Arcoxia

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

Composition:

Active substance: etoricoxib;

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

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium croscarmellose, magnesium stearate;

Tablet coating: Opadry® II blue-green 39K11526 (for 30 mg dosage), Opadry® II green 39K11520 (for 60 mg dosage), Opadry® II white 39K18305 (for 90 mg dosage), Opadry® II green 39K11529 (for 120 mg dosage), carnauba wax;

Composition of colorant Opadry® II blue-green 39K11526, Opadry® II green 39K11520, Opadry® II green 39K11529: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin; indigo carmine (E 132); iron oxide yellow (E 172);

Composition of colorant Opadry® II white 39K18305: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg tablets: biconvex, apple-shaped tablets, film-coated in blue-green color, engraved with <101> on one side and <ACX 30> on the other.

60 mg tablets: biconvex, apple-shaped tablets, film-coated in dark green color, engraved with <200> on one side and <ARCOXIA 60> on the other.

90 mg tablets: biconvex, apple-shaped tablets, film-coated in white color, engraved with <202> on one side and <ARCOXIA 90> on the other.

120 mg tablets: biconvex, apple-shaped tablets, film-coated in pale green color, engraved with <204> on one side and <ARCOXIA 120> on the other.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. 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, Arcoxia® 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 prostaglandin formation. Two isoforms have been identified – COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme, induced by inflammatory stimuli, and is considered the primary factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, regulation of kidney function and the central nervous system (fever induction, pain perception, cognitive function). It may also participate in ulcer healing. COX-2 has been identified in gastric ulcer tissue in humans, but its role in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis, etoricoxib 60 mg once daily significantly improved pain symptoms and patient assessment of disease status. These positive effects were observed as early as day 2 of treatment and were maintained throughout the period up to 52 weeks. In studies using etoricoxib 30 mg once daily, the efficacy of this agent exceeded that of placebo over 12 weeks of treatment (using endpoints applied in other studies). In a dose-ranging study, etoricoxib 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 60 mg and 90 mg once daily significantly improved pain intensity, inflammation, and joint mobility. In studies evaluating 60 mg and 90 mg doses, positive effects were maintained throughout the 12-week treatment period. In a study comparing 60 mg and 90 mg doses, both etoricoxib regimens – 60 mg once daily and 90 mg once daily – were more effective than placebo. The 90 mg dose was 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 mm (95% CI: -4.98 mm, -0.45 mm).

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

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

In a clinical study of postoperative dental pain, etoricoxib 90 mg once daily was administered for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated analgesic efficacy similar to ibuprofen 600 mg (16.11 vs. 16.39; P=0.722), and superior to acetaminophen/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001), as measured by total pain relief 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 acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% in the placebo group. 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 Duration and Long-term use 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 impact, 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 median of 20.3 months (maximum 42.3 months, median 21.3 months). In this study, only serious adverse reactions and treatment discontinuations due to any adverse reactions were recorded.

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 OA dose) or diclofenac 150 mg daily for a median 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 median 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 median 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 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 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 analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse events with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Table 1

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

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 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 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 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 program studies. The rates of discontinuation due to GI clinical reactions 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

Overall upper GI events were defined as perforations, ulcers, and bleeding. A subgroup of overall upper GI events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of overall 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 the effect on the upper GI tract 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 was assessed in elderly patients; 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 rate of discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac discontinued treatment due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 with etoricoxib and 1.84 with diclofenac (p-value < 0.001 for etoricoxib compared to diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic complications

During clinical trials, excluding the MEDAL program studies, approximately 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 ≥ 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 for 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 incidence of ulcers was higher with etoricoxib than with placebo.

Renal function study in elderly patients

A randomized, double-blind, placebo-controlled parallel-group study evaluated the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after 2 weeks of 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 after oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is observed at approximately 1 hour (Tmax) after dosing in adults fasting. The geometric mean AUC0–24hr is 37.8 µg·hr/mL. Within the clinical dosing range, the pharmacokinetics of etoricoxib are linear.

Administration of the 120 mg dose 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 data 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 at concentrations ranging from 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 also 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 weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Excretion.

After a single intravenous dose of 25 mg radiolabeled etoricoxib 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 120 mg once daily, with an accumulation ratio of approximately 2, corresponding to an elimination half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient populations.

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

Gender. Pharmacokinetics of etoricoxib are similar in males and females.

Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh score 5–6), the mean AUC after administration of etoricoxib 60 mg once daily is approximately 16% higher than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (Child-Pugh score 7–9), the mean AUC after administration of etoricoxib 60 mg every other day is similar to that in healthy volunteers receiving etoricoxib 60 mg once daily 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. Etoricoxib is minimally removed by hemodialysis (dialysis clearance approximately 50 mL/min).

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

In a pharmacokinetic study (n=16) involving adolescents (aged 12 to 17 years), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight 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 for pain and inflammatory signs associated with acute gouty arthritis.

Short-term treatment of moderate postoperative dental pain.

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

Contraindications.

