Forsanek film-coated tablets 120 mg No. 28

Instructions Forsanek film-coated tablets 120 mg No. 28

Composition

active ingredient: etoricoxib;

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

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

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

Dosage form

Film-coated tablets.

Main physicochemical properties:

film-coated tablets, 60 mg: oval, biconvex, white to off-white film-coated tablets with a breakline on one side and a flat surface on the other side;

Film-coated tablets, 90 mg and 120 mg: round, biconvex, white to off-white, film-coated tablets with a smooth surface on both sides.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. Coxibs.

ATX code M01A H05.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Etoricoxib is an oral, selective inhibitor of cyclooxygenase-2 (COX-2) over the clinical dose range. There is evidence of dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg/day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms have been identified, COX-1 and COX-2. COX-2 is the isoform of the enzyme that is induced by a proinflammatory stimulus and is considered the main factor responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is also involved in the processes of ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and the central nervous system (induction of fever, pain perception, cognitive function). It may also play a role in the healing process of ulcers. COX-2 has been identified in the tissue surrounding gastric ulcers in humans, but the importance of the enzyme for ulcer healing has not been established.

Clinical efficacy and safety

Efficiency

In patients with osteoarthritis, etoricoxib 60 mg once daily resulted in significant pain relief and improvement in patient-reported disease activity. These beneficial effects were observed as early as day 2 after initiation of treatment and were maintained through 52 weeks. Studies of etoricoxib 30 mg daily demonstrated superior efficacy to placebo over 12 weeks of treatment (as described above). Etoricoxib 60 mg demonstrated significantly greater efficacy than 30 mg for all three primary endpoints over 6 weeks of treatment. Studies of etoricoxib 30 mg have not been conducted in patients with hand osteoarthritis.

In patients with rheumatoid arthritis, etoricoxib 60 mg or 90 mg once daily resulted in significant reductions in pain, inflammation, and improvement in motor function. In studies evaluating the 60 mg and 90 mg doses, the beneficial effects were maintained for

12-week treatment period. In a comparative study of etoricoxib at a dose of 60 mg 1 time per day and 90 mg 1 time per day, both dosages were more effective than placebo.

In patients with acute gouty arthritis attacks, etoricoxib 120 mg once daily for 8 days resulted in greater reductions in moderate to severe pain and inflammation compared with indomethacin 50 mg three times daily. Pain relief was observed as early as 4 hours after initiation of treatment.

In patients with ankylosing spondylitis, etoricoxib 90 mg once daily significantly reduced pain and inflammation, and improved motor function and functional capacity. The clinical benefit of etoricoxib was observed as early as the second day after initiation of therapy and was maintained through a 52-week treatment period. Etoricoxib 60 mg or 90 mg daily was similarly effective compared with naproxen 1000 mg daily. In patients who did not respond adequately to 60 mg daily for 2 weeks, etoricoxib 90 mg once daily was significantly more effective than naproxen 1000 mg daily.

At 6 weeks, increasing the dose to 90 mg daily improved the rate of reduction in back pain intensity compared to continuing to take 60 mg daily.

In a study of postoperative dental pain, etoricoxib 90 mg once daily for up to three days was more effective than placebo in providing pain relief. In the subgroup of patients with moderate pain, etoricoxib 90 mg provided pain relief that was similar to ibuprofen 600 mg and superior to paracetamol/codeine 600 mg/60 mg. The proportion of patients who used rescue medication within 24 hours was 40.8% for etoricoxib 90 mg, 25.5% for ibuprofen 600 mg every 6 hours, and 46.7% for paracetamol/codeine 600 mg/60 mg every 6 hours, compared with 76.2% for placebo. The onset of analgesic effect (significant pain relief) of 90 mg of etoricoxib was observed as early as 28 minutes after administration of the drug.

There were no significant differences in the incidence of thrombotic cardiovascular events between etoricoxib and diclofenac. Cardiorenal adverse reactions were more common with etoricoxib than with diclofenac; this effect was dose-dependent. Gastrointestinal (GI) and hepatic adverse reactions were significantly more common with diclofenac than with etoricoxib. The incidence of adverse reactions considered serious or leading to discontinuation was higher with etoricoxib than with diclofenac.

