DAZATINIB-TEVA

INSTRUCTIONS FOR MEDICAL USE OF FORSANEK^®MEDICINAL PRODUCT

FORCANEK^®(FORSANEC^®)

COMPOSITION:

Active substance: etoricoxib; 1 film-coated tablet contains etoricoxib 60 mg or 90 mg or 120 mg; excipients: anhydrous calcium hydrogen phosphate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate; film coating: Opadry II 31G58920 white (hydroxypropylmethylcellulose, lactose monohydrate, titanium dioxide (E 171), polyethylene glycols, talc).

PHARMACEUTICAL FORM.

Tablets, film-coated.

MAIN PHYSICOCHEMICAL PROPERTIES:

60 mg film-coated tablets: oval, biconvex, film-coated tablets, white to almost white, with a score line on one side and a flat surface on the other; 90 mg and 120 mg film-coated tablets: round, biconvex, film-coated tablets, white to almost white, with a flat surface on both sides.

PHARMACOTHERAPEUTIC GROUP.

Nonsteroidal anti-inflammatory and antirheumatic products. 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 used at doses up to 150 mg per day. Etoricoxib does not inhibit the synthesis of gastric prostaglandins 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 an isoform of the enzyme that is induced by an inflammatory impulse 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, regulation of kidney function, and central nervous system (induction of fever, pain, cognitive function). It may also be involved in the healing of ulcers. COX-2 has been identified in the tissue around gastric ulcers in humans, but its significance for ulcer healing has not been established.

EFFECTIVENESS

In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improved the condition with pain and the patient's assessment of the disease. These positive effects were observed as early as the second day of treatment and persisted throughout the 52-week treatment period. In studies with the use of etoricoxib at a dose of 30 mg once daily, the effectiveness of this drug exceeded placebo for 12 weeks of treatment (using the same assessments as in other studies). During the dose selection study, etoricoxib at a dose of 60 mg showed significantly greater improvement than at a dose of 30 mg in all three main endpoints after 6 weeks of treatment. The use of a dose of 30 mg for osteoarthritis of the hand has not been studied.

In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved the condition in terms of pain, inflammation, and mobility. In studies evaluating doses of 60 mg and 90 mg, the positive effect persisted throughout the 12-week treatment period. In a study evaluating the dose of 60 mg compared to the dose of 90 mg, both doses of etoricoxib - 60 mg once daily and 90 mg once daily - were more effective than placebo. The dose of 90 mg was more effective than the dose of 60 mg according to the method of General Assessment of Pain by Patients (0-100 mm visual analog scale), with a mean improvement of 2.71 mm (95% CI: -4.98 mm, -0.45 mm).

In patients with acute gouty arthritis attacks, etoricoxib at a dose of 120 mg once daily for 8 days relieved joint pain of moderate and severe degree and inflammation compared to indomethacin at a dose of 50 mg three times daily. Reduction of pain severity is observed as early as 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provides significant improvement in back pain, inflammation, limited mobility, and functional ability. Clinical benefits of etoricoxib were observed on the second day after the start of therapy and persisted throughout the 52-week treatment period. In a second study evaluating the dose of 60 mg compared to the dose of 90 mg, etoricoxib at a dose of 60 mg once daily and 90 mg once daily showed similar effectiveness compared to naproxen 1000 mg daily. In patients who did not show an adequate response during the use of a dose of 60 mg daily for 6 weeks, increasing the dose to 90 mg daily improved the assessment of back pain intensity (0-100 mm visual analog scale) compared to continuing to take 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

During a clinical study of postoperative dental pain, etoricoxib at a dose of 90 mg was used once daily for up to three days. In a subgroup of patients with moderate pain in the initial state, etoricoxib at a dose of 90 mg showed an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722) and exceeded the effect of paracetamol/codeine 600 mg/60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001), which was determined by the indicator of complete pain relief within 6 hours (TOPAR6). The number of patients who reported taking emergency pain relief 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 taking placebo. In this study, the onset of analgesic action (perceived pain relief) of 90 mg etoricoxib was observed as early as 28 minutes after taking the drug.

