm) compared to continuing the 60 mg dose, 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 was administered once daily for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated analgesic efficacy similar to that of ibuprofen 600 mg (16.11 vs 16.39; P=0.722) and superior to that of acetaminophen/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001), as determined by the Total Pain Relief over 6 hours (TOTPAR6) score. The proportion of patients reporting use of rescue analgesics 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% of patients receiving placebo. In this study, onset of analgesic effect (perceptible pain relief) with 90 mg etoricoxib occurred as early as 28 minutes after dosing.

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 comparator-controlled trials (the MEDAL, EDGE II, and EDGE studies).

In the MEDAL study, designed to assess cardiovascular effects, 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 OA patients received etoricoxib 90 mg daily (1.5 times higher than the recommended dose for OA treatment) 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 RA patients 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 more than 24 months. Patients enrolled in this program had various 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. 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 were more frequently observed 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 reactions (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 in any of the analyzed subgroups, including patients with cardiovascular risk. When considered separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions 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 events
Per protocol		1.24 (1.11; 1.38)		1.30 (1.17; 1.45)		0.95 (0.81; 1.11)
As treated		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)
As treated		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)
As treated	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)
As treated	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 (except 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 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 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, but higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg compared to 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 frequency 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 results in the MEDAL program

A significantly lower rate of treatment discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcers) 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.

Safety results of the MEDAL program for the GI tract

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 concurrently taking low-dose aspirin (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 the small or large intestine, obstruction, or bleeding) did not differ statistically between etoricoxib and diclofenac.

Safety results of the MEDAL program for the liver

Etoricoxib was associated with a statistically significantly lower frequency of treatment discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients taking etoricoxib and 2.7% of patients taking 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 compared to 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 cardiovascular thrombotic complications in patients taking 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 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 patients receiving naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The ulcer incidence was higher with etoricoxib than with placebo.

Kidney function studies 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 a similar effect on sodium excretion during two-week treatment. All active comparator drugs showed an increase in systolic blood pressure relative to placebo; however, 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 following oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, peak plasma concentration (geometric mean Cmax = 3.6 µg/mL) is observed at approximately 1 hour (Tmax) after dosing in adults under fasting conditions. 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 independent 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 major metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Excretion.

After a single intravenous dose of 25 mg radiolabeled etoricoxib administered to healthy volunteers, 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 an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient populations.

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

Sex. 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 AUC approximately 16% higher than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (Child-Pugh score 7–9), administration of etoricoxib 60 mg every other day resulted in a mean AUC similar to that in healthy volunteers receiving 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) (see sections "Indications", "Contraindications").

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 minimally removed by hemodialysis (dialysis clearance approximately 50 mL/min) (see sections "Indications", "Contraindications").

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

In pharmacokinetic studies (n=16) conducted in 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 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 children have not been established (see section "Indications").

Clinical characteristics.

Indications.

Etoryx® is indicated for adults and children aged 16 years and older for symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and inflammatory signs associated with acute gouty arthritis.

Etoryx® is indicated for adults and children aged 16 years and older for short-term treatment of moderate postoperative dental pain.

The decision to prescribe a selective COX-2 inhibitor should be based on assessment of all individual patient risks (see sections "Contraindications" and "Special precautions").

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• active peptic ulcer or active gastrointestinal bleeding;
• bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after administration of acetylsalicylic acid or NSAIDs, including COX-2 inhibitors;
• pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding");
• severe hepatic impairment (serum albumin <25 g/L or ≥10 points on the Child-Pugh scale);
• calculated creatinine clearance <30 mL/min;
• children under 16 years of age;
• inflammatory bowel disease;
• congestive heart failure (NYHA II–IV);
• patients with arterial hypertension whose blood pressure values are consistently above 140/90 mm Hg and are inadequately controlled;
• 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 stabilized on chronic warfarin therapy, administration of etoricoxib at a dose of 120 mg once daily is associated with an approximately 13% increase in international normalized ratio (INR). Therefore, patients receiving oral anticoagulants should be monitored frequently for INR values, especially during the first days of etoricoxib treatment or upon dose adjustment (see section "Special precautions").

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may reduce the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with cyclooxygenase-inhibiting agents 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 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 administered concomitantly with low-dose acetylsalicylic acid used for cardiovascular prophylaxis. 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 prophylactic doses, as well as with other NSAIDs, is not recommended.

