INSTRUCTION for medical use of the medicinal product Kostarox (kostarox)

Composition:

Active substance: etoricoxib;

One film-coated tablet contains 30 mg, or 60 mg, or 90 mg, or 120 mg of etoricoxib;

Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, povidone, magnesium stearate, sodium croscarmellose (E 468), coating mixture* (hypromellose 15 cPs (E 464), lactose monohydrate, titanium dioxide (E 171), triacetin (E 1518), indigo carmine (E 132) (11-14) (3-5%)**, iron oxide yellow (E 172)**).

* Coating mixture:

30 mg	Opadry® II Green 32K510001
60 mg	Opadry® II Green 32K510002
90 mg	Opadry® II White 32K580000C
120 mg	Opadry® II Green 32K510003

** Not present in the 90 mg dosage.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg tablets: round, biconvex, film-coated tablets, blue-green in color;

60 mg tablets: round, biconvex, film-coated tablets, dark green in color;

90 mg tablets: round, biconvex, film-coated tablets, white in color;

120 mg tablets: round, biconvex, film-coated tablets, pale green in color.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01A H05.

Pharmacological Properties

Pharmacodynamics

Etoricoxib is an oral, selective inhibitor of cyclooxygenase-2 (COX-2) within the clinical dose range.

Data indicate that etoricoxib dose-dependently inhibits COX-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 (cyclooxygenase-1) and COX-2. COX-2 is the inducible isoform of the enzyme triggered by inflammatory stimuli and is considered the primary factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, as well as in regulation of kidney and central nervous system function (fever induction, pain perception, cognitive function). It may also participate in ulcer healing. COX-2 has been identified in perilesional gastric tissue in humans, but its role in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improves pain symptoms and patient assessment of disease status. Beneficial effects were observed as early as the second day after initiation of treatment and were maintained for 52 weeks. Studies evaluating etoricoxib at a dose of 30 mg daily demonstrated superior efficacy compared to placebo over a 12-week treatment period. Etoricoxib at 60 mg showed significantly better improvement than at 30 mg across all three primary endpoints over a 6-week treatment period. Studies evaluating etoricoxib at 30 mg in patients with hand osteoarthritis have not been conducted.

In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain intensity, inflammation, and joint mobility. Positive effects were maintained throughout the 12-week treatment period. In a comparative study of etoricoxib at 60 mg once daily versus 90 mg once daily, both doses were more effective than placebo. The 90 mg dose was more effective according to patients' overall pain assessment (0**–**100 mm visual analogue scale), with a mean improvement of -2.71 mm (95% CI: -4.98 mm, -0.45 mm).

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

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provides significant improvement in spinal pain, inflammation, restricted mobility, and functional capacity. Clinical benefits of etoricoxib were observed on the second day after initiation of therapy and were maintained throughout the 52-week treatment period. In a second study comparing 60 mg and 90 mg doses, etoricoxib at 60 mg daily and 90 mg daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response to 60 mg daily over 6 weeks, dose escalation to 90 mg daily improved assessment of back pain intensity (0**–**100 mm visual analogue scale) compared to continued 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

In a study of postoperative dental pain, etoricoxib administered at 90 mg once daily for up to three days demonstrated greater analgesic effect than placebo. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg showed analgesic efficacy similar to ibuprofen 600 mg (16.11 vs 16.39; P = 0.722) and superior to acetaminophen/codeine 600 mg/60 mg (11.00; P < 0.001) and placebo (6.84; P < 0.001), as measured by total pain relief over the first 6 hours (TOPAR6). The proportion of patients reporting use of rescue analgesics within 24 hours was 40.8% in the etoricoxib 90 mg group, 25.5% in the ibuprofen 600 mg every 6 hours group, and 46.7% in the acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% in the placebo group. In this study, onset of analgesic effect (perceptible pain relief) with 90 mg etoricoxib occurred as early as 28 minutes after administration.

Safety

Additional cardiovascular safety data regarding thrombotic complications

In studies, approximately 3100 patients received etoricoxib at doses ≥ 60 mg daily for 12 weeks or longer. There was no significant difference in the rate of confirmed serious thrombotic cardiovascular complications between patients receiving etoricoxib at doses ≥ 60 mg, placebo, or other nonsteroidal anti-inflammatory drugs (NSAIDs), except naproxen. However, the frequency of such events was higher in patients receiving etoricoxib compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between certain 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 systemic (and possibly endothelial) prostacyclin production without affecting platelet thromboxane. The clinical significance of these data is unknown.

Additional gastrointestinal (GI) safety data

The incidence of gastroduodenal ulcers was significantly lower in patients treated with etoricoxib 120 mg once daily compared to those 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.

Kidney function studies in elderly patients

Data from parallel-group studies evaluated the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on sodium excretion, blood pressure, and other kidney function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on sodium excretion during 2 weeks of treatment. All active comparator drugs caused increases in systolic blood pressure compared to placebo, but etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: etoricoxib – 7.7 mm Hg, celecoxib – 2.4 mm Hg, naproxen – 3.6 mm Hg).

Pharmacokinetics

Absorption

Etoricoxib is well absorbed after oral administration. Absolute bioavailability is approximately 100%.

After administration of 120 mg once daily to steady state, maximum plasma concentration (geometric mean Cmax = 3.6 µg/mL) is reached approximately 1 hour (Tmax) after dosing in adults under fasting conditions. The geometric mean AUC0**–**24 is 37.8 µg·h/mL. Within the clinical dose range, the pharmacokinetics of etoricoxib are linear.

Administration of 120 mg with food (high-fat meal) did not result in clinically significant effects on the extent of absorption. The rate of absorption was altered, characterized by a 36% reduction in Cmax and a 2-hour increase in Tmax. These changes are not considered clinically significant. In clinical studies, etoricoxib was administered independently of food intake.

Distribution

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

Etoricoxib crosses the placental and blood-brain barriers in animals.

Metabolism

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted in urine as unchanged drug. 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.

In humans, five metabolites have been identified. The major metabolite is the 6’-carboxylic acid derivative of etoricoxib, formed by further oxidation of the 6’-hydroxymethyl derivative. These primary metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.

Elimination

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

Elimination of etoricoxib occurs almost entirely via metabolism followed by renal excretion. Steady-state concentrations of etoricoxib are 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.

Elderly patients

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

Gender

Pharmacokinetics of etoricoxib are similar in men and women.

Hepatic impairment

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

Renal impairment

The pharmacokinetics of a single 120 mg dose of etoricoxib in patients with moderate to severe renal impairment, as well as in patients with end-stage renal disease undergoing hemodialysis, do not differ significantly from those in healthy individuals. Etoricoxib is not substantially 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.

In a pharmacokinetic study (n = 16) conducted in 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 >60 kg receiving etoricoxib 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in children have not been established.

Clinical characteristics.

Indications.

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and inflammatory signs associated with acute gouty arthritis.

Short-term treatment of moderate postoperative pain 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.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Active peptic ulcer or active gastrointestinal bleeding.
Bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or allergic reactions after administration of acetylsalicylic acid or NSAIDs, including COX-2 inhibitors.
Pregnancy and breastfeeding period.
Severe hepatic impairment (serum albumin < 25 g/L or ≥ 10 points on the Child-Pugh scale).
Calculated creatinine clearance < 30 mL/min.
Patient age under 16 years.
Inflammatory bowel diseases.
Congestive heart failure (NYHA II–IV).
Arterial hypertension with blood pressure values persistently exceeding 140/90 mm Hg and insufficiently controlled.
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 stabilized on chronic warfarin therapy, administration of etoricoxib at a dose of 120 mg once daily is associated with an approximately 13% increase in the international normalized ratio (INR). Therefore, in patients receiving oral anticoagulants, INR should be monitored frequently, especially during the first days of etoricoxib treatment or when changing its dosage.

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

NSAIDs may attenuate the effect of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with cyclooxygenase-inhibiting drugs may lead to further deterioration in renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients 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 combination therapy and periodically thereafter.

Acetylsalicylic acid

In a study involving healthy volunteers at steady state, administration of etoricoxib 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib may be administered concomitantly with 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 with etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid at doses higher than those established for prophylaxis, as well as with other NSAIDs, is not recommended.

Cyclosporines and tacrolimus

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

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium

NSAIDs reduce renal excretion of lithium, thereby increasing plasma lithium levels. Careful monitoring of lithium blood levels and dose adjustment of lithium should be performed if necessary during concomitant use of these drugs, as well as upon discontinuation of NSAIDs.

Methotrexate

The effects of etoricoxib at doses of 60 mg, 90 mg, or 120 mg once daily for 7 days were studied in patients receiving weekly methotrexate at doses of 7.5 mg to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 mg 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 signs of methotrexate toxicity should be performed when etoricoxib and methotrexate are used concomitantly.

Oral contraceptives

Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 µg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the AUC_0–24 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_0–24 of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with different ethinylestradiol content for concomitant use with etoricoxib. Increased ethinylestradiol exposure may increase the 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 conjugated estrogens) for 28 days increased the steady-state AUC_0–24 of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) has not been studied. The effect of etoricoxib 120 mg on exposure (AUC_0–24) of estrogenic components of conjugated estrogens was half that observed with monotherapy using conjugated estrogens and increasing the dose from 0.625 mg to 1.25 mg. Concomitant use of high-dose conjugated estrogens with etoricoxib has not been studied. The increased estrogen concentration should be considered when selecting a hormonal preparation for use during the postmenopausal period concomitantly with etoricoxib, as increased estrogen exposure raises the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone

In drug 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_0–24 or renal excretion of digoxin. An increase in digoxin C_max (approximately 33%) was observed. This increase is generally not considered clinically significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are used concomitantly.

Effect of etoricoxib on drugs metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and is capable of increasing serum ethinylestradiol concentrations. Since data on the effects of numerous sulfotransferases are still limited and the clinical effects of many drugs are under investigation, etoricoxib should be prescribed cautiously concomitantly 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 a study 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 suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, but their quantitative contributions have not been studied in vivo.

Ketoconazole

Ketoconazole is a potent inhibitor of CYP3A4. When administered at 400 mg once daily for 11 days to healthy volunteers, ketoconazole had no clinically important 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 (both potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure, which, however, 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 and may be associated with disease relapse. Although such data may suggest the need for increasing the etoricoxib dose, it is not recommended to use etoricoxib at doses exceeding those specified for each indication, as concomitant use of rifampicin and etoricoxib at such doses has not been studied.

Antacids

Antacids have no clinically significant effect on the pharmacokinetics of etoricoxib.

Special precautions for use.

Effect on the gastrointestinal tract

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

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

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

Effect on the cardiovascular system

Clinical studies indicate that the use of selective COX-2 inhibitors may be associated with thrombotic complications (particularly myocardial infarction and stroke). 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 doses. The need for symptomatic pain relief and the extent of response to treatment should be periodically reassessed, especially in patients with osteoarthritis.

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

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

Effect on the kidneys

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions associated with impaired renal perfusion, etoricoxib use may lead to reduced prostaglandin production and, consequently, decreased renal blood flow, thereby worsening renal function. Patients at high risk of such reactions include those with severe renal impairment, decompensated heart failure, or cirrhosis. Renal function should be monitored in these patients.

Fluid retention, edema, and arterial hypertension

As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All NSAIDs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "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. Appropriate measures, including discontinuation of etoricoxib, should be taken if clinical signs of worsening condition occur.

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 controlled 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 starting therapy and then periodically. 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 above the upper limit of normal) have been observed in approximately 1% of patients participating in clinical trials and receiving etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily.

All patients with symptoms of hepatic dysfunction or with 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 the upper limit of normal).

General instructions

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

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

Serious skin reactions, in some cases fatal, including exfoliative dermatitis, Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, mostly 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 with warfarin or other oral anticoagulants should be done with caution.

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

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Reproductive toxicity was observed in animal studies. The potential risk of using etoricoxib in pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may result in uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking NSAIDs from the 20th week of pregnancy onward. In some cases, this may lead to impaired renal function in newborns. These effects may occur soon after starting NSAID therapy; oligohydramnios is usually reversible upon discontinuation of treatment. The use of etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib must be discontinued.

Lactation period

It is unknown whether etoricoxib is excreted in human breast milk. In animals, etoricoxib is excreted in milk. Women taking etoricoxib should not breastfeed.

Fertility

The use of etoricoxib, as with other medicinal products that inhibit COX-2, is not recommended for women planning pregnancy.

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Etoricoxib is administered orally, independent of food intake. The onset of action of the drug occurs faster when taken on an empty stomach. This should be considered when rapid symptom relief is required.

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

Osteoarthritis

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

Rheumatoid Arthritis

The recommended dose is 60 mg once daily. In some patients with inadequate symptom relief, increasing the dose to 90 mg once daily may improve efficacy. After the patient's condition has stabilized from a clinical standpoint, dose reduction to 60 mg once daily may be necessary. If no therapeutic benefit is observed, alternative treatment options should be considered.

Ankylosing Spondylitis

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 beyond etoricoxib during the 3-day treatment period.

Doses exceeding those recommended for each indication have either not been shown to provide additional efficacy or have not been studied. Therefore:

The dosage for osteoarthritis should not exceed 60 mg once daily.
The dosage for rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg once daily.
The dosage for acute gout should not exceed 120 mg once daily for a maximum treatment duration of 8 days.
The dosage for acute dental postoperative pain should not exceed 90 mg once daily for a maximum duration of 3 days.

Special Patient Populations

Elderly Patients

No dose adjustment is necessary for elderly patients. However, the drug should be prescribed with caution in this population.

Patients with Hepatic Impairment

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

Experience with the drug is limited, particularly in patients with moderate hepatic impairment; therefore, it should be used with caution. There is no clinical experience with etoricoxib in patients with severe hepatic impairment (Child–Pugh score ≥ 10); thus, the use of the drug is contraindicated in these patients.

Patients with Renal Impairment

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

Children

Etoricoxib is contraindicated in