Etoricoxib-teva: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Etoricoxib-Teva (Etoricoxib-Teva)

Composition:

Active substance: etoricoxib;

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

Excipients:

Core: calcium hydrogen phosphate anhydrous, microcrystalline cellulose (Type 101), microcrystalline cellulose (Type 102), crospovidone (Type A), povidone (K25), magnesium stearate;

Film coating:

60 mg and 120 mg tablets: hypromellose, hydroxypropylcellulose, talc, medium-chain triglycerides, titanium dioxide (E 171), diamond blue (blue 1) aluminium lake (E 133), indigocarmine (blue 2) aluminium lake (E 132), iron oxide yellow (E 172), iron oxide black (E 172);

90 mg tablets: hypromellose, hydroxypropylcellulose, talc, medium-chain triglycerides, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: dark green, round, biconvex, film-coated tablets, marked with "60" on one side and smooth on the other;

90 mg tablets: white, round, biconvex, film-coated tablets, marked with "90" on one side and smooth on the other;

120 mg tablets: pale green, round, biconvex, film-coated tablets, marked with "120" on one side and smooth 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, etoricoxib dose-dependently inhibited COX-2 without inhibiting cyclooxygenase-1 (COX-1) at doses up to 150 mg per day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the production of prostaglandins. Two isoforms have been identified – COX-1 and COX-2. COX-2 is the inducible enzyme isoform triggered 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 arterial duct, regulation of kidney and central nervous system function (fever induction, pain perception, cognitive function), and may also participate in ulcer healing. COX-2 has been identified in perilesional gastric tissue in humans, but its role in ulcer healing has not been established.

Efficacy. In patients with osteoarthritis (OA), 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 persisted throughout the treatment period up to 52 weeks. In studies using etoricoxib at 30 mg once daily, the efficacy of the drug was superior to placebo over a 12-week treatment period (using endpoints applied in other studies). In a dose-finding study, etoricoxib at 60 mg demonstrated significantly greater improvement compared to 30 mg across all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in hand osteoarthritis.

In patients with rheumatoid arthritis (RA), etoricoxib at doses of 60 mg and 90 mg once daily resulted in significant pain relief, reduced inflammation, and improved mobility. Positive effects were maintained throughout the 12-week treatment period in studies evaluating these doses. In a study comparing etoricoxib 60 mg and 90 mg, both doses – 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 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 as early as 4 hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in back pain, inflammation, and restricted mobility, as well as improved functional capacity. Clinical benefits of etoricoxib were observed on day 2 after initiation of therapy and persisted throughout the 52-week treatment period. In a second study evaluating 60 mg versus 90 mg doses, etoricoxib at 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response to the 60 mg daily dose over 6 weeks, increasing the dose to 90 mg daily improved assessment of back pain intensity (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 was administered at a dose of 90 mg once daily for up to 3 days. In the subgroup of patients with moderate pain at baseline, 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 the Total Pain Relief over 6 hours (TOPAR6) scale. Within the first 24 hours, rescue analgesics were used by 40.8% of patients after etoricoxib 90 mg, 25.5% after ibuprofen 600 mg every 6 hours, 46.7% after acetaminophen/codeine 600 mg/60 mg every 6 hours, and 76.2% after placebo. In this study, the median time to onset of analgesia (meaningful pain relief) with etoricoxib 90 mg was 28 minutes after administration.

Safety

International Program of Studies on Long-term Use of Etoricoxib and Diclofenac in Arthritis Therapy (MEDAL)

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

The MEDAL cardiovascular outcomes study included 17,804 patients with OA and 5,700 with RA who received etoricoxib 60 mg (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for a mean duration of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse events and treatment discontinuations due to any adverse events were recorded in this study.