SAFETY

International Research Program for Long-Term Use of Etoricoxib and Diclofenac in Arthritis (MEDAL)

The MEDAL program was a prospectively designed program of outcomes related to cardiovascular safety based on combined data from three randomized, double-blind, active-controlled comparator studies (MEDAL, EDGE II, and EDGE studies).

In the MEDAL study, which was aimed at determining the impact on the cardiovascular system, 17,804 patients with osteoarthritis and 5,700 with rheumatoid arthritis participated, who used etoricoxib at a dose of 60 mg (osteoarthritis) or 90 mg (osteoarthritis and rheumatoid arthritis) or diclofenac at a dose of 150 mg per day for an average of 20.3 months (maximum - 42.3 months, median - 21.3 months). In this study, only serious adverse reactions and discontinuation of treatment due to the occurrence of any adverse reactions were recorded.

In the EDGE and EDGE II studies, the gastrointestinal tolerability of etoricoxib and diclofenac was compared. In the EDGE study, 7,111 patients with osteoarthritis participated, who used etoricoxib at a dose of 90 mg per day (1.5 times higher than the recommended dose for the treatment of osteoarthritis) or diclofenac at a dose of 150 mg per day for an average of 9.1 months (maximum - 16.6 months, median - 11.4 months). In the EDGE II study, 4,086 patients with rheumatoid arthritis participated, who used etoricoxib at a dose of 90 mg per day or diclofenac at a dose of 150 mg per day for an average of 19.2 months (maximum - 33.1 months, median - 24 months).

In the combined MEDAL program, 34,701 patients with osteoarthritis and rheumatoid arthritis participated, who received treatment for an average of 17.9 months (maximum - 42.3 months, median - 16.3 months); approximately 12,800 patients received treatment for more than 24 months. In patients registered in this program, there were various initial risk factors for cardiovascular and gastrointestinal (GI) systems. Patients who had recently undergone myocardial infarction, aortocoronary bypass grafting, or percutaneous coronary angioplasty within 6 months prior to registration in the study were excluded from the study. The use of gastroprotective agents and low-dose aspirin was allowed in the studies.

GENERAL SAFETY

There were no significant differences in the frequency of thrombotic cardiovascular complications when using etoricoxib and diclofenac. Cardiovascular reactions occurred more frequently when using etoricoxib than diclofenac; this effect was dose-dependent (see detailed results below). Adverse reactions from the GI tract and liver occurred significantly more frequently when using diclofenac than etoricoxib. The frequency of adverse reactions in the EDGE and EDGE II studies, as well as adverse reactions considered serious or leading to discontinuation of treatment in the MEDAL study, was higher when using etoricoxib than diclofenac.

SAFETY FOR THE CARDIOVASCULAR SYSTEM

The frequency of confirmed thrombotic serious cardiovascular adverse reactions (including reactions from the heart, cerebrovascular reactions, and reactions from peripheral vessels) was compared between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the frequency of thrombotic complications when using etoricoxib and diclofenac in all analyzed subgroups, including patients with cardiovascular risk. When considering the relative risk of confirmed serious thrombotic cardiovascular adverse reactions from the cardiovascular system when using etoricoxib at a dose of 60 mg or 90 mg and diclofenac at a dose of 150 mg, it was the same.

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

CARDIORENAL COMPLICATIONS

About 50% of patients enrolled in the MEDAL study had arterial hypertension in their history at the initial stage. In this study, the frequency of discontinuation of treatment due to the occurrence of adverse reactions related to arterial hypertension was statistically significantly higher in the etoricoxib group than in the diclofenac group. The frequency of such an adverse reaction as congestive heart failure (discontinuation of treatment and serious reactions) was similar when taking etoricoxib 60 mg and diclofenac 150 mg, but the frequency of these reactions was higher when taking etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference when taking etoricoxib 90 mg compared to 150 mg of diclofenac in the OA MEDAL group). The frequency of discontinuation of treatment due to edema was significantly higher when taking etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference when taking etoricoxib 90 mg, but not etoricoxib 60 mg).

