Brutaflam®-60

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRUTAFLAM®-60 (BRUTAFLAM®-60) BRUTAFLAM®-90 (BRUTAFLAM®-90) BRUTAFLAM®-120 (BRUTAFLAM®-120)

Composition:

Active substance: etoricoxib (etoricoxib);

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

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate, "Opadry II" green 32K510053* (for 60 mg dosage), "Opadry II" white 32K580000** (for 90 mg dosage), "Opadry II" green 32K510054* (for 120 mg dosage).

* "Opadry II" green 32K510053, "Opadry II" green 32K510054: hypromellose; lactose monohydrate; titanium dioxide (E 171); triacetin; FD&C Blue No. 2 / indigo carmine aluminum lake (E 132); iron oxide yellow (E 172).

**"Opadry II" white 32K580000: hypromellose; lactose monohydrate; titanium dioxide (E 171); triacetin.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

60 mg tablets: round, biconvex, film-coated tablets of dark green color, smooth on both sides.

90 mg tablets: round, biconvex, beveled-edge, film-coated tablets of white color, smooth on both sides.

120 mg tablets: round, biconvex, film-coated tablets of pale green color, smooth on both sides.

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 Brutfam® dose-dependently inhibited COX-2 (cyclooxygenase-2) without inhibiting COX-1 when administered at doses up to 150 mg per day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for prostaglandin formation. Two isoforms have been identified—COX-1 and COX-2. COX-2 is the inducible isoform of the enzyme 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 arterial duct, as well as in 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 period 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 assessment scales applied in other studies). In a dose-finding study, etoricoxib at a dose of 60 mg demonstrated significantly greater improvement compared to 30 mg with respect to 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. In studies evaluating the 60 mg and 90 mg doses, positive effects were maintained over the 12-week treatment period. In a dose-comparison study of 60 mg versus 90 mg, both etoricoxib doses—60 mg once daily and 90 mg once daily—were more effective than placebo. The 90 mg dose was more effective than the 60 mg dose according to the overall patient assessment of pain (0–100 mm visual analogue scale), with a mean improvement of –2.71 mm (95% CI [confidence interval]: –4.98 mm, –0.45 mm).

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

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal pain, inflammation, restricted mobility, and enhanced 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-evaluation study comparing 60 mg to 90 mg, etoricoxib at doses of 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 60 mg daily treatment over 6 weeks, increasing the dose to 90 mg daily improved assessment of back pain intensity (0–100 mm visual analogue scale) compared to continuing 60 mg daily, with a mean improvement of –2.70 mm (95% CI: –4.88 mm, –0.52 mm).

In a clinical study of postoperative dental pain, etoricoxib 90 mg 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 that of 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 at 6 hours (TOPAR6). 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 paracetamol/codeine 600 mg / 60 mg every 6 hours group, compared to 76.2% of patients receiving placebo. In this study, onset of analgesic action (meaningful pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after drug administration.

Safety

International etoricoxib versus diclofenac clinical trial program for long-term treatment of arthritis (MEDAL)

MEDAL was a prospectively designed safety program evaluating cardiovascular safety using 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 (OA) and 5,700 with rheumatoid arthritis (RA) received either etoricoxib 60 mg (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for a mean duration of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse 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. In the EDGE study, 7,111 patients with OA received etoricoxib 90 mg daily (1.5 times higher than the recommended dose for OA treatment) or diclofenac 150 mg daily for a mean duration of 9.1 months (maximum 16.6 months, median 11.4 months). In the EDGE II study, 4,086 patients with RA received etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean duration of 19.2 months (maximum 33.1 months, median 24 months).

The combined MEDAL program included 34,701 patients with OA and RA 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 risk factors for cardiovascular and gastrointestinal (GI) systems. Patients who had experienced myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study initiation were excluded. Concomitant use of gastroprotective agents and low-dose acetylsalicylic acid was permitted in the studies.

Overall safety

There were no significant differences in the frequency of thrombotic cardiovascular events between etoricoxib and diclofenac. Cardiorenal adverse reactions occurred more frequently with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Cardiovascular safety

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

Table 1

Incidence of confirmed thrombotic cardiovascular complications (combined MEDAL program)

Complications	Etoricoxib (N = 16819) 25836 patient-years		Diclofenac (N = 16483) 24766 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)
Intention-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)
Intention-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)
Intention-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)
Intention-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 therapy or within 14 days after its discontinuation (excluding patients who took <75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs for >10% of the total period). Intention-to-treat: all confirmed complications until the end of the study (including patients who may have received non-study interventions leading to discontinuation of the study drug). Total number of randomized patients: 17412 in the etoricoxib group and 17289 in the diclofenac group.

