Forsanek®

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

Composition:

Active substance: etoricoxib;

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

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

Film coating: Opadry II 31G58920 white (hydroxypropylmethylcellulose, lactose monohydrate, titanium dioxide (E 171), polyethylene glycols, talc).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg film-coated tablets: oval, film-coated tablets with a biconvex surface, white to almost white in color, with a dividing line on one side and a flat surface on the other side;

90 mg and 120 mg film-coated tablets: round, film-coated tablets with a biconvex surface, white to almost white in color, with flat surfaces on both sides.

Pharmacotherapeutic group. Non-steroidal 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) when administered at doses up to 150 mg daily. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the formation 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 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, 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 perilesional gastric tissue in humans, although 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-reported 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 a dose of 30 mg once daily, the efficacy of the drug exceeded that of placebo over a 12-week treatment period (using the same assessment criteria as in other studies). In a dose-ranging study, etoricoxib at a dose of 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, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain severity, inflammation, and joint mobility. In studies evaluating 60 mg and 90 mg doses, the positive effect was maintained over a 12-week treatment period. In a study comparing the 60 mg and 90 mg doses, both etoricoxib regimens — 60 mg once daily and 90 mg once daily — were more effective than placebo. The 90 mg dose was more effective than the 60 mg dose according to patients' overall pain assessment (0–100 mm — visual analog scale), with a mean improvement of 2.71 mm (95% CI [confidence interval]: –4.98; –0.45).

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 treatment initiation.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal pain, inflammation, restricted mobility, and enhanced functional capacity. Clinical benefits of etoricoxib were observed as early as day 2 after therapy initiation and persisted throughout the 52-week treatment period. In a second dose-comparison study evaluating 60 mg versus 90 mg, etoricoxib at both 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; –0.52).

In a clinical study of postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated an analgesic effect comparable to ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722) and superior to that of paracetamol/codeine 600 mg / 60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001), as measured by total pain relief over 6 hours (TOPAR6). The proportion of patients requiring rescue analgesics within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the paracetamol/codeine 600 mg / 60 mg every 6 hours group, compared to 76.2% in the placebo group. In this study, the onset of analgesic action (meaningful pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after administration.

Safety

Medicinal Osteoarthritis and Rheumatoid Arthritis Long-term Etoricoxib and Diclofenac Safety Program (MEDAL)

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

In the MEDAL study, which focused on cardiovascular outcomes, 17,804 patients with osteoarthritis and 5,700 with rheumatoid arthritis received either etoricoxib 60 mg (for osteoarthritis) or 90 mg (for both osteoarthritis and rheumatoid arthritis) 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 who received 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 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 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 received treatment for over 24 months. Patients enrolled in this program had varying baseline cardiovascular and gastrointestinal (GI) risk factors. Patients who had experienced 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). Adverse reactions related to the gastrointestinal tract and liver 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 frequency of confirmed serious thrombotic cardiovascular adverse reactions (including cardiac events, cerebrovascular events, and peripheral vascular events) was compared between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the frequency of thrombotic complications between etoricoxib and diclofenac across all analyzed subgroups, including patients with cardiovascular risk. When considered separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.

Table 1

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

Complications		Etoricoxib (N = 16,819) 25,836 patient-years		Diclofenac (N = 16,483) 24,766 patient-years		Comparison between treatment groups
		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 (excluding 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 study completion (including patients who may have received non-study interventions leading to discontinuation of the study drug). Total number of randomized patients: 17,412 in the etoricoxib group and 17,289 in the diclofenac group.

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

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

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

In individual studies of the MEDAL program, the absolute rate 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 rate of drug discontinuation observed with etoricoxib 90 mg compared to 60 mg.

Gastrointestinal tolerability results in the MEDAL program. A significantly lower rate of treatment discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib compared to diclofenac in each of the three MEDAL program studies. The rates of treatment 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 regarding 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 the effect on the upper gastrointestinal tract was not statistically significant in patients who were concurrently using low-dose acetylsalicylic acid (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical events in the upper gastrointestinal tract (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).

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

Liver safety results from the MEDAL program. Etoricoxib was associated with a statistically significantly lower rate of treatment discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving diclofenac discontinued 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 compared to diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic complications

During clinical trials, excluding the MEDAL program studies, approximately 3,100 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 in patients taking etoricoxib at doses ≥ 60 mg compared to 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 receiving etoricoxib 120 mg once daily compared to patients receiving naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The incidence of ulcers was higher with etoricoxib compared to placebo.