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

The combined MEDAL program included 34,701 patients with OA and RA receiving treatment for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients received treatment for more than 24 months. At enrollment, patients had various baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study 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 events (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no statistically significant differences in the rates of thrombotic complications between etoricoxib and diclofenac in any analyzed subgroup, including patients with baseline cardiovascular risk. When analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse events with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

Table 1

Complications	Etoricoxib (N=16819) 25836 patient-years	Diclofenac (N=16483) 24766 patient-years	Comparison between treatment groups
Complications	Incidence rate† (95% CI)	Incidence rate† (95% CI)	Relative risk (95% CI)
Confirmed serious thrombotic cardiovascular adverse events
Per protocol	1.24 (1.11; 1.38)	1.30 (1.17; 1.45)	0.95 (0.81; 1.11)
Intent-to-treat	1.25 (1.14; 1.36)	1.19 (1.08; 1.30)	1.05 (0.93; 1.19)
Confirmed cardiac complications
Per protocol	0.71 (0.61; 0.82)	0.78 (0.68; 0.90)	0.90 (0.74; 1.10)
Intent-to-treat	0.69 (0.61; 0.78)	0.70 (0.62; 0.79)	0.99 (0.84; 1.17)
Confirmed cerebrovascular complications
Per protocol	0.34 (0.28; 0.42)	0.32 (0.25; 0.40)	1.08 (0.80; 1.46)
Intent-to-treat	0.33 (0.28; 0.39)	0.29 (0.24; 0.35)	1.12 (0.87; 1.44)
Confirmed peripheral vascular complications
Per protocol	0.20 (0.15; 0.27)	0.22 (0.17; 0.29)	0.92 (0.63; 1.35)
Intent-to-treat	0.24 (0.20; 0.30)	0.23 (0.18; 0.28)	1.08 (0.81; 1.44)
†Events per 100 patient-years; CI – confidence interval. N – total number of patients in the per-protocol population. Per protocol: all complications during the study treatment or within 14 days after its discontinuation (except for patients who took < 75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs (NSAIDs) for > 10% of the total period). Intent-to-treat: all confirmed complications up to the end of the study (including in patients who may have received interventions unrelated to the study, followed by discontinuation of the study drug). Total number of randomized patients: 17412 in the etoricoxib group and 17289 in the diclofenac group.

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

Cardiorenal complications. Approximately 50% of patients enrolled in the MEDAL study had a history of arterial hypertension at baseline. In the study, the rate of discontinuation due to adverse events related to hypertension was statistically significantly higher with etoricoxib than with diclofenac. The incidence of the adverse reaction of congestive heart failure (drug 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 vs. 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 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 those observed in the MEDAL study. In individual studies of the MEDAL program, the absolute rate of discontinuation in any etoricoxib treatment group (60 mg or 90 mg) was up to 2.6% for arterial hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, with higher discontinuation rates observed with 90 mg etoricoxib compared to 60 mg.

Gastrointestinal tolerability outcomes in the MEDAL program. A significantly lower rate of drug discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib compared to diclofenac in each of the three MEDAL studies. The rates of discontinuation due to GI clinical events per 100 patient-years over the entire study period were: 3.23 for etoricoxib and 4.96 for diclofenac in the MEDAL study; 9.12 for etoricoxib and 12.28 for diclofenac in the EDGE study; 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Gastrointestinal safety outcomes in the MEDAL program. Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of overall upper gastrointestinal events was observed with etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and diclofenac in the rate of complicated events. For the subgroup of upper gastrointestinal bleeding (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper gastrointestinal effects was not statistically significant in patients who were also taking low-dose aspirin (approximately 33% of patients).

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

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

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

Additional cardiovascular safety data regarding thrombotic complications

In clinical trials outside the MEDAL program, 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 between patients taking etoricoxib ≥60 mg, placebo, or other NSAIDs (except naproxen). However, the rate 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 relevant in patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce systemic (and thus possibly endothelial) prostacyclin production without affecting platelet thromboxane. The clinical significance of these data is not established.

