Runia

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

Composition:

Active substance: etoricoxib;

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

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

Film-coating for 60 mg tablet: Opadry II Green 39K11529 (composition: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin; indigo carmine (E 132); iron oxide yellow (E 172));

Film-coating for 90 mg tablet: Opadry II White 39K18305 (composition: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin);

Film-coating for 120 mg tablet: Opadry II Green 39K11529 (composition: lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin; indigo carmine (E 132); iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: oval green film-coated tablets.

90 mg tablets: round white film-coated tablets.

120 mg tablets: round green 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, the medicinal product Runia dose-dependently inhibited COX-2 without inhibiting cyclooxygenase-1 (COX-1) when administered at doses up to 150 mg per day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the production of prostaglandins. Two isoforms have been identified – COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme triggered by inflammatory stimuli and is considered the main factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, as well as in the regulation of kidney and central nervous system functions (fever induction, pain perception, cognitive function). It may also participate in the process of ulcer healing. COX-2 has been identified in tissue surrounding gastric ulcers in humans, but its significance for 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 on day 2 of treatment and persisted throughout the treatment period of up to 52 weeks. In studies using etoricoxib at a dose of 30 mg once daily, the efficacy of this drug exceeded that of placebo over a 12-week treatment period (using the same assessment scales as in other studies). In a dose-finding study, etoricoxib at a dose of 60 mg showed 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, 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 these studies. In a study comparing the 60 mg and 90 mg doses, both etoricoxib 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 experiencing acute gouty arthritis attacks, etoricoxib at a dose of 120 mg once daily for 8 days reduced moderate to severe joint pain and inflammation compared to indomethacin at 50 mg three times daily. Reduction in pain intensity was observed as early as 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal 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 dose-comparison study evaluating 60 mg versus 90 mg, etoricoxib at 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response during 6 weeks of treatment with 60 mg daily, dose escalation 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 was administered for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722), and superior to that of 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 (TOTPAR6) score. The proportion of patients reporting use of rescue analgesic medication within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% of patients receiving placebo. In this study, onset of analgesic effect (meaningful pain relief) with 90 mg etoricoxib occurred as early as 28 minutes after dosing.

Safety

Medial: A Long-term Safety Study Program of Etoricoxib and Diclofenac in Arthritis

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).

The MEDAL study, designed to assess cardiovascular effects, included 17,804 patients with osteoarthritis (OA) and 5,700 with rheumatoid arthritis, who received either etoricoxib 60 mg or 90 mg (for OA and rheumatoid arthritis, respectively) or diclofenac 150 mg daily for a mean duration of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse reactions and discontinuations due to any adverse reactions were recorded in this study.

The EDGE and EDGE II studies compared gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7,111 patients with osteoarthritis receiving etoricoxib 90 mg daily (1.5 times higher than the recommended dose for osteoarthritis 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 rheumatoid arthritis receiving 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 osteoarthritis and rheumatoid arthritis treated for a mean duration of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients were treated for more than 24 months. Patients enrolled in this program had varying baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study enrollment were excluded. The 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 were more frequently observed with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular Safety

The incidence of confirmed serious thrombotic cardiovascular adverse events (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the rates of thrombotic complications between etoricoxib and diclofenac across all analyzed subgroups, including patients with cardiovascular risk. When analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse events with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Table 1

Incidence of Confirmed Thrombotic Cardiovascular Complications (Combined MEDAL Program)

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

Cardiorenal complications

Approximately 50% of patients enrolled in the MEDAL study had a history of arterial hypertension at baseline. In this study, the rate of discontinuation due to adverse reactions related to arterial hypertension was statistically significantly higher in the etoricoxib group than in the diclofenac group. The frequency of the adverse reaction of congestive heart failure (treatment discontinuation and serious events) was similar with etoricoxib 60 mg and diclofenac 150 mg, but the frequency of these reactions was higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg versus diclofenac 150 mg in the osteoarthritis subgroup of the MEDAL study). The frequency of confirmed adverse reactions related to congestive heart failure (events that were serious and required hospitalization or emergency care) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The rate of treatment discontinuation due to adverse reactions related to edema was significantly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference with etoricoxib 90 mg, but not with etoricoxib 60 mg).