Cardiovascular results obtained 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 frequency of discontinuation of treatment in any treatment group 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 discontinuation of treatment observed when taking etoricoxib 90 mg than 60 mg.

RESULTS OF GASTROINTESTINAL TOLERABILITY IN THE MEDAL PROGRAM

A significantly lower rate of discontinuation of treatment due to the occurrence of any clinical complication from the GI tract (e.g., dyspepsia, abdominal pain, ulcers) was observed when using etoricoxib compared to diclofenac in each of the three studies of the MEDAL program. The rates of discontinuation of treatment due to clinical reactions from the GI tract per 100 patient-years for 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.

MEDAL PROGRAM RESULTS FOR LIVER SAFETY

Etoricoxib was associated with a statistically significantly lower frequency of discontinuation of treatment due to adverse reactions from the liver compared to diclofenac. In the combined MEDAL program, 0.3% of patients who used etoricoxib and 2.7% of patients who used diclofenac discontinued treatment due to adverse reactions from the liver. The rate per 100 patient-years was 0.22 when using etoricoxib and 1.84 when using diclofenac (p-value was <0.001 for etoricoxib compared to diclofenac). However, in the MEDAL program, most adverse reactions from the liver were non-serious.

ADDITIONAL SAFETY DATA FOR THE CARDIOVASCULAR SYSTEM REGARDING THROMBOTIC COMPLICATIONS

In clinical studies, excluding the MEDAL program studies, approximately 3,100 patients used etoricoxib at doses of ≥60 mg per day for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular complications in patients taking etoricoxib at a dose of ≥60 mg, placebo, or other NSAIDs (except for naproxen). However, the frequency of such reactions was higher in patients taking etoricoxib compared to those taking naproxen at a dose of 500 mg twice daily. The difference in anti-thrombotic activity between some NSAIDs that inhibit COX-1 and selective COX-2 inhibitors may be clinically significant in patients at risk of developing thromboembolic complications. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these data is unknown.

ADDITIONAL SAFETY DATA FOR THE GI TRACT

In two 12-week double-blind endoscopic studies, the cumulative frequency of developing gastroduodenal ulcers was significantly lower in patients taking etoricoxib at a dose of 120 mg once daily than in patients taking naproxen at a dose of 500 mg twice daily or ibuprofen at a dose of 800 mg three times daily. The frequency of ulcers was higher when using etoricoxib than placebo.

STUDY OF KIDNEY FUNCTION IN ELDERLY PATIENTS

In a randomized, double-blind, placebo-controlled study with parallel groups, the effect of 15-day treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on sodium excretion, blood pressure, and other indicators of kidney function was evaluated in patients aged 60 to 85 years who followed a diet with a salt content of 200 mEq/day. Etoricoxib, celecoxib, and naproxen had a similar effect on sodium excretion. All active comparison drugs showed an increase in systolic blood pressure compared to placebo; however, etoricoxib was associated with a statistically significant increase compared to celecoxib and naproxen on day 14 (mean change in systolic pressure compared to baseline: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, naproxen 3.6 mmHg).

PHARMACOKINETICS.

ABSORPTION

Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%. After taking 120 mg once daily to reach a steady state, the maximum plasma concentration (mean geometric value Cmax = 3.6 μg/mL) is observed approximately 1 hour (Tmax) after administration to adults on an empty stomach. The mean geometric value of AUC0-24h is 37.8 μg × h/mL. Within the clinical dose range, the pharmacokinetics of etoricoxib is linear.

When taking the drug at a dose of 120 mg during a meal (food with a high fat content), no effect on the degree of absorption of etoricoxib was observed. The rate of absorption changed, which was characterized by a decrease in Cmax by 36% and an increase in Tmax by 2 hours. Such data are not considered clinically significant. During clinical studies, etoricoxib was administered regardless of food intake.