Renal function study in elderly patients

In a randomized, double-blind, placebo-controlled, parallel-group study, the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on 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 sodium excretion after 2 weeks of treatment. All active comparator drugs showed an increase in systolic blood pressure compared 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 following 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 reached approximately 1 hour (Tmax) after dosing in adults under fasting conditions. The geometric mean AUC0–24h is 37.8 µg×h/mL. Within the clinical dose range, the pharmacokinetics of etoricoxib are linear.

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

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days with a daily dose of 120 mg, 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 males and females.

Hepatic impairment. In patients with mild hepatic impairment (5–6 points on the Child–Pugh scale), the mean area under the pharmacokinetic concentration–time curve (AUC) after administration of etoricoxib 60 mg once daily was approximately 16% higher than in healthy volunteers receiving the same dose. In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), the mean AUC after administration of etoricoxib 60 mg every other day was similar to that in healthy volunteers receiving etoricoxib 60 mg once daily daily; administration of etoricoxib 30 mg once daily has not been studied in this patient group. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (≥ 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, are not significantly different from those in healthy volunteers. Etoricoxib is minimally removed during hemodialysis (dialysis clearance approximately 50 mL/min).

Children. 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 signs of inflammation associated with acute gouty arthritis.

Short-term treatment of moderate postoperative dental pain.

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

Contraindications. Forzanec® is contraindicated:

• in hypersensitivity to the active substance or to any of the excipients;
• in active peptic ulcer or active gastrointestinal bleeding;
• in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors;
• 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 functional class II–IV);
• in patients with arterial hypertension whose blood pressure values consistently exceed 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 prothrombin time/international normalized ratio (INR). Therefore, in patients receiving oral anticoagulants, prothrombin time/INR should be monitored frequently, especially during the first days of etoricoxib treatment or when changing its dosage.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration in renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combined treatment 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 medicinal products 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 agents.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs reduce renal lithium excretion, thereby increasing its plasma concentration. If necessary, careful monitoring of lithium plasma levels and dose adjustment should be performed 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 7.5–20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg did not affect methotrexate plasma concentration or renal clearance. In one study, 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 is co-administered with methotrexate.

Oral contraceptives. Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 mcg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0–24h of ethinylestradiol by 37%. Etoricoxib 120 mg, when administered concomitantly with or 12 hours apart from these oral contraceptives, increased the steady-state AUC0–24h of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with varying ethinylestradiol content for concomitant use with etoricoxib. Increased ethinylestradiol exposure may increase the frequency of adverse reactions associated with oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of 120 mg etoricoxib with hormone replacement therapy containing conjugated estrogens (0.625 mg Premarin™) for 28 days increased the steady-state AUC0–24h of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (60 mg and 90 mg) has not been studied. Compared to doubling the dose from 0.625 mg to 1.25 mg of Premarin™ monotherapy, the effect of etoricoxib 120 mg on the AUC0–24h 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 hormone replacement therapy.

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

Digoxin. Administration of etoricoxib 120 mg once daily for 10 days in healthy volunteers did not affect the steady-state AUC0–24h or renal digoxin excretion. 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 monitored when etoricoxib and digoxin are co-administered.

Effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum ethinylestradiol concentrations. Since data on the effects of numerous sulfotransferases are still limited and the clinical effects of many drugs are under investigation, etoricoxib should be co-administered with caution 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) 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 is a potent inhibitor of CYP3A4. When administered to healthy volunteers at 400 mg once daily for 11 days, ketoconazole did not exert 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 voriconazole (oral) or miconazole (as an oral gel for local use)—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 etoricoxib plasma concentration. This may be associated with recurrence of symptoms during concomitant use with etoricoxib. While these data may suggest a need for dose adjustment, it is not recommended to use etoricoxib at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.

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

Special precautions for use

Gastrointestinal (GI) tract effects

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

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

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

Cardiovascular effects

Clinical studies indicate that the use of selective COX-2 inhibitors may be associated with an increased risk of thrombotic events (particularly myocardial infarction and stroke) compared to placebo and some NSAIDs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib treatment, the drug should be administered 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 reviewed regularly, especially in patients with osteoarthritis.

Etoricoxib should be prescribed to patients with significant cardiovascular risk factors (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, the use of etoricoxib may lead to reduced prostaglandin synthesis and, consequently, reduced renal blood flow, thereby worsening renal function. The risk of such reactions is particularly high in patients with pre-existing severe renal impairment, decompensated heart failure, or cirrhosis. Renal function should be monitored in these patients.

Fluid retention, edema, and arterial hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients treated with etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics." The drug should be prescribed with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema from any other cause. Appropriate measures, including discontinuation of etoricoxib, should be taken if clinical signs of worsening condition occur.