Cardiorenal outcomes from the EDGE and EDGE II studies were consistent with the data reported from the MEDAL study.

In individual studies of the MEDAL program, the absolute frequency of treatment discontinuation in any etoricoxib treatment group (60 mg or 90 mg) was up to 2.6% for arterial hypertension, up to 1.9% for edema, and up to 1.1% for congestive heart failure, with a higher discontinuation rate observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability results in the MEDAL program

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

Gastrointestinal safety results from the MEDAL program

Overall upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of overall upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of overall upper gastrointestinal events 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 events such as upper gastrointestinal bleeding (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper gastrointestinal effects was not statistically significant in patients who were also taking low-dose acetylsalicylic acid (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper gastrointestinal events (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57; 0.77) with etoricoxib and 0.97 (95% CI 0.85; 1.10) with diclofenac, with a relative risk of 0.69 (95% CI 0.57; 0.83).

The 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).

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

Hepatic safety results from the MEDAL program

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

Additional cardiovascular safety data regarding thrombotic complications

In clinical trials, excluding the MEDAL program studies, approximately 3100 patients received etoricoxib at doses ≥60 mg daily for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular complications between patients taking etoricoxib ≥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 the formation of systemic (and thus possibly endothelial) prostacyclin 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 taking etoricoxib 120 mg once daily compared to those taking 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 effect of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after 2 weeks of treatment. All active comparator drugs showed an increase in systolic blood pressure compared to placebo; however, etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: etoricoxib 7.7 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).

Pharmacokinetics.

Absorption

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

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

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins over a concentration range of 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.

Etoricoxib crosses the placental barrier in rats and rabbits and crosses the blood-brain barrier in rats.

Metabolism

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. The primary metabolic pathway is the formation of the 6'-hydroxymethyl derivative, catalyzed by cytochrome enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway, but their quantitative contributions have not been studied in vivo.

Five metabolites of etoricoxib have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, formed by further oxidation of the 6'-hydroxymethyl derivative. These 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 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 achieved within 7 days with 120 mg once daily, with a cumulative index of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.

Special patient populations

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

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

Hepatic impairment. In patients with mild hepatic impairment (5–6 points on the Child–Pugh scale), administration of etoricoxib 60 mg once daily resulted in a mean AUC approximately 16% higher than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), administration of etoricoxib 60 mg every other day resulted in a mean AUC similar to that in healthy volunteers receiving 60 mg once daily; administration of etoricoxib 30 mg once daily has not been studied in this patient group. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (≥10 points on the Child–Pugh scale).

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 not substantially 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 pharmacokinetic studies (n = 16) involving adolescents (aged 12 to 17 years), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight over 60 kg receiving etoricoxib 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in 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.

Runiya is contraindicated:

• in patients with 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;
• during pregnancy and breastfeeding;
• in severe hepatic impairment (serum albumin < 25 g/L or ≥10 points on the Child-Pugh scale);
• when the calculated creatinine clearance is < 30 mL/min;
• in children under 16 years of age;
• in inflammatory bowel diseases;
• in congestive heart failure (NYHA II–IV);
• in patients with arterial hypertension whose blood pressure values are consistently above 140/90 mm Hg and are inadequately controlled;
• in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

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

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may reduce the effectiveness 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 ACE inhibitors or angiotensin II receptor antagonists with cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. 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 initiation 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 the interaction between etoricoxib and these drugs has not been studied, concomitant use of any NSAID with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with either of these agents.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs reduce renal excretion of lithium, thereby increasing plasma lithium concentrations. Careful monitoring of lithium blood levels and dose adjustment may be necessary during concomitant use of these drugs, as well as after 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 did not affect plasma concentrations or renal clearance of methotrexate. 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 methotrexate toxicity should be performed when etoricoxib and methotrexate are used concomitantly.

