Etoricoxib stada®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETOLOXIB STADA® (ETORICOXIBSTADA®)

Composition:

Active substance: etoricoxib;

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

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, povidone, sodium croscarmellose (E 468), magnesium stearate;

Coating of the tablet:

tablets of 60 mg: hypromellose 15 cPs (E 464), lactose monohydrate, titanium dioxide (E 171), triacetin (E 1518), indigo carmine dye (E 132) (11-14) (3-5%), iron oxide yellow dye (E 172);

tablets of 90 mg: hypromellose 15 cPs (E 464), lactose monohydrate, titanium dioxide (E 171), triacetin (E 1518);

tablets of 120 mg: hypromellose 15 cPs (E 464), lactose monohydrate, titanium dioxide (E 171), triacetin (E 1518), indigo carmine dye (E 132) (11-14) (3-5%), iron oxide yellow dye (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

tablets of 60 mg: dark green, round, biconvex film-coated tablets;

tablets of 90 mg: white, round, biconvex film-coated tablets;

tablets of 120 mg: pale green, round, biconvex film-coated tablets.

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, Etoricoxib® dose-dependently inhibited COX-2 without inhibiting COX-1 when administered at doses up to 150 mg daily. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function. Cyclooxygenase is responsible for prostaglandin production. Two isoforms have been identified: COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme, activated 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 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, although its role in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis, etoricoxib at a dose of 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 treatment period of up to 52 weeks. In a dose-finding study, etoricoxib 60 mg demonstrated significantly greater improvement compared to 30 mg across all three primary endpoints after 6 weeks of treatment.

In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain intensity, inflammation, and joint mobility. Positive effects were maintained throughout the 12-week treatment period in dose evaluation studies. In a dose comparison study of 60 mg versus 90 mg, both etoricoxib doses—60 mg once daily and 90 mg once daily—were more effective than placebo. The 90 mg once-daily dose was more effective than the 60 mg dose according to the Patient's Global Assessment of Pain (0–100 mm visual analog scale), with a mean improvement of -2.71 mm (95% CI: -4.98 mm, -0.45 mm).

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

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal pain, inflammation, and mobility limitations, as well as improved functional capacity. Clinical benefits of etoricoxib were observed as early as day 2 after initiation of therapy and were maintained 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 to naproxen 1000 mg daily. In patients who did not show an adequate response to 60 mg daily over 6 weeks, increasing the dose to 90 mg daily improved assessment of back pain intensity (0–100 mm visual analog scale) compared to continuing 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

In a clinical study of postoperative dental pain, etoricoxib 90 mg once daily for up to 3 days demonstrated greater analgesic effect than placebo. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg showed 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. The proportion of patients requiring rescue analgesic medication within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% in the placebo group. In this study, the onset of analgesic effect (meaningful pain relief) with 90 mg etoricoxib occurred as early as 28 minutes after administration.

Safety

Medicines for Etoricoxib and Diclofenac Administration in Arthritis Long-term (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). 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 the recommended OA dose) or diclofenac 150 mg daily for a mean 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 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 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 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 entry 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 complications between etoricoxib and diclofenac. Cardiorenal adverse reactions occurred more frequently with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular Safety

The incidence of confirmed serious thrombotic cardiovascular 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 across all analyzed subgroups, including patients with cardiovascular risk. When analyzed 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 Events (Combined MEDAL Program)

Table 1

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 frequency of treatment discontinuation due to adverse reactions related to arterial hypertension was statistically 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 the frequency of these events was 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 subgroup). The frequency of confirmed adverse reactions related to congestive heart failure (events that were serious and required hospitalization or emergency care) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The frequency 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 within 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 frequency of drug discontinuation observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability outcomes in the MEDAL program.

A significantly lower rate of treatment discontinuation due to any clinical gastrointestinal (GI) 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 clinical GI 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.

Gastrointestinal safety outcomes in the MEDAL program.