Additional gastrointestinal safety data

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

Renal function study in elderly patients

In a randomized, double-blind, placebo-controlled parallel-group study, 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 were evaluated in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after two weeks of treatment. All active comparator drugs showed an increase in systolic blood pressure relative to placebo, but etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: etoricoxib 7.7 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).

Pharmacokinetics.

Absorption. Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, peak plasma concentration (geometric mean Cmax = 3.6 µg/mL) is reached approximately 1 hour (Tmax) after dosing in fasting adults. The geometric mean AUC0–24hr is 37.8 µg·hr/mL. Over the clinical dose range, the pharmacokinetics of etoricoxib are linear.

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

Distribution. Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans. Etoricoxib crosses the placental barrier in rats and rabbits and the blood-brain barrier in rats.

Metabolism. Etoricoxib is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. The primary metabolic pathway is formation of the 6'-hydroxymethyl derivative, catalyzed by cytochrome P450 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 formed by further oxidation of the 6'-hydroxymethyl derivative. These major metabolites are either inactive or weakly active inhibitors of COX-2. None of these metabolites inhibit COX-1.

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

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days with 120 mg once daily, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient groups.

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

Gender. Pharmacokinetics of etoricoxib are similar in men and women.

Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh score 5–6), the mean AUC after administration of etoricoxib 60 mg once daily is approximately 16% higher than in healthy volunteers receiving 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 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this patient group. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child-Pugh score ≥10).

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

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

In a pharmacokinetic study (n=16) 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 >60 kg receiving etoricoxib 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in children have not been established.

Clinical characteristics.

Indications.

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

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

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Active peptic ulcer or active gastrointestinal bleeding.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors.
Pregnancy or breastfeeding period.
Severe impairment of liver function (serum albumin < 25 g/L or ≥10 points on the Child-Pugh scale).
Calculated creatinine clearance < 30 mL/min.
Children under 16 years of age.
Inflammatory bowel diseases.
Congestive heart failure [NYHA (New York Heart Association) functional class II–IV].
Patients with arterial hypertension whose blood pressure values are persistently above 140/90 mm Hg and are inadequately controlled.
Diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular diseases.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

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

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may attenuate the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised kidney function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonists with drugs that inhibit COX may lead to further deterioration of renal function, including potentially acute renal failure, usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Such combinations should be prescribed cautiously, 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 administered concomitantly with low-dose acetylsalicylic acid used for cardiovascular prophylaxis. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid doses higher than those used for prophylaxis, as well as with other NSAIDs, is not recommended.

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

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other medicinal products.

Lithium. NSAIDs reduce renal excretion of lithium, thereby increasing plasma lithium levels. Careful monitoring of lithium blood levels and dose adjustment of lithium may be necessary during concomitant use of these medicinal products, as well as upon discontinuation of NSAID therapy.

MTX (Methotrexate). Two studies evaluated the effects of etoricoxib administered at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days in patients receiving weekly methotrexate at doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg had no effect on methotrexate plasma concentration or renal clearance. In one study, administration of etoricoxib 120 mg had no effect on methotrexate plasma concentration or renal clearance, whereas in another study, etoricoxib 120 mg increased methotrexate plasma concentration by 28% and 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 (EE) and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0–24hr of EE by 37%. Etoricoxib 120 mg administered concomitantly with the above-mentioned oral contraceptives either simultaneously or 12 hours apart increased the steady-state AUC0–24hr of EE by 50–60%. This increase in EE concentration should be considered when selecting an oral contraceptive to be used concomitantly with etoricoxib. Increased EE exposure may increase the incidence of adverse reactions associated with oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of 120 mg etoricoxib with hormone replacement agents containing conjugated estrogens (0.625 mg of Premarin™) for 28 days increased the mean steady-state AUC0–24hr of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effects of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) have not been studied. Compared to increasing the dose from 0.625 mg to 1.25 mg during monotherapy with Premarin™, the effect of 120 mg etoricoxib on exposure (AUC0–24hr) of estrogenic components of Premarin™ was less than half. The clinical significance of this increase is unknown, and the concomitant use of high-dose Premarin™ with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use during concomitant administration with etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions during HRT.