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 AUC0–24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the same oral contraceptives either simultaneously or with a 12-hour interval increased the steady-state AUC0–24hr of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with different ethinylestradiol content for concomitant use with etoricoxib. Increased ethinylestradiol 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 Premarin™) for 28 days increased the steady-state mean AUC0–24hr of unconjugated estrone by 41%, equilin by 76%, and 17-β-estradiol by 22%. The effect of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 mg to 1.25 mg during monotherapy with Premarin™, the effect of 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 use of high-dose Premarin™ concomitantly with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal agent 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 AUC0–24hr or renal excretion of digoxin. However, an increase in digoxin Cmax (by approximately 33%) was observed. This increase is generally not clinically significant in most patients. Nevertheless, patients at high risk of digoxin toxicity should be closely monitored when etoricoxib and digoxin are used concomitantly.

Effect of etoricoxib on drugs metabolized by sulfotransferases

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

Effect of etoricoxib on drugs metabolized by CYP isoenzymes

In vitro data indicate no expected inhibition of cytochrome P450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4. 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 etoricoxib metabolism in vivo. In vitro studies suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, although their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at 400 mg once daily for 11 days to healthy volunteers, ketoconazole had no 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 based on published data.

Rifampicin. Concomitant administration of etoricoxib and rifampicin (a potent inducer of CYP enzymes) resulted in a 65% reduction in plasma concentrations of etoricoxib. This may be associated with recurrence of symptoms when used concomitantly with etoricoxib. While these data may suggest the need for dose adjustment, etoricoxib should not be used at doses exceeding those specified for each indication, as the combination 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.

Gastrointestinal effects

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

NSAIDs should be prescribed with caution to patients at increased risk of gastrointestinal complications; elderly patients, patients taking any other NSAID or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disorders (such as peptic ulcers or gastrointestinal bleeding).

There is an increased risk of gastrointestinal adverse reactions (gastrointestinal ulceration or other gastrointestinal complications) with concomitant use of etoricoxib and 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 nonsteroidal anti-inflammatory drugs + acetylsalicylic acid.

Cardiovascular effects

Clinical studies indicate that use of drugs in the class of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (particularly myocardial infarction and stroke) compared to placebo and some NSAIDs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib use, the drug should be prescribed for the shortest possible duration and at the lowest effective daily dose. The need for symptomatic pain relief and the patient's response to treatment should be regularly reviewed, especially in patients with osteoarthritis.

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

Selective COX-2 inhibitors do not replace the use of acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet effects. 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 lead to reduced prostaglandin synthesis and, consequently, reduced 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 drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients treated with etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics." The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema due to any other cause. If clinical signs of worsening condition occur in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

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

Hepatic effects

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

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

General instructions

If deterioration in function of any of the organ systems mentioned above occurs during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. Appropriate medical monitoring is required when etoricoxib is administered to elderly patients and 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 very rarely been 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 treatment, and onset is usually within the first month of therapy. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been observed in patients taking etoricoxib. Some selective COX-2 inhibitors increase the risk of skin reactions in patients with a history of allergic reactions to any drug. Etoricoxib should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

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

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 for women planning pregnancy.

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

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk to pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may lead to uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking 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 starting NSAID therapy; oligohydramnios is usually reversible after discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while taking etoricoxib, the drug should be discontinued immediately.

Lactation period

It is unknown whether etoricoxib passes into 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 for women planning pregnancy.

Ability to influence reaction speed when driving or operating machinery.

Patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should not drive or operate machinery.

Method of Administration and Dosage

The medicinal product Runia is administered orally. The drug can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken before a meal. This should be taken into account when rapid symptom relief is required.