DISTRIBUTION

Etoricoxib is approximately 92% bound to human plasma proteins with a concentration of 0.05 to 5 μg/mL. The volume of distribution at steady state (Vdss) is approximately 120 liters 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 in the urine as an unchanged drug. The main pathway of metabolism is the formation of a 6'-hydroxymethyl derivative by catalysis of cytochrome enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the main pathway of metabolism, but their quantitative characteristics have not been studied in vivo.

In humans, five metabolites have been identified. The main metabolite is a 6'-carboxylic acid derivative of etoricoxib, which is formed by further oxidation of the 6'-hydroxymethyl derivative. These main metabolites either have no activity or are weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

ELIMINATION

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

The elimination of etoricoxib occurs almost entirely through metabolism, followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days when administered at a dose of 120 mg once daily, with an accumulation ratio of approximately 2, which corresponds to a half-life of approximately 22 hours. The clearance of etoricoxib from plasma after intravenous administration of 25 mg is approximately 50 mL/min.

SPECIAL POPULATIONS

Elderly patients.

The pharmacokinetics in elderly patients (aged 65 and over) is similar to that in younger patients.

Sex.

The pharmacokinetics of etoricoxib is similar in men and women.

Liver function impairment.

In patients with mild liver function impairment (5-6 points on the Child-Pugh scale), when using etoricoxib at a dose of 60 mg once daily, the mean area under the pharmacokinetic curve (AUC) was approximately 16% higher than in healthy volunteers at the same dosing. In patients with moderate liver function impairment (7-9 points on the Child-Pugh scale), when using etoricoxib at a dose of 60 mg once daily, the mean AUC was similar to that in healthy volunteers who took the drug at a dose of 60 mg once daily; the use of etoricoxib at a dose of 30 mg once daily has not been studied in this group of patients. There are no clinical or pharmacokinetic data on patients with severe liver function impairment (≥10 points on the Child-Pugh scale).

Kidney function impairment.

The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate and severe kidney function impairment, as well as in patients with end-stage kidney disease undergoing hemodialysis, does not differ significantly from the pharmacokinetics in healthy volunteers. During hemodialysis, the drug is almost not removed (dialysis clearance is approximately 50 mL/min).

Children.

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

In a pharmacokinetic study (n = 16) conducted in adolescents (aged 12 to 17 years), the pharmacokinetics in patients with a body weight of 40-60 kg who were prescribed etoricoxib at a dose of 60 mg once daily, and in patients with a body weight over 60 kg who were prescribed the drug at a dose of 90 mg once daily, was similar to the pharmacokinetics in adults who used etoricoxib at a dose of 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 pain associated with dental surgery.

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

CONTRAINDICATIONS.

The medicinal product FORSANEK^®is contraindicated:

• in case of hypersensitivity to the active substance or to any of the excipients of the product;
• in active peptic ulcer or active gastrointestinal bleeding;
• in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors;
• during pregnancy and breastfeeding;
• in severe liver function impairment (albumin in blood serum <25 g/L or ≥10 points on the Child-Pugh scale);
• if the calculated creatinine clearance is <30 mL/min;
• in children under 16 years of age;
• in inflammatory bowel disease;
• in congestive heart failure (NYHA II-IV);
• in patients with arterial hypertension, in whom blood pressure values are consistently above 140/90 mmHg and are not adequately controlled;
• in diagnosed ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER TYPES OF INTERACTIONS.

PHARMACODYNAMIC INTERACTIONS

Oral anticoagulants.

In patients whose condition has been stabilized by constant use of warfarin, taking etoricoxib at a dose of 120 mg per day is accompanied by an increase of approximately 13% in the international normalized ratio (INR) of prothrombin time. Therefore, in patients taking oral anticoagulants, it is necessary to frequently monitor INR, especially in the first days of taking etoricoxib or when changing its dosage.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists.

NSAIDs may weaken the effect of diuretics and other antihypertensive drugs. In some patients with impaired kidney function (e.g., in patients with dehydration or in elderly patients with impaired kidney function), the simultaneous use of an ACE inhibitor or angiotensin II receptor antagonist and drugs that inhibit cyclooxygenase may lead to further impairment of kidney function, including acute kidney failure, which is usually reversible. It should be remembered that such interactions are possible in patients taking etoricoxib simultaneously with any of these drugs. Therefore, such combinations should be prescribed with caution, especially in elderly patients. It is necessary to conduct proper hydration and consider the issue of monitoring kidney function at the beginning of combination therapy and periodically thereafter.