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

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect the steady-state AUC0–24hr or renal excretion of digoxin. 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 medicinal products metabolized by sulfotransferases. Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum ethinylestradiol concentrations. Since data on the effects of numerous sulfotransferases are currently limited and the clinical effects of many drugs are still under investigation, etoricoxib should be prescribed cautiously when used concomitantly with other medicinal products primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

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

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

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

Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole oral gel (both potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure; however, this 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 interaction may be associated with recurrence of symptoms when used concomitantly with etoricoxib. Although these data may suggest the need for dose adjustment, etoricoxib should not be used at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.

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

Special precautions for use.

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

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

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

Cardiovascular effects. Clinical studies indicate that the 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 NSAIDs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib use, the drug should be prescribed for the shortest possible duration and at the lowest effective daily doses. The need for symptomatic pain relief and response to treatment should be periodically reassessed, especially in patients with osteoarthritis.

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

Selective COX-2 inhibitors do not replace acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet activity. Therefore, antiplatelet agents should not be discontinued.

Renal effects. Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions associated with impaired renal perfusion, etoricoxib use may reduce prostaglandin formation and consequently decrease renal blood flow, thereby worsening renal function. The risk of such a reaction is 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 inhibitors of prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All NSAIDs, including etoricoxib, may lead to development or exacerbation of congestive heart failure. For information on dose-dependent effects, see section "Pharmacological properties. Pharmacodynamics."

Etoricoxib should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema due to any other cause. If clinical signs of worsening condition occur, 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. Particular attention should be paid to monitoring blood pressure 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.

Hepatic effects. Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels (approximately 3 times or more above the upper limit of normal [ULN]) have been observed in approximately 1% of patients participating in clinical trials and receiving etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily for up to 1 year. All patients with symptoms or signs of hepatic dysfunction, as well as patients with abnormal liver function tests, should be monitored. Etoricoxib should be discontinued in the presence of signs of hepatic dysfunction or persistent abnormal liver function tests (≥3 times ULN).

General precautions. If deterioration in 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 is required when etoricoxib is used in elderly patients and in patients with renal, hepatic, or cardiac impairment.

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

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

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

Etoricoxib should be used with caution when administered concomitantly with warfarin or other oral anticoagulants.

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

Use during pregnancy or breastfeeding.

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

Breastfeeding. It is unknown whether etoricoxib is excreted in human breast milk. In rats, etoricoxib is excreted in milk. Women taking etoricoxib should not breastfeed.

Fertility. The use of etoricoxib, as with other drugs that inhibit COX-2, is not recommended in women attempting to conceive.

Ability to affect reaction rate when driving or operating machinery.

The medicinal product may have a moderate effect on the ability to drive or operate machinery. Patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should not drive or operate machinery.

Method of Administration and Dosage

The medicinal product Etoricoxib-Teva is administered orally, independent of food intake. The onset of the drug's effect occurs faster when taken before a meal. This should be considered when rapid symptom relief is required.

Since the risk of cardiovascular disorders associated with the use of etoricoxib increases with higher doses and longer duration of treatment, the shortest possible treatment courses using the lowest effective daily doses should be applied. The patient's need for symptom relief and response to therapy should be periodically evaluated, especially in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients, if symptoms are not adequately relieved, increasing the dose to 60 mg once daily may enhance efficacy. If no therapeutic improvement is observed, alternative treatment options should be considered.

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients, if symptoms are not adequately relieved, increasing the dose to 90 mg once daily may improve the therapeutic effect. After clinical stabilization of the patient, reducing the dose to 60 mg once daily is advisable. If no improvement in therapeutic effect is observed, alternative treatment options should be considered.