Cyclosporine and tacrolimus. Although the interaction between etoricoxib and these agents has not been studied, concomitant use of any NSAID with cyclosporine or tacrolimus may potentiate their nephrotoxic effects. 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 excretion of lithium, thereby increasing plasma lithium levels. If necessary, careful monitoring of blood lithium levels and dose adjustment of lithium should be performed during concomitant use of these agents, as well as upon discontinuation of NSAID therapy.

Methotrexate. Two studies evaluated the effects of etoricoxib administered at doses of 60, 90, 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 and 90 mg did not affect plasma concentration or renal clearance of methotrexate. In one study, administration of etoricoxib 120 mg did not affect 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 co-administered.

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 AUC_0–24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the above-mentioned oral contraceptives either simultaneously or 12 hours apart increased the steady-state AUC_0–24hr 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 agents containing conjugated estrogens (0.625 mg of Premarin™) for 28 days increased the steady-state mean AUC_0–24hr 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, 60, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 to 1.25 mg with Premarin™ monotherapy, the effect of etoricoxib 120 mg on exposure (AUC_0–24hr) of Premarin™ estrogenic components was less than half. The clinical significance of this increase is unknown, and concomitant use of high-dose Premarin™ with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal agent for postmenopausal use when co-administered with etoricoxib, as increased estrogen exposure raises 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 AUC_0–24hr or renal excretion of digoxin. An increase in digoxin C_max (approximately 33%) was observed. This increase is generally not significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are co-administered.

Effect of etoricoxib on drugs metabolized by sulfotransferases

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

Effect of etoricoxib on drugs metabolized by CYP isoenzymes

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

Effect of other drugs on the pharmacokinetics of etoricoxib

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

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at 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 (43% increase in AUC).

Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole in the form of an oral gel for local use (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. While these data may suggest the need for dose escalation, it is not recommended to use etoricoxib at doses exceeding those specified for each indication, as 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.

Effects on the gastrointestinal tract (GIT)

Serious complications of the upper gastrointestinal tract (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients treated with etoricoxib.

NSAIDs should be prescribed with caution to patients at increased risk of gastrointestinal complications; elderly patients, patients taking any other nonsteroidal anti-inflammatory drug or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disorders, specifically peptic ulcers and gastrointestinal bleeding.

There is an increased risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) with concomitant use of etoricoxib and acetylsalicylic acid (even at low doses). Long-term clinical studies have not shown a significant difference in gastrointestinal safety between the use of selective COX-2 inhibitors + acetylsalicylic acid and NSAIDs + acetylsalicylic acid.

Effects on the cardiovascular system

Clinical studies indicate that the use of drugs from 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 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.

Effects on the kidneys

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, decreased renal blood flow, thereby worsening renal function. The risk of such reactions is particularly high in patients with pre-existing severe renal impairment, decompensated heart failure, or cirrhosis. Renal function should be monitored in such 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 "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 causes. If clinical signs of worsening condition occur in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

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

Effects on the liver

Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 times or more above the upper limit of normal) have been observed in approximately 1% of patients participating in clinical trials who received etoricoxib at doses of 30, 60, and 90 mg daily for up to 1 year.

All patients with symptoms of hepatic dysfunction or 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 tests (3 times above the upper limit of normal).

General precautions

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 supervision is required when etoricoxib is administered to elderly patients and patients with impaired renal, hepatic, or cardiac function.

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

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

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

Concomitant use of etoricoxib with warfarin or other oral anticoagulants should be done with caution (see section "Interaction with other medicinal products and other forms of interaction").

The use of etoricoxib, as with other drugs that inhibit cyclooxygenase/prostaglandin synthesis, is not recommended for women planning pregnancy (see sections "Pharmacodynamics" and "Use during pregnancy or lactation").

Use during pregnancy or lactation.

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk for 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. Etoricoxib is contraindicated during pregnancy (see section "Contraindications"). If pregnancy occurs during treatment, etoricoxib should be discontinued.

Lactation

It is unknown whether etoricoxib passes into human breast milk. In rats, etoricoxib has been shown to pass into milk. Women taking etoricoxib should not breastfeed (see section "Contraindications").