Acetylsalicylic acid.

In a study involving healthy volunteers under steady-state conditions, the use of etoricoxib at a dose of 120 mg once daily did not affect the anti-aggregant activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be prescribed simultaneously with acetylsalicylic acid in doses used for the prevention of cardiovascular diseases (use of acetylsalicylic acid in low doses). However, the simultaneous use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulcers and other complications compared to monotherapy with etoricoxib. It is not recommended to use etoricoxib simultaneously with acetylsalicylic acid in doses higher than prophylactic or with other NSAIDs.

Cyclosporine and tacrolimus.

Although the interaction of etoricoxib with these drugs has not been studied, the simultaneous use of any NSAID with cyclosporine or tacrolimus may enhance the nephrotoxic effect of the latter. It is necessary to monitor kidney function when using etoricoxib simultaneously with either of these drugs.

PHARMACOKINETIC INTERACTIONS

Influence of etoricoxib on the pharmacokinetics of other drugs.

Lithium.

NSAIDs weaken the excretion of lithium by the kidneys, thereby increasing its level in the blood. If necessary, careful monitoring of lithium levels in the blood and adjustment of the lithium dose is carried out during simultaneous use of these drugs and when discontinuing NSAIDs.

Methotrexate.

In two studies, the effects of etoricoxib at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days were studied in patients who used methotrexate once a week at a dose of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg and 90 mg did not affect the concentration of methotrexate in plasma or its renal clearance. In one study, when using etoricoxib at a dose of 120 mg, no effect on the concentration of methotrexate in plasma and its renal clearance was observed, while in another study, when using etoricoxib at a dose of 120 mg, the concentration of methotrexate in plasma increased by 28%, and the renal clearance of methotrexate decreased by 13%. When prescribing etoricoxib and methotrexate simultaneously, it is necessary to monitor for signs of methotrexate toxicity.

Oral contraceptives.

Etoricoxib at a dose of 60 mg, when used simultaneously with oral contraceptives containing 35 μg of ethinyl estradiol and 0.5-1 mg of norethindrone for 21 days, led to an increase in the area under the concentration-time curve (AUC) at steady state for ethinyl estradiol by 37%. Etoricoxib at a dose of 120 mg, when used with the specified oral contraceptives simultaneously or 12 hours apart, increased the AUC at steady state for ethinyl estradiol by 50-60%. Such an increase in ethinyl estradiol concentration should be considered when choosing an oral contraceptive with a different ethinyl estradiol content to be used simultaneously with etoricoxib. The increase in ethinyl estradiol exposure may increase the frequency of adverse reactions associated with the use of oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy.

When taking 120 mg of etoricoxib with hormone replacement therapy drugs containing conjugated estrogens (0.625 mg of Premarin^™), for 28 days, the mean AUC at steady state increased for 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 the increase in dosage from 0.625 mg to 1.25 mg when using Premarin^™monotherapy, the effect of etoricoxib at a dose of 120 mg on the AUC of estrogenic components of Premarin^™was less than half. The clinical significance of such an increase is unknown, and the use of high doses of Premarin^™simultaneously with etoricoxib has not been studied. It is necessary to consider such an increase in estrogen concentration when choosing a hormonal drug for use during menopause simultaneously with etoricoxib, as an increase in estrogen exposure may increase the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone.

In interaction studies, etoricoxib did not have a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin.

When using etoricoxib at a dose of 120 mg once daily for 10 days in healthy volunteers, no effect on the AUC at steady state and renal clearance of digoxin was observed. An increase in the maximum concentration of digoxin (approximately by 33%) was observed. Such an increase is usually not significant in most patients. However, it is necessary to monitor the condition of patients at high risk of digoxin toxicity when prescribing etoricoxib and digoxin simultaneously.