Etoricoxib, particularly at high doses, may cause 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 blood pressure should be closely monitored 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]) were 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, 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 instructions

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

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

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, with most cases beginning within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been observed in patients taking etoricoxib. Some selective COX-2 inhibitors 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 signs of fever and other symptoms of inflammation.

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

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

Excipients

The medicinal product Forcenac® contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically 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 nonsteroidal anti-inflammatory drugs (NSAIDs) from the 20th week of gestation onwards. In some cases, this may lead to impaired renal function in newborns. These effects may occur soon after initiation of NSAID therapy; oligohydramnios is usually reversible after discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while on treatment, etoricoxib should be discontinued immediately.

Breastfeeding period

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

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

Method of Administration and Dosage

The medicinal product Forzanek® should be administered orally. Tablets can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken before meals. This should be considered when rapid symptom relief is required.

The 60 mg tablet can be divided in half. Do not divide the 90 mg and 120 mg tablets.

Since the risk of cardiovascular adverse events increases with higher doses and longer duration of treatment with etoricoxib, the shortest possible treatment courses at the lowest effective daily doses should be used. The need for symptom relief and response to treatment should be periodically re-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 effect 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 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, if symptoms are not adequately relieved, 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 the case of acute pain, etoricoxib should be used only during the acute symptomatic period.

Acute Gouty Arthritis

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

Postoperative Dental Pain

The recommended dose is 90 mg once daily for 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 in 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. However, as with other medications, etoricoxib should be prescribed with caution in elderly patients.

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

Renal Impairment

Dose adjustment is not required in patients with creatinine clearance ≥30 mL/min. The use of etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min.

Children. Forcenac® is contraindicated in children under 16 years of age.

Overdose

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

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

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

Adverse Reactions

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

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

Table 2

System Organ Classes	Adverse Reactions	Frequency Category*
Infections and infestations	alveolar osteitis	common
	gastroenteritis, upper respiratory tract infections, urinary tract infections	uncommon
Blood and lymphatic system disorders	anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia	uncommon
Immune system disorders	hypersensitivity‡ ß	uncommon
	angioedema, anaphylactic/anaphylactoid reactions, including shock‡	rare
Metabolism and nutrition disorders	edema / fluid retention	common
	decreased or increased appetite, weight gain	uncommon
Psychiatric disorders	anxiety, depression, impaired cognition, hallucinations‡	uncommon
	confusion‡, restlessness‡	rare
Nervous system disorders	dizziness, headache	common
	dysgeusia, insomnia, paresthesia/hypesthesia, somnolence	uncommon
	intracranial hemorrhage¶	unknown
Eye disorders	blurred vision, conjunctivitis	uncommon
Ear and labyrinth disorders	tinnitus, dizziness	uncommon
Cardiac disorders	palpitations, arrhythmia‡	common
	atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§	uncommon
Vascular disorders	hypertension	common
	flushing, cerebral ischemia§, transient ischemic attack, hypertensive crisis‡, vasculitis‡	uncommon
	deep vein thrombosis	unknown
Respiratory, thoracic and mediastinal disorders	bronchospasm‡	common
	cough, dyspnea, epistaxis	uncommon
	pulmonary embolism	unknown
Gastrointestinal disorders	abdominal pain	very common
	constipation, flatulence, gastritis, heartburn / acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, oral ulcers	common
	abdominal distension, altered intestinal peristalsis, dry mouth, gastroduodenal ulcers, peptic ulcers including perforation and gastrointestinal hemorrhage, irritable bowel syndrome, pancreatitis‡	uncommon
Hepatobiliary disorders	elevated ALT levels, elevated AST levels	common
	hepatitis‡	rare
	hepatic failure‡, jaundice‡	rare†
Skin and subcutaneous tissue disorders	ecchymosis	common
	facial swelling, pruritus, rash, erythema‡, urticaria‡	uncommon
	Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, drug-induced fixed erythema‡	rare†
Musculoskeletal and connective tissue disorders	muscle cramps/spasms, musculoskeletal pain/stiffness	uncommon
Renal and urinary disorders	proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section "Special precautions")	uncommon
General disorders and administration site conditions	asthenia/fatigue, influenza-like symptoms	common
	chest pain	uncommon
Investigations	increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid levels	uncommon
	decreased blood sodium levels	rare

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

‡ Adverse reaction identified during post-marketing surveillance. Frequency was determined based on the maximum frequency observed in clinical trials (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% CI 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 = 15,470).

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

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

§ 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 increase in risk of such events exceeds 1% per year (uncommon).

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as 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

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer

Kusum Healthcare Pvt Ltd /

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of manufacturing site

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India /

Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.