Since the risk of cardiovascular adverse events associated with etoricoxib use increases with higher doses and longer duration of exposure, treatment should be initiated using the shortest duration possible and the lowest effective daily dose. The need for symptom relief and response to therapy should be periodically reassessed, especially in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients with insufficient symptom relief, increasing the dose to 60 mg once daily may enhance efficacy. If no improvement is observed, alternative treatment options should be considered.

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients with inadequate symptom control, increasing the dose to 90 mg once daily may improve therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Ankylosing Spondylitis

The recommended dose is 60 mg once daily. In some patients with insufficient symptom relief, increasing the dose to 90 mg once daily may improve therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Acute Pain

In cases of acute pain, etoricoxib should be used only during the acute symptomatic period.

Acute Gouty Arthritis

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

Postoperative Dental Pain

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

Doses exceeding those recommended for each indication have not demonstrated additional efficacy or have not been studied. Therefore:

• the dose in osteoarthritis should not exceed 60 mg per day;
• the dose in rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg per day;
• the dose in acute gout should not exceed 120 mg per day for a maximum treatment duration of 8 days;
• the dose for acute pain following dental surgery should not exceed 90 mg per day for a maximum of 3 days.

Elderly Patients

No dose adjustment is necessary for elderly patients. As with other medicinal products, 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 (5–6 points on the Child–Pugh scale). In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), the dose should not exceed 30 mg once daily, regardless of the indication.

Clinical experience with etoricoxib use is limited, especially 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 (≥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

During clinical trials, single doses of etoricoxib up to 500 mg or multiple doses up to 150 mg daily 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 reported. The most commonly observed adverse reactions were consistent with the safety profile of etoricoxib (gastrointestinal, cardiac, and renal events).

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

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

Adverse reactions.

Summary of safety profile

The safety of etoricoxib was evaluated in clinical studies involving 9,295 patients, including 6,757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis received treatment for 1 year or longer).

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

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

In the cardiovascular safety assessment program, data from three active-comparator-controlled studies included 17,412 patients with osteoarthritis or rheumatoid arthritis who received etoricoxib (at doses of 60 mg or 90 mg) for a mean duration of approximately 18 months. Safety data and more detailed information on this program are provided in the section "Pharmacological properties".

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

Summary table of adverse reactions

The following adverse reactions 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 up to three and a half years, short-term acute pain studies up to 7 days, and post-marketing experience).

Table 2

* The frequency category is defined for each adverse reaction term according to the frequency in the clinical trial database: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). The frequency of adverse reactions reported during post-marketing use cannot be determined, as they are derived from spontaneous reports.

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

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

ß Hypersensitivity includes the following terms: allergy, drug allergy, drug hypersensitivity, hypersensitivity, hypersensitivity not specified, hypersensitivity reaction, and unspecified allergy.

¶ Intracranial hemorrhage was observed in patients with additional risk factors such as arterial hypertension, thrombocytopenia, and warfarin use.

§ Based on results from long-term, placebo- 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 NSAID use, such as nephrotoxicity, including interstitial nephritis and nephrotic syndrome, have been reported; therefore, the occurrence of such events cannot be excluded with etoricoxib use.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 ºC. Keep out of reach of children.

Packaging.

For 60 mg and 90 mg tablets.

7 tablets in a blister; 1 or 2 blisters in a cardboard pack.

For 120 mg tablets.

7 tablets in a blister; 1 blister in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Atlantik Farmácia Produções Farmacêuticas S.A. / Atlantic Pharma Producoes Farmaceuticas S.A.

Manufacturer's address and location of its operations.

Rua De Tapada Grande 2, Abrunheira, Sintra, 2710-228, Portugal / Rua De Tapada Grande 2, Abrunheira, Sintra, 2710-228, Portugal.

Marketing Authorization Holder.

LLC "FORC-PHARMA DISTRIBUTION".

Address of the Marketing Authorization Holder.

132 Hryshko Avenue, Kyiv, 03127, Ukraine.