Influence of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, in particular SULT1E1, and may also increase the concentration of ethinyl estradiol in serum. Since there is currently insufficient data on the effect on numerous sulfotransferases, and the clinical effects of many drugs are still being studied, it is advisable to prescribe etoricoxib simultaneously with other drugs that are primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil) with caution.

Influence of etoricoxib on drugs metabolized by CYP isoenzymes

Based on in vitro data, it is not expected that cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 will be inhibited. In a study involving healthy volunteers, daily administration of etoricoxib at a dose of 120 mg did not affect the activity of hepatic CYP3A4, as determined by the erythromycin breath test.

Influence of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism depends on cytochrome enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the main pathway of etoricoxib metabolism, but their quantitative characteristics have not been studied in vivo.

Ketoconazole.

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

Voriconazole and miconazole.

The simultaneous use of voriconazole orally or miconazole in the form of an oral gel for local use (potent inhibitors of CYP3A4) with etoricoxib resulted in a small increase in etoricoxib exposure, which was not considered clinically significant according to published data.

Rifampicin.

The simultaneous use of etoricoxib and rifampicin (a potent inducer of CYP enzymes) led to a decrease in etoricoxib plasma concentration by 65%. This may be accompanied by a recurrence of symptoms when used simultaneously with etoricoxib. While such data may indicate the need to increase the dose, it is not recommended to use etoricoxib in doses exceeding those indicated for each indication, as the combined use of rifampicin and etoricoxib in such doses has not been studied.

Antacids.

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

SPECIAL FEATURES OF USE.

EFFECT ON THE GI TRACT

There have been reports of complications from the upper GI tract (perforations, ulcers, or bleeding), sometimes with a fatal outcome, in patients taking etoricoxib.

Caution should be exercised when prescribing NSAIDs to patients with an increased risk of complications from the GI tract, elderly patients, patients taking any other NSAID or acetylsalicylic acid simultaneously, or patients with a history of gastrointestinal diseases, namely ulcers and gastrointestinal bleeding.

There is an additional risk of developing adverse reactions from the GI tract (gastrointestinal ulcers or other complications) when using etoricoxib and acetylsalicylic acid (even in low doses) simultaneously. In long-term clinical studies, no significant difference was observed in the safety of the GI tract when using selective COX-2 inhibitors + acetylsalicylic acid and NSAIDs + acetylsalicylic acid.

EFFECT ON THE CARDIOVASCULAR SYSTEM

Clinical studies indicate that the use of drugs of the class of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (especially myocardial infarction and stroke) compared to placebo and some NSAIDs. Since the risk of cardiovascular complications increases with increasing dose and duration of etoricoxib use, the drug should be prescribed for as short a period as possible and in the lowest effective daily dose. It is necessary to periodically review the need for patients to have symptomatic pain relief and their response to treatment, especially in patients with osteoarthritis.

Patients with pronounced risk factors for cardiovascular complications (e.g., arterial hypertension, hyperlipidemia, diabetes, smoking) should be prescribed etoricoxib only after careful assessment of the risk of complications.

EFFECT ON THE KIDNEYS

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions accompanied by impaired renal perfusion, the use of etoricoxib may lead to a weakening of prostaglandin production and, consequently, to renal blood flow, thereby worsening kidney function. A high risk of developing such a reaction is observed in patients with already existing pronounced kidney function impairment, decompensated heart failure, or cirrhosis. In such patients, it is necessary to monitor kidney function.

FLUID RETENTION, EDEMA, AND ARTERIAL HYPERTENSION

As with the use of other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients taking etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or recurrence of congestive heart failure. Information on dose-dependent reactions can be found in the "Pharmacological Properties. Pharmacodynamics" section. Caution should be exercised when prescribing the drug to patients with heart failure, left ventricular dysfunction, or arterial hypertension in their history, as well as to patients with edema that has arisen for any other reason. In clinical signs of deterioration in such patients, it is necessary to take appropriate measures, including discontinuation of etoricoxib.