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

Cardiorenal complications

Approximately 50% of patients enrolled in the MEDAL study had a history of arterial hypertension at baseline. In 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 frequency of the adverse reaction of congestive heart failure (treatment discontinuation and serious reactions) was similar with etoricoxib 60 mg and diclofenac 150 mg; however, the frequency of these reactions 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 from the EDGE and EDGE II studies were consistent with the data reported in the MEDAL study.

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

Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of 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. Regarding 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 upper gastrointestinal tract was not statistically significant in patients concurrently taking low-dose aspirin (approximately 33% of patients).

The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper 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] per 100 patient-years with etoricoxib compared to 2.78 [95% CI 2.14, 3.56] with diclofenac).

The 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 treatment 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 compared to diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

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 in patients taking etoricoxib ≥60 mg, placebo, or other nonsteroidal anti-inflammatory drugs (NSAIDs), except naproxen. However, the frequency of such reactions 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 than with placebo.

Renal function study in elderly patients

In a randomized, double-blind, placebo-controlled, parallel-group study, the effect of 15-day treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other renal function parameters was evaluated in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had a similar effect on urinary sodium excretion after 2 weeks of treatment. All active comparator drugs showed an increase in systolic blood pressure relative to placebo; however, etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic 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 until steady state is reached, maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is observed approximately 1 hour (Tmax) after dosing in adults fasting. 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% reduction in Cmax and a 2-hour increase in Tmax. These data 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 at concentrations ranging from 0.05 to 5 µg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.

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

Metabolism. Etoricoxib is actively 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 inhibitors of COX-2. None of these metabolites inhibit COX-1.

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

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

Special patient populations.

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

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

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

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

For short-term treatment of moderate postoperative pain related to dental surgery.

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

Contraindications.

Brutaflem® is contraindicated:

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

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Oral anticoagulants. In patients whose condition is stabilized with long-term warfarin therapy, administration of etoricoxib at a dose of 120 mg 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 its dosage is changed.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist 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. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combined 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 acetylsalicylic acid at doses used for cardiovascular disease prevention (low-dose acetylsalicylic acid). However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid doses higher than prophylactic doses, as well as with other nonsteroidal anti-inflammatory drugs, is not recommended.

Cyclosporine and tacrolimus. Although the interaction between etoricoxib and these drugs has not been studied, concomitant use of any nonsteroidal anti-inflammatory drug 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. Nonsteroidal anti-inflammatory drugs reduce renal elimination of lithium, thereby increasing plasma lithium levels. Careful monitoring of lithium blood levels and dose adjustment of lithium should be performed during concomitant use of these drugs, as well as upon discontinuation of NSAIDs.

MTX (Methotrexate). Two studies evaluated the effects of etoricoxib administered at doses of 60, 90, or 120 mg once daily for 7 days in patients receiving weekly methotrexate at doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 and 90 mg did not affect plasma concentration or renal clearance of methotrexate. In one study, administration of etoricoxib 120 mg had no effect on plasma concentration or renal clearance of methotrexate, 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 co-administered.

Oral contraceptives. Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 µg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC_0–24hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the above-mentioned oral contraceptives either simultaneously or 12 hours apart increased the steady-state AUC_0–24hr of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with varying ethinylestradiol content to be used concomitantly 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 mean steady-state AUC_0–24hr of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (30, 60, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 to 1.25 mg during monotherapy with Premarin™, the effect of etoricoxib 120 mg on exposure (AUC_0–24hr) of estrogenic components of Premarin™ was less than half. The clinical significance of this increase is unknown, and the use of high-dose Premarin™ concomitantly with etoricoxib has not been studied. This increase in estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use during concomitant 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 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 AUC_0–24hr or renal elimination of digoxin. An increase in digoxin C_max (by approximately 33%) was observed. This increase is generally not clinically significant in most patients. However, patients at high risk of digoxin toxicity should be closely 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 numerous sulfotransferases are currently limited and the clinical effects of many drugs are still under investigation, etoricoxib should be used with caution when co-administered with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by CYP isoenzymes

Based on in vitro studies, inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. In studies involving healthy volunteers, daily administration of etoricoxib 120 mg did not affect hepatic CYP3A4 activity, as determined 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 indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, although their quantitative contributions have not been studied in vivo.

Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered to healthy volunteers at 400 mg once daily for 11 days, ketoconazole did not 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 oral voriconazole or miconazole in the form of an oral gel for local use (potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure; however, this was not considered clinically significant according to published data.

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

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

Special precautions for use.

Gastrointestinal tract effects

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

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

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

Cardiovascular effects

Clinical studies indicate that 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 nonsteroidal anti-inflammatory drugs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib treatment, the drug should be prescribed for the shortest possible duration and at the lowest effective daily dose. The need for symptomatic pain relief and the patient's response to treatment should be periodically reassessed, 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 evaluation of the risk of complications.