Fertility

The use of etoricoxib, as with other COX-2 inhibitors, is not recommended for women planning pregnancy.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience dizziness, vertigo, or somnolence during etoricoxib treatment should not drive or operate machinery.

Method of Administration and Dosage

Method of Administration

Etoricoxib, film-coated tablets, should be taken orally, independent of food intake. The onset of the drug's effect occurs faster when taken before meals. This should be considered when rapid symptom relief is required.

Since the risk of cardiovascular adverse events increases with higher doses and longer duration of exposure to etoricoxib, treatment should be initiated using the shortest duration possible and the lowest effective daily dose. The need for symptom relief and response to therapy should be periodically re-evaluated, especially in patients with osteoarthritis (see sections "Pharmacodynamics", "Contraindications", "Special Warnings and Precautions for Use", and "Adverse Effects").

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients with inadequate symptom relief, increasing the dose to 60 mg once daily may improve 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 with inadequate symptom relief, increasing the dose to 90 mg once daily may enhance therapeutic effect. After achieving clinical stabilization, 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 with inadequate symptom relief, increasing the dose to 90 mg once daily may improve therapeutic effect. After achieving clinical stabilization, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Acute Pain

Etoricoxib may be used only during the acute symptomatic period for acute pain.

Acute Gouty Arthritis

The recommended dose is 120 mg once daily. In clinical trials of acute gouty arthritis, etoricoxib was administered for up to 8 days.

Postoperative Dental Pain

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

Doses exceeding those recommended for each indication have not been studied or shown to provide additional benefit. 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 in acute dental postoperative pain should not exceed 90 mg per day for a maximum of 3 days.

Elderly Patients

No dose adjustment is necessary for elderly patients. However, as with other medications, the drug should be used with caution in elderly patients (see section "Special Warnings and Precautions for Use").

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 the indication.

Clinical experience with etoricoxib in patients with hepatic impairment is limited, particularly in those with moderate impairment; therefore, the drug should be used with caution. There is no clinical experience with etoricoxib in patients with severe hepatic impairment (Child–Pugh score ≥10); therefore, the drug is contraindicated in such patients (see sections "Pharmacokinetics", "Contraindications", and "Special Warnings and Precautions for Use").

Renal Impairment

Dose adjustment is not required in patients with creatinine clearance ≥30 mL/min (see section "Pharmacokinetics"). Etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Children

Etoricoxib is contraindicated in children under 16 years of age.

Overdose

Symptoms

In clinical trials, single doses of etoricoxib up to 500 mg or multiple daily doses up to 150 mg for 21 days did not result in significant toxic effects. Cases of acute etoricoxib overdose have been reported, although most cases did not result in adverse reactions. The most commonly observed adverse reactions were consistent with the known safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal effects).

Treatment

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

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

Adverse reactions.

Summary of safety profile

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-comparator-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.

List of adverse reactions in tabular form

The adverse reactions listed below were reported more frequently with 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 (MEDAL program studies, short-term acute pain studies, and post-marketing experience).

Table 2

System organ class	Adverse reactions	Frequency*
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
	angioedema, 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
	confusional state‡, 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, oral ulcers	common
	abdominal distension, altered bowel habit, dry mouth, gastroduodenal ulcers, peptic ulcers including gastrointestinal perforation and bleeding, 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 swelling, pruritus, rash, erythema‡, urticaria‡	uncommon
	Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, drug-induced fixed erythema‡	rare†
Musculoskeletal and connective tissue disorders	muscle cramps/spasms, musculoskeletal pain/stiffness	uncommon
Renal and urinary disorders	proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section "Special warnings and precautions for use")	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 levels	rare

* The frequency category is defined for each adverse reaction term according to the frequency in the clinical study 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. The 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% confidence interval 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 preferred terms: allergy, drug allergy, drug hypersensitivity, hypersensitivity, hypersensitivity NOS, hypersensitivity reaction, and unspecified allergy.

§ Based on the analysis of long-term, placebo-controlled and active-comparator 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, such as interstitial nephritis and nephrotic syndrome; therefore, occurrence of these events cannot be excluded with etoricoxib use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Information on any suspected adverse reactions should be reported in accordance with applicable legal requirements.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 7 tablets in a blister; 1 or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's location and address of its place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.