Etoricoxib, especially at high doses, may lead to more frequent and severe arterial hypertension compared to some other NSAIDs and selective COX-2 inhibitors. Therefore, arterial hypertension should be monitored before starting etoricoxib treatment, and special attention should be paid to blood pressure control during treatment with etoricoxib. Blood pressure should be monitored within 2 weeks after starting treatment and then periodically. If blood pressure increases significantly, it is necessary to consider alternative treatment.

EFFECT ON THE LIVER

An increase in the level of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 or more times compared to the upper limit of normal (ULN)) was observed in approximately 1% of patients who participated in clinical studies and used etoricoxib at doses of 30 mg, 60 mg, and 90 mg per day for a period of up to 1 year.

It is necessary to monitor the condition of all patients with symptoms of liver function impairment, as well as the condition of patients with abnormal liver function indicators. In case of signs of liver function impairment and persistent abnormal changes in liver function indicators (3 times higher than ULN), etoricoxib should be discontinued.

GENERAL GUIDELINES

If during treatment, a patient's condition worsens in any of the above systems, it is necessary to take appropriate measures and consider discontinuing etoricoxib. It is necessary to ensure proper medical supervision when using etoricoxib in elderly patients and patients with impaired kidney, liver, or heart function.

Cautiously start treatment with etoricoxib in patients with dehydration. Rehydration is recommended before starting etoricoxib treatment.

DEVELOPMENT OF SERIOUS SKIN REACTIONS, IN SOME CASES WITH A FATAL OUTCOME, INCLUDING EXFOLIATIVE DERMATITIS, STEVENS-JOHNSON SYNDROME, AND TOXIC EPIDERMAL NECROLYSIS, HAS BEEN REPORTED VERY RARELY WHEN USING NSAIDs AND SOME SELECTIVE COX-2 INHIBITORS DURING POSTMARKETING SURVEILLANCE (SEE "ADVERSE REACTIONS" SECTION). THE HIGHEST RISK OF DEVELOPING SUCH REACTIONS IS IN PATIENTS AT THE BEGINNING OF THERAPY, AND THE ONSET OF THESE REACTIONS USUALLY OCCURS 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 ALLERGY TO ANY DRUG. ETORICOXIB SHOULD BE DISCONTINUED AT THE FIRST SIGN OF A RASH, MUCOUS MEMBRANE DAMAGE, OR OTHER SIGNS OF HYPERSENSITIVITY.

When using etoricoxib, the manifestations of fever and other signs of inflammation may be masked.

Cautiously prescribe etoricoxib simultaneously with warfarin or other oral anticoagulants.

The use of etoricoxib, like other COX-2 inhibitors, is not recommended for women planning pregnancy.

EXCIPIENTS

The medicinal product FORSANEK^®contains lactose. If a patient has been diagnosed with an intolerance to some sugars, it is necessary to consult a doctor before taking this medicinal product.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, 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 last trimester of pregnancy, like other drugs that inhibit prostaglandin synthesis, may lead to the absence of uterine contractions and premature closure of the ductus arteriosus. There have been reports of cases of impaired kidney function in the fetus, which led to a decrease in the amount of amniotic fluid (oligohydramnios) in pregnant women who took NSAIDs at the 20th week of pregnancy or later. In some cases, this can lead to impaired kidney function in newborns. The specified effects can occur soon after starting NSAID treatment; oligohydramnios is usually reversible after stopping treatment. The use of etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant during treatment, etoricoxib should be discontinued.

BREASTFEEDING

It is unknown whether etoricoxib passes into breast milk. In rats, etoricoxib is excreted in milk. Women who use etoricoxib should not breastfeed.

FERTILITY

The use of etoricoxib, like other COX-2 inhibitors, is not recommended for women planning pregnancy.

ABILITY TO INFLUENCE THE RATE OF REACTION WHEN DRIVING VEHICLES OR WORKING WITH OTHER MECHANISMS.

Patients who experience dizziness, vertigo, or drowsiness when taking etoricoxib should not drive vehicles or work with other mechanisms.