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

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 production and, consequently, decreased renal blood flow, thereby worsening renal function. Patients with pre-existing severe renal impairment, decompensated heart failure, or cirrhosis are at high risk of such reactions. Renal function should be monitored in these patients.

Fluid retention, edema, and arterial hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All nonsteroidal anti-inflammatory drugs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. For dose-dependent effects, see section "Pharmacological properties. Pharmacodynamics". The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema from any other cause. If clinical signs of worsening condition occur, appropriate measures should be taken, including discontinuation of etoricoxib.

Etoricoxib, especially at high doses, may lead to more frequent and severe arterial hypertension compared to some other nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors. Therefore, arterial pressure should be monitored before initiating etoricoxib therapy, and particular attention should be paid to blood pressure monitoring during treatment. Blood pressure should be monitored within the first 2 weeks of treatment 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) were observed in approximately 1% of patients participating in clinical trials who received etoricoxib at doses of 30, 60, and 90 mg daily for up to 1 year.

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

General instructions

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

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

During post-marketing surveillance, very rare cases of serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, some with fatal outcomes, have been reported with the use of nonsteroidal anti-inflammatory drugs and certain 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 receiving 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.

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

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

The medicinal product Brutaflym®, film-coated tablets, contains lactose. Patients with rare hereditary intolerance to galactose, lactase deficiency, or glucose-galactose malabsorption syndrome should not use this medicinal product.

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 shown 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 reduced uterine contractions and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking nonsteroidal anti-inflammatory drugs (NSAIDs) from the 20th week of pregnancy onward. In some cases, this may lead to impaired renal function in newborns. These effects may occur soon after initiating NSAID therapy; oligohydramnios is usually reversible upon discontinuation of treatment.

Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib must be discontinued.

Lactation

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 COX-2 inhibitors, is not recommended in women planning pregnancy.

Ability to influence the speed of reactions 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 Brutaflym® is administered orally. The drug can be taken regardless of food intake. However, the onset of effect occurs faster when taken before meals. This should be considered if rapid symptom relief is required.

Since the risk of cardiovascular adverse events with etoricoxib increases with higher doses and longer duration of treatment, the shortest possible treatment courses using the lowest effective daily doses should be used. The need for symptom relief and response to treatment should be periodically reassessed, 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 improvement is observed, alternative treatment options should be considered.

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients, if symptoms are not sufficiently controlled, increasing the dose to 90 mg once daily may improve therapeutic effect. After achieving clinical stability, the dose should be reduced to 60 mg once daily. If there is no improvement, alternative treatment approaches 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. After achieving clinical stability, the dose should be reduced to 60 mg once daily. If no improvement occurs, 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. However, as with other medications, Brutaflym® 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 is limited, particularly in patients with moderate hepatic impairment; therefore, the drug should be used with caution. There is no clinical experience with etoricoxib in patients with severe hepatic impairment (≥10 points on the Child–Pugh scale); therefore, Brutaflym® 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.

* To ensure appropriate dosing, etoricoxib in another pharmaceutical form should be used.

Children

Etoricoxib is contraindicated in children under 16 years of age.

Overdose

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

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

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

Adverse reactions

The safety of etoricoxib was evaluated in clinical studies involving 9295 patients, including 6757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, 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-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 presented in the section "Pharmacological properties".

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

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

Table 2

Body systems	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
	confusional state‡, restlessness‡	rare
Nervous system disorders	dizziness, headache	common
	dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence	uncommon
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, cerebrovascular disorder§, transient ischemic attack, hypertensive crisis‡, vasculitis‡	uncommon
Respiratory, thoracic and mediastinal disorders	bronchospasm‡	common
	cough, dyspnea, epistaxis	uncommon
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 bowel motility, dry mouth, gastroduodenal ulcers, peptic ulcers including gastrointestinal perforation and hemorrhage, irritable bowel syndrome, pancreatitis‡	uncommon
Hepatobiliary disorders	elevation of ALT, elevation of AST	common
	hepatitis‡	rare
	liver 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 lupus erythematosus‡	rare†
Musculoskeletal and connective tissue disorders	muscle spasms/cramps, musculoskeletal pain/stiffness	uncommon
Renal and urinary disorders	proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section “Special precautions for use”)	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	uncommon
	decreased blood sodium	rare

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

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

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

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

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

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

Reporting of suspected adverse reactions

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

Reporting of adverse reactions following marketing authorization of the medicinal product is of significant importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should 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.

2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging, protected from moisture and light.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer. Mankind Pharma Limited, Unit-II.

Manufacturer's address and location of operations.

Village Kishanpura, P.O. Jamniwal, Tehsil Paonta Sahib, District Sirmour 173025, Himachal Pradesh, India.