Arcoxia® is contraindicated:

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

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

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

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the efficacy of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of a COX inhibitor with ACE inhibitors or angiotensin II receptor antagonists may lead to further deterioration in renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, particularly 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 co-administered with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared 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 drugs 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 agents.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs.

Lithium. NSAIDs reduce renal clearance of lithium, thereby increasing plasma lithium levels. If necessary, careful monitoring of lithium blood levels and dose adjustment should be performed during concomitant use of these drugs, as well as upon discontinuation of NSAID therapy.

MTX (Methotrexate). Two studies evaluated the effects of etoricoxib administered at doses of 60, 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 methotrexate plasma concentrations or renal clearance. 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 decreased 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 mcg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0-24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the above 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 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, 60, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 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 use of high-dose Premarin™ concomitantly with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use during concomitant therapy with etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions during hormone replacement therapy.

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

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect the steady-state AUC0-24hr or renal excretion of digoxin. However, an increase in digoxin Cmax (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 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 concentrations of ethinylestradiol. 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 with caution 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 assessed by the erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

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

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

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 CYP enzyme inducer) resulted in a 65% decrease in etoricoxib plasma concentration. This may be associated with recurrence of symptoms when used concomitantly with etoricoxib. While such data may suggest the need for dose escalation, etoricoxib should not be used at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.

Antacids. Antacid agents do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Special precautions.

Gastrointestinal effects

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

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be prescribed with caution to patients at increased risk of gastrointestinal complications; elderly patients, patients taking any other NSAID or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disorders, particularly peptic ulcers and gastrointestinal bleeding.

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

Cardiovascular effects

Clinical studies indicate that use of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (particularly myocardial infarction and stroke) compared to placebo and some nonselective 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 regularly reassessed, especially in patients with osteoarthritis.

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

Selective COX-2 inhibitors do not replace acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet 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, administration of etoricoxib may lead to reduced prostaglandin synthesis 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 treated with etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics". The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema from 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 severe arterial hypertension compared to some other NSAIDs and selective COX-2 inhibitors. Therefore, arterial hypertension should be controlled before initiating etoricoxib therapy, and special attention should be paid to monitoring blood pressure during treatment. Blood pressure should be monitored within the first 2 weeks after starting therapy and then periodically. If blood pressure increases significantly, alternative therapy should be considered.

Hepatic effects

Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels (approximately 3 times or more above the upper limit of normal) 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 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 instructions

If deterioration in 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 administered to elderly patients and patients with renal, hepatic, or cardiac impairment.

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

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance 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 (such as anaphylaxis and angioedema) have been observed in patients taking etoricoxib. Some selective COX-2 inhibitors may increase the risk of skin reactions in patients with a history of allergic 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 such as fever and other signs of inflammation.

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

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

The medicinal product Arcoxia® film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk to pregnant women is unknown. Use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may lead to uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking nonsteroidal anti-inflammatory drugs (NSAIDs) from the 20th week of gestation onward. In some cases, this may result in renal impairment 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 while on treatment, etoricoxib should be discontinued immediately.

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

Use of etoricoxib, as with other COX-2 inhibitors, 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 refrain from driving or operating machinery.

Dosage and Administration

Arcoxia® is administered orally. The drug can be taken regardless of food intake. However, 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 associated with etoricoxib use increases with higher doses and longer duration of exposure, 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 regularly re-evaluated, particularly in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients with insufficient symptom relief, 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 with inadequate symptom relief, 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 with insufficient symptom relief, 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 a maximum of 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

Dosage adjustment is not required in elderly patients. However, as with other medications, the drug should be prescribed with caution in this population.

Hepatic Impairment

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

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

Renal Impairment

Dosage adjustment is not required in patients with creatinine clearance ≥30 mL/min. Etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min.

Pediatric Population

Etoricoxib is contraindicated in children under 16 years of age.

Overdose

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 adverse reactions were generally not observed in most cases. The most commonly reported adverse reactions were consistent with the known safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal events).

In the event of overdose, standard supportive measures should be implemented, 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

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, based on data from three active-comparator controlled studies, 17,412 patients with osteoarthritis or rheumatoid arthritis 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 provided in the section "Pharmacological properties".

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

The following adverse reactions 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 (MEDAL program studies, short-term acute pain studies, and post-marketing experience).

Table 2

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

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

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

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

§ Based on analyses of long-term, placebo-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, including interstitial nephritis and nephrotic syndrome; therefore, occurrence of these events cannot be excluded with etoricoxib use.

Reporting suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

3 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

For 30 mg, 60 mg and 90 mg tablets.

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

For 120 mg tablets.

7 tablets per blister. 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Merck Sharp & Dohme B.V., the Netherlands / Merck Sharp & Dohme B.V., the Netherlands.

Organon Heist bv, Belgium / Organon Heist bv, Belgium.

Manufacturer's address and location of its operations.

Waarderweg 39, 2031 BN Haarlem, the Netherlands / Waarderweg 39, 2031 BN Haarlem, the Netherlands.

Industriepark 30, 2220, Heist-op-den-Berg, Belgium / Industriepark 30, 2220, Heist-op-den-Berg, Belgium.