Ankylosing Spondylitis

Acute Pain

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

Acute Gouty Arthritis

The recommended dose is 120 mg once daily. In clinical studies, etoricoxib was used for the treatment of acute gouty arthritis for up to 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 during the three-day period.

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 period of 8 days;
The dose for acute pain following dental surgery should not exceed 90 mg per day for a maximum of 3 days.

Elderly Patients. Dose adjustment is not necessary for elderly patients. However, the medicinal product should be prescribed with caution in this population.

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

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

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

Children.

Etoricoxib is contraindicated in children under 16 years of age.

Overdose.

In clinical 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 in most cases no adverse reactions were observed. The adverse reactions reported most frequently were consistent with the safety profile of etoricoxib (gastrointestinal, cardiac, and renal effects).

In the event of overdose, standard supportive measures should be applied, such as removal of the unabsorbed drug from the gastrointestinal tract, clinical monitoring, and, if necessary, supportive treatment. Etoricoxib is not eliminated by hemodialysis; it is unknown whether it is eliminated 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).

In clinical studies, the adverse reaction profile was consistent among patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

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

In the cardiovascular safety assessment program, 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 further details on the program are provided in the section "Pharmacological Properties".

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

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

Frequency categories are defined for each adverse reaction term based on the frequency in the clinical study database: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000).

Infections and infestations. Common: alveolar osteitis. Uncommon: gastroenteritis, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders. Uncommon: anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia.

Immune system disorders. Uncommon: hypersensitivity‡ß. Rare: angioneurotic edema, anaphylactic/anaphylactoid reactions, including shock‡.

Metabolism and nutrition disorders. Common: edema/fluid retention. Uncommon: decreased or increased appetite, weight gain.

Psychiatric disorders. Uncommon: anxiety, depression, impaired cognition, hallucinations‡. Rare: confusion‡, restlessness‡.

Nervous system disorders. Common: dizziness, headache. Uncommon: dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence.

Eye disorders. Uncommon: blurred vision, conjunctivitis.

Ear and labyrinth disorders. Uncommon: tinnitus, vertigo.

Cardiovascular disorders. Common: palpitations, arrhythmia‡, hypertension. Uncommon: atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§, flushing, cerebrovascular accident§, transient ischemic attack, hypertensive crisis‡, vasculitis‡.

Respiratory, thoracic and mediastinal disorders. Common: bronchospasm‡. Uncommon: cough, dyspnea, epistaxis.

Gastrointestinal disorders. Very common: abdominal pain. Common: constipation, flatulence, gastritis, heartburn/acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, oral ulcers. Uncommon: abdominal distension, altered bowel motility, dry mouth, gastroduodenal ulcers, peptic ulcers, including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis‡.

Hepatobiliary disorders. Common: increased ALT, increased AST. Rare: hepatitis‡, hepatic failure‡†, jaundice‡†.

Skin and subcutaneous tissue disorders. Common: ecchymosis. Uncommon: facial swelling, pruritus, rash, erythema‡, urticaria‡. Rare†: Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, persistent drug erythema‡.

Musculoskeletal and connective tissue disorders. Uncommon: muscle spasms/cramps, musculoskeletal pain/stiffness.

Renal and urinary disorders. Uncommon: proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section "Special precautions for use").

General disorders and administration site conditions. Common: asthenia/fatigue, influenza-like symptoms. Uncommon: chest pain.

Investigations. Uncommon: increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid. Rare: decreased blood sodium.

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

† The frequency category "rare" was defined according to the Guideline on summary of product characteristics (SmPC) (2nd revision, September 2009), based on the calculated upper limit of the 95% confidence interval for 0 events, taking into account the number of participants who received etoricoxib in the pooled Phase III analysis combined by dose and indication (n=15470).

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

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

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

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. The medicinal product does not require special storage temperature conditions. Store in the original packaging to protect from light. Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

Manufacturer's address and site of operations.

Unit 1; H-4042 Debrecen, Pallagi str. 13, Hungary.