Overall upper gastrointestinal (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 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 ≥75 years of age (1.35 [95% CI 0.94, 1.87] events per 100 patient-years for 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.

Hepatic safety outcomes in the MEDAL program.

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 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 versus 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 rate of confirmed serious thrombotic cardiovascular complications in patients taking etoricoxib at doses ≥60 mg, placebo, or other NSAIDs (except naproxen). However, the frequency of such events was higher in patients receiving etoricoxib compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between 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 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-day treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion during two-week treatment. All active comparator drugs showed increases 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, the maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is reached approximately 1 hour (Tmax) after dosing in fasting adults at steady state. The geometric mean AUC0–24 is 37.8 µg×h/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 result in a clinically significant effect on the extent of absorption. The rate of absorption was altered, characterized by a 36% reduction in Cmax and a 2-hour increase in Tmax. These data are not considered clinically significant. 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 crosses the blood-brain barrier in rats.

Metabolism.

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted in urine as unchanged drug. The primary metabolic pathway is 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 have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, formed by further oxidation of the

6'-hydroxymethyl derivative. These major metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination.

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

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are achieved within 7 days with 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 dosage. 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. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh score ≥10).

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

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

In pharmacokinetic studies (n=16) 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.

Clinical characteristics.

Indications.

Symptomatic therapy in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as in pain and inflammatory signs associated with acute gouty arthritis.

Short-term treatment of moderate postoperative pain associated with dental surgery.

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

Contraindications.

The drug ETOREXIB STADA® is contraindicated:

• in hypersensitivity to the active substance or to any of the excipients;
• in active peptic ulcer or active gastrointestinal bleeding;
• in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors (cyclooxygenase-2);
• during pregnancy or breastfeeding;
• in severe impairment of liver function (serum albumin <25 g/L or ≥10 points on the Child–Pugh scale);
• when 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 insufficiently controlled;
• in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

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

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed 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 disease prevention. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib increases the frequency of gastrointestinal ulcers and other complications compared to etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid doses higher than those established for prophylaxis, as well as with other nonsteroidal anti-inflammatory drugs, is not recommended.

Cyclosporine and tacrolimus. Although interactions between etoricoxib and these drugs have not been studied, concomitant use of nonsteroidal anti-inflammatory drugs with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with either of these drugs.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs.

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

Methotrexate. 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 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 µg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0–24 of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the above-mentioned oral contraceptives, either simultaneously or with a 12-hour interval, increased the steady-state AUC0–24 of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with varying ethinylestradiol content for concomitant use with etoricoxib. Increased exposure to ethinylestradiol 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 Premarin™) for 28 days increased the steady-state AUC0–24 of unconjugated estrone by 41%, equilin by 76%, and 17-β-estradiol by 22%. The effect of etoricoxib doses recommended for long-term use (60 and 90 mg) has not been studied. Compared to the increase observed with monotherapy using Premarin™ at doses increased from 0.625 to 1.25 mg, the effect of etoricoxib 120 mg on exposure (AUC0–24) 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 in patients receiving etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions during hormone replacement therapy.

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

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect the steady-state AUC0–24 or renal excretion of digoxin. An increase in digoxin Cmax (approximately 33%) was observed. This increase is generally not clinically significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are 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 under investigation, etoricoxib should be used cautiously when co-administered with other drugs primarily metabolized by human sulfotransferases (such as oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by CYP isoenzymes

Based on in vitro studies, inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. 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, 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 (increase in AUC by 43%).

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

Rifampicin. Concomitant 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 such data may suggest 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 for use.

Effect on the gastrointestinal tract.

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 in 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, specifically peptic ulcers and gastrointestinal bleeding.

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

Effect on the cardiovascular system.

Clinical studies indicate that the use of selective COX-2 inhibitors may be associated with an increased risk of thrombotic events (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 (such as arterial hypertension, hyperlipidemia, diabetes mellitus, or 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 events, as they lack antiplatelet activity. Therefore, antiplatelet agents should not be discontinued.

Effect 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 reduce prostaglandin synthesis and, consequently, renal blood flow, thereby worsening renal function. The risk of such a reaction 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 section "Pharmacological properties", "Pharmacodynamics". The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema due to other causes. If clinical signs of worsening condition occur, 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 blood pressure monitoring during treatment. Blood pressure should be monitored within the first 2 weeks of treatment initiation and periodically thereafter. If blood pressure increases significantly, alternative therapy should be considered.

Effect on the liver.

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

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

General instructions.

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

Treatment with etoricoxib should be initiated with caution in dehydrated patients. Rehydration is recommended prior to starting etoricoxib.

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, with onset typically 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.

The use of 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.

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

The medicinal product ETOXICOXIB STADA® contains lactose. This product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk to pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may lead to impaired uterine contractions 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 lead to impaired renal function in newborns. These effects may occur soon after initiating NSAID therapy; oligohydramnios is usually reversible after discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib should be discontinued immediately.

Breastfeeding period

It is unknown whether etoricoxib passes into human breast milk. It is known that etoricoxib passes into milk in rats. Women taking etoricoxib should not breastfeed.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

ETORICOXIB STADA® is administered orally. The medication can be taken independently of food intake. The onset of the drug's effect occurs faster when taken on an empty stomach. 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 possible duration and the lowest effective daily dose. The need for symptom relief and the 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 inadequate 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 insufficient symptom relief, increasing the dose to 90 mg once daily may improve therapeutic effect. Once clinical stability is achieved, reducing the dose to 60 mg once daily is advisable. 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. Once clinical stability is achieved, reducing the dose to 60 mg once daily is advisable. If no improvement is observed, alternative treatment options should be considered.

Acute Pain.

In the case of acute pain, etoricoxib may be used only during the acute symptomatic period.

Acute Gouty Arthritis.

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

Postoperative Dental Pain.

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

Doses exceeding those recommended for each indication have either not been shown to provide 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 for elderly patients. As with other medications, the drug should be prescribed with caution in elderly patients.

Hepatic Impairment.

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

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 a creatinine clearance ≥30 mL/min. The use of etoricoxib is contraindicated in patients with a creatinine clearance <30 mL/min.

Children.

Etoricoxib is contraindicated in children under 16 years of age.

Overdose.

In clinical studies, single doses of etoricoxib up to 500 mg or multiple daily doses up to 150 mg for 21 days did not cause significant toxic effects. Cases of acute etoricoxib overdose have been reported, although adverse reactions were not commonly reported. The most frequently observed adverse reactions were consistent with the safety profile of etoricoxib (e.g., gastrointestinal, cardiovascular, 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, if necessary, supportive treatment.

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, and ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis received treatment for up to 1 year).

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

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 provided in the section "Pharmacological properties".

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

The adverse reactions listed below were reported more frequently with 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 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 its 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 pooled across indications and approved 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 the drug, in the pooled phase III analysis of ETOREXIB STADA®, combined by dose and indication (n=15,470).

ßHypersensitivity 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-controlled 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).

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.

Serious adverse reactions such as nephrotoxicity, including interstitial nephritis and nephrotic syndrome, have been reported with NSAID use; therefore, these cannot be excluded with the use of etoricoxib.

Shelf life.

4 years.

Storage conditions.

This medicinal product requires no special storage conditions.

Keep out of reach and sight of children.

Packaging.

For 60 mg and 90 mg tablets

7 tablets in a blister, 1 blister in a cardboard box.

10 tablets in a blister, 2, 5, or 10 blisters in a cardboard box.

For 120 mg tablets

7 tablets in a blister, 1 blister in a cardboard box.

10 tablets in a blister, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

STADA Arzneimittel AG, Germany (batch release).

Manufacturer's address and location of operations.

Stadaweg 2-18, 61118 Bad Vilbel, Germany.