Cardiovascular safety results.

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

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

Cardiorenal complications.

The incidence of discontinuation due to hypertension-related adverse reactions was statistically higher for etoricoxib than for diclofenac. The incidence of adverse reactions such as congestive heart failure (discontinuation and serious reactions) was similar for etoricoxib 60 mg and diclofenac 150 mg, but the incidence of these reactions was higher for etoricoxib 90 mg compared to diclofenac 150 mg. The incidence of confirmed adverse reactions related to congestive heart failure (events that were serious and led to hospitalization or emergency room visit) was slightly higher for etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The incidence of discontinuation due to edema-related adverse reactions was significantly higher with etoricoxib compared with diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference for etoricoxib 90 mg but not for etoricoxib 60 mg).

Gastrointestinal tolerability results.

A significantly lower rate of drug discontinuation due to any clinical GI complication (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib than with diclofenac.

Results regarding gastrointestinal safety.

The general upper GI reactions were defined as perforations, ulcers, and bleeding. The subgroup of general upper GI reactions considered complicated included perforations, obstructions, and complicated bleeding; the subgroup of general upper GI reactions considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of general upper GI reactions was observed with etoricoxib than with diclofenac. There was no significant difference between etoricoxib and diclofenac in the rate of complicated reactions. For the subgroup of reactions such as upper GI bleeding (complicated and uncomplicated combined), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib in terms of upper GI effects compared to diclofenac was not statistically significant in patients who were concomitantly taking low-dose acetylsalicylic acid (ASA) (approximately 33% of patients).

The rates of confirmed clinical reactions from the lower gastrointestinal tract (small or large bowel perforation, obstruction or bleeding) were not statistically different between etoricoxib and diclofenac.

Results regarding safety for the liver.

Etoricoxib was associated with a statistically significantly lower rate of discontinuation due to hepatic adverse reactions than diclofenac. Most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic events. There was no significant difference in the rate of confirmed serious thrombotic cardiovascular events in patients receiving etoricoxib ≥ 60 mg, placebo, or other nonsteroidal anti-inflammatory drugs (NSAIDs) (excluding naproxen). However, the incidence of such events was higher in patients receiving etoricoxib compared with those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between some COX-1-inhibiting NSAIDs and selective COX-2 inhibitors may be clinically relevant in patients at risk for thromboembolic events. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these findings is unknown.

It is known that the incidence of gastroduodenal ulcers was significantly lower in patients treated with etoricoxib 120 mg once daily than in patients treated with naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The incidence of ulcers was higher with etoricoxib than with placebo.

Study of kidney function in elderly patients.

Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion over 2 weeks of treatment. All active comparators showed increases relative to placebo in systolic blood pressure, but etoricoxib was associated with a statistically significant increase at day 14 compared with celecoxib and naproxen.

Pharmacokinetics

Absorption.

Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, peak plasma concentrations (geometric mean Cmax = 3.6 μg/mL) are achieved approximately 1 hour (Tmax) after administration to adults in the fasted state. The geometric mean AUC0-24 is 37.8 μg×h/mL. The pharmacokinetics of etoricoxib are linear within the clinical dose range.

When taking the drug at a dose of 120 mg with food (high-fat meal), there was no clinically significant effect on the extent of absorption. The rate of absorption was altered, characterized by a decrease in Cmax by 36% and an increase in Tmax by 2 hours. Such data are not considered clinically significant. It is known that during the studies, etoricoxib was used regardless of food intake.

Distribution.

Etoricoxib is approximately 92% bound to human plasma proteins over concentrations ranging from 0.05 to 5 μg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans. Etoricoxib has been shown to cross the placental barrier in rats and rabbits and the blood-brain barrier in rats.

Metabolism.

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted in the urine as parent drug. The primary route of metabolism is the formation of a 6'-hydroxymethyl derivative catalyzed by 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 primary metabolic pathway, but their quantitative characteristics have not been studied in vivo.

Five metabolites have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, which is formed by further oxidation of the derivative.

6'-hydroxymethyl. These major metabolites are either inactive or weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

Breeding.

It is reported that after a single intravenous administration of 25 mg of radiolabeled etoricoxib to healthy volunteers, 70% of the radioactive drug is excreted in the urine and 20% in the feces, mainly as metabolites. Less than 2% is excreted as unchanged drug.

Etoricoxib is eliminated almost entirely by metabolism with subsequent renal excretion. Steady-state concentrations of etoricoxib are reached after 7 days of administration of 120 mg once daily with an accumulation index of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg of the drug is approximately 50 ml/min.

Certain patient groups

Elderly patients.

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

Sex.

The pharmacokinetics of etoricoxib are similar in men and women.

Liver dysfunction.

In patients with mild hepatic impairment (Child-Pugh score 5-6) the mean AUC was approximately 16% higher when etoricoxib was administered 60 mg once daily than in healthy volunteers at the same dose. In patients with moderate hepatic impairment (Child-Pugh score 7-9) the mean AUC was similar to that in healthy volunteers receiving 60 mg once daily; etoricoxib 30 mg has not been studied in this patient population. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score ≥10).

Kidney dysfunction.

The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate to severe renal impairment and in patients with end-stage renal disease undergoing hemodialysis do not differ significantly from those in healthy volunteers. The drug is almost not removed by hemodialysis (dialysis clearance is approximately 50 ml/min).

Children.

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

It is known that the pharmacokinetics in adolescents aged 12 to 17 years with a body weight of 40-60 kg, who were prescribed etoricoxib at a dose of 60 mg 1 time / day, and with a body weight of more than 60 kg, who were prescribed the drug at a dose of 90 mg 1 time / day, were similar to the pharmacokinetics in adults who used etoricoxib at a dose of 90 mg 1 time / day. The safety and efficacy of etoricoxib in children have not been established.

Indication

Symptomatic therapy for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as for 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.

Contraindication

- Hypersensitivity to the active substance or to any of the excipients.

- Active peptic ulcer or active gastrointestinal bleeding.

- Bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 (cyclooxygenase-2) inhibitors.

- Pregnancy or breastfeeding.

- Severe liver dysfunction (serum albumin < 25 g/l or ≥ 10 points on the Child-Pugh scale).

- Estimated renal creatinine clearance < 30 ml/min.

- Patient's age is up to 16 years.

- Inflammatory bowel diseases.

- Congestive heart failure (NYHA II–IV).

- Arterial hypertension, in which blood pressure readings consistently exceed 140/90 mm Hg and are not adequately controlled.

- Diagnosed with ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions.

Oral anticoagulants.

In patients stabilized on continuous warfarin therapy, etoricoxib 120 mg daily was associated with an approximately 13% increase in prothrombin time (INR) as measured by international normalized ratio (INR). Therefore, patients receiving oral anticoagulants should have their prothrombin time (INR) monitored frequently, especially during the first few days of etoricoxib therapy or when the dosage is changed.

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

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the concomitant use of an ACE inhibitor or angiotensin II receptor antagonists and drugs that inhibit COX may result in further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be borne in mind 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 maintained and consideration should be given to monitoring renal function at the beginning of combination therapy and periodically thereafter.

Acetylsalicylic acid.

In a study in healthy volunteers, etoricoxib 120 mg once daily did not affect the antiplatelet activity of ASA (81 mg once daily). Etoricoxib can be administered concomitantly with ASA at doses used for the prevention of cardiovascular disease (low-dose ASA). However, concomitant administration of low-dose ASA and etoricoxib may increase the incidence of gastrointestinal ulcers and other complications compared with etoricoxib monotherapy. Concomitant administration of etoricoxib with ASA at doses higher than those recommended for prophylaxis or with other NSAIDs is not recommended.

Cyclosporine and tacrolimus.

Although the interaction of etoricoxib with these drugs has not been studied, concomitant use of NSAIDs with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with any of these drugs.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs.

Lithium.

NSAIDs reduce the renal excretion of lithium, thereby increasing the level of lithium in the blood plasma. If necessary, careful monitoring of lithium levels in the blood should be carried out and the lithium dose adjusted during concomitant use of these drugs, as well as when discontinuing NSAIDs.

Methotrexate.

Two studies examined the effects of etoricoxib at doses of 60, 90, or 120 mg once daily for 7 days in patients receiving once-weekly methotrexate at doses ranging from 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 and 90 mg had no effect on the plasma concentration or renal clearance of methotrexate. The data on the effect of etoricoxib at a dose of 120 mg on the pharmacokinetics of methotrexate are conflicting. Thus, in one study, etoricoxib at a dose of 120 mg had no effect on the plasma concentration or renal clearance of methotrexate, whereas in another study, the same dose of etoricoxib increased plasma methotrexate concentrations by 28% and decreased renal clearance of methotrexate by 13%. When etoricoxib and methotrexate are used concomitantly, appropriate monitoring for methotrexate toxicity should be performed.

Etoricoxib 60 mg co-administered with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5-1 mg norethindrone increased the AUC0-24 of EE by 37% over 21 days. Etoricoxib 120 mg co-administered with the above oral contraceptives or 12 hours apart increased the AUC0-24 of EE at steady state by 50-60%. This increase in EE concentration should be considered when selecting an oral contraceptive with a different EE content to be co-administered with etoricoxib. Increased EE exposure may increase the incidence of adverse reactions associated with the use of oral contraceptives (e.g. venous thromboembolism in women at risk).

Hormone replacement therapy (HRT).

Coadministration of 120 mg of etoricoxib with HRT containing conjugated estrogens (0.625 mg of conjugated estrogens) for 28 days increased the mean steady-state AUC0-24 of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effects of etoricoxib doses recommended for chronic use (30, 60, and 90 mg) have not been studied. The effect of etoricoxib at doses of 120 mg on exposure (AUC0-24) to the estrogenic components of conjugated estrogens was about half that observed with conjugated estrogens alone and with increasing doses from 0.625 to 1.25 mg. The use of high doses of conjugated estrogens concomitantly with etoricoxib has not been studied. The increased estrogen concentration should be taken into account when choosing a hormonal drug for use in the postmenopausal period concomitantly with etoricoxib, as increased estrogen exposure increases the risk of adverse reactions during HRT.

Prednisone/prednisolone.

Etoricoxib had no clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin.

When etoricoxib was administered at a dose of 120 mg once daily for 10 days to healthy volunteers, there was no effect on the AUC0-24 at steady state or on the renal excretion of digoxin. An increase in Cmax of digoxin (approximately 33%) was observed. This increase is usually not significant in most patients. However, patients at high risk for digoxin toxicity should be monitored when etoricoxib and digoxin are co-administered.

Effect of etoricoxib on drugs metabolized by sulfotransferases.

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

Effect of etoricoxib on drugs metabolized by CYP isoenzymes.

In vitro studies do not indicate that inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is expected. In a study in healthy volunteers, daily administration of etoricoxib at a dose of 120 mg had no effect on 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 is mediated by CYP enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, but their quantitative characteristics have not been studied in vivo.

Ketoconazole.

Ketoconazole is a potent inhibitor of CYP3A4. When administered to healthy volunteers at doses of 400 mg once daily for 11 days, ketoconazole had no clinically important effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (43% increase in AUC).

Voriconazole and miconazole.

Co-administration of oral voriconazole or miconazole topical oral gel (potent CYP3A4 inhibitors) with etoricoxib resulted in a small increase in etoricoxib exposure, which was not considered clinically relevant based on published data.

Rifampicin.

Concomitant use of etoricoxib and rifampicin (a potent CYP enzyme inducer) resulted in a 65% decrease in etoricoxib plasma concentrations. This interaction may result in disease relapse. Although these data may indicate the need for an increase in the dose of etoricoxib, it is not recommended to use etoricoxib at doses higher than those specified for each indication, since the concomitant use of rifampicin and etoricoxib at such doses has not been studied.

Antacids.

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

Application features

Effects on the gastrointestinal tract (GI)

There is an additional risk of gastrointestinal adverse reactions (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is used concomitantly with ASA, even at low doses (see section 4.5). In long-term clinical trials, no significant difference in gastrointestinal safety was observed between combinations of a selective COX-2 inhibitor and ASA and NSAIDs and ASA (see section 5.1).

Effects on the cardiovascular system

Clinical studies suggest that the use of selective COX-2 inhibitors may be associated with thrombotic events (especially myocardial infarction and stroke). Since the risk of cardiovascular events increases with increasing dose and duration of etoricoxib use, the drug should be prescribed for the shortest possible period of time and at the lowest effective daily dose. The need for symptomatic pain relief and the severity of the response to treatment should be periodically reviewed, especially in patients with osteoarthritis (see sections "Pharmacological properties", "Contraindications", "Method of administration and dosage" and "Adverse reactions").

Patients with significant risk factors for cardiovascular complications (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed etoricoxib only after careful assessment of the risk of developing complications (see section "Pharmacological properties").

Selective COX-2 inhibitors do not replace the use of ASA for the prevention of thromboembolic cardiovascular diseases, since they do not have antiplatelet activity. Therefore, antiplatelet drugs should not be discontinued (see sections "Pharmacological properties" and "Interaction with other medicinal products and other types of interactions").

Effect on the kidneys.

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 a decrease in prostaglandin formation and, consequently, renal blood flow, thereby worsening renal function. Patients with severe renal impairment, uncompensated heart failure, or cirrhosis are at increased risk of developing this reaction. Renal function should be monitored in such patients.

Fluid retention, edema, and hypertension.

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and hypertension have been reported in patients receiving etoricoxib. All NSAIDs, including etoricoxib, may precipitate or recur congestive heart failure (see section 5.1 for dose-related responses). The drug should be used with caution in patients with a history of heart failure, left ventricular dysfunction, or hypertension, or in patients with edema from any other cause. Appropriate measures, including discontinuation of etoricoxib, should be initiated if clinical signs of deterioration in such patients occur.

Etoricoxib, especially at high doses, may cause more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors. Therefore, hypertension should be controlled before initiating etoricoxib therapy (see section 4.3) and special attention should be paid to blood pressure control during treatment with etoricoxib. Blood pressure should be monitored for 2 weeks after initiation of treatment and periodically thereafter. If blood pressure increases significantly, alternative treatment should be considered.

Effect on the liver.

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

All patients with symptoms of liver dysfunction, as well as patients with abnormal liver function tests, should be monitored. If signs of liver dysfunction develop and persistent abnormal liver function tests (>3 times the upper limit of normal), etoricoxib should be discontinued.

General instructions.

If during treatment a patient experiences deterioration in the function of any of the organ systems listed above, appropriate measures should be taken and consideration should be given to discontinuing etoricoxib. Appropriate medical supervision should be provided when using etoricoxib in elderly patients and in patients with impaired renal, hepatic or cardiac function.

Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely with NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance (see section 4.8). Patients are at highest risk of developing such reactions early in therapy, most often within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients taking etoricoxib (see section 4.8). 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 appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

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

Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants (see section 4.5).

The use of etoricoxib, as with other drugs that inhibit COX and prostaglandin synthesis, is not recommended in women planning pregnancy (see sections “Pharmacological properties” and “Use during pregnancy or lactation”).

Forsanek® film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Excipients.

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

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 last trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may result in the absence of uterine contractions and premature closure of the botal duct. The use of etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant during treatment, etoricoxib should be discontinued.

Breastfeeding period

It is not known whether etoricoxib passes into breast milk. Etoricoxib is known to pass into milk in animals. Women taking etoricoxib should not breast-feed.

Fertility

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

Ability to influence reaction speed when driving vehicles or other mechanisms

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

Method of administration and doses

Etoricoxib is administered orally, regardless of food intake. The onset of action of the drug occurs more quickly when taken on an empty stomach. This should be taken into account if rapid relief of symptoms is required.

Since the risk of cardiovascular events with etoricoxib increases with increasing dose and exposure, the shortest duration of treatment should be used, using the lowest effective daily dose. The need for symptomatic relief and the effectiveness of symptomatic treatment in patients should be reviewed periodically, especially