Method of Application and Dosage

Since the risk of cardiovascular adverse events with etoricoxib increases with dose and duration of exposure, the shortest duration and lowest effective daily dose should be used. The need for symptomatic relief and response to therapy should be periodically reassessed, especially in patients with osteoarthritis.

Osteoarthritis

The recommended dose is 30 mg once daily. In some patients, increasing the dose to 60 mg once daily may provide additional symptomatic relief. If no effect is observed after 4-6 weeks of treatment, alternative treatment options should be considered.

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients, increasing the dose to 90 mg once daily may improve therapeutic effects. Once clinical stabilization is achieved, the dose can 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, increasing the dose to 90 mg once daily may improve therapeutic effects. Once clinical stabilization is achieved, the dose can be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.

Acute Pain

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

Acute Gouty Arthritis

The recommended dose is 120 mg once daily. In clinical trials for 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 pain relief.

Doses exceeding the recommended dose for each indication have not demonstrated additional efficacy or have not been studied; therefore:

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

Elderly Patients

No dose adjustment is necessary for elderly patients. As with other medications, etoricoxib should be used with caution in elderly patients.

Liver Function Impairment

Regardless of the indication, patients with mild liver function impairment (Child-Pugh score 5-6) should not exceed a dose of 60 mg once daily. Patients with moderate liver function impairment (Child-Pugh score 7-9) should not exceed a dose of 30 mg once daily.

Clinical experience is limited, particularly in patients with moderate liver function impairment; therefore, the medication should be used with caution. There is no clinical experience in patients with severe liver function impairment (Child-Pugh score ≥ 10); therefore, etoricoxib is contraindicated in these patients.

Kidney Function Impairment

No dose adjustment is necessary for patients with a creatinine clearance ≥ 30 mL/min. The use of etoricoxib is contraindicated in patients with a creatinine clearance < 30 mL/min.

Overdose

In clinical trials, no significant toxic effects were observed after a single dose of etoricoxib up to 500 mg or multiple doses up to 150 mg daily for 21 days. Acute overdoses of etoricoxib have been reported, although in most cases, no adverse reactions were observed. The most common adverse reactions observed were consistent with the safety profile of etoricoxib (gastrointestinal, cardiac, and renal reactions).

In the event of an overdose, standard supportive measures should be taken, such as removing unabsorbed medication from the gastrointestinal tract, monitoring clinically, and providing supportive treatment as necessary.

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

Adverse Reactions

The safety of etoricoxib was evaluated in clinical trials 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 trials, the profile of adverse events was similar in patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

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

In a cardiovascular safety evaluation program involving three active-comparator-controlled trials, 17,412 patients with osteoarthritis or rheumatoid arthritis received etoricoxib (at doses of 60 mg or 90 mg) for an average of approximately 18 months. Safety data and more detailed information about this program are presented in the "Pharmacological Properties" section.

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

The following adverse reactions were reported more frequently with etoricoxib than with placebo in clinical trials 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 trials, short-term pain trials, and postmarketing experience).

* The frequency category is defined for each adverse reaction term by the frequency in the clinical trials database: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); unknown (cannot be estimated from available data). The frequency of adverse reactions reported during postmarketing use cannot be determined, as these events were reported voluntarily from a population of uncertain size.

‡ Adverse reaction identified during postmarketing surveillance. The frequency was determined based on the maximum frequency observed in clinical trials (data collected for approved indications and doses).

† The frequency category "rare" was determined 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, considering the number of patients treated with etoricoxib, in the pooled phase III data analysis by dose and indication (n=15470).

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

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

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

With the use of NSAIDs, serious adverse reactions such as nephrotoxicity, including interstitial nephritis and nephrotic syndrome, have been reported; therefore, these cannot be ruled out with etoricoxib.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals, patients, or their representatives should report any suspected adverse reactions via the automated information system for pharmacovigilance at: https://aisf.dec.gov.ua.

Shelf Life

3 years.

Storage Conditions

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

Keep out of reach of children.

Packaging

7 tablets per blister pack; 1 or 4 blister packs per carton.

Marketing Authorization Holder

KUSUM HEALTHCARE PVT LTD.

Manufacturer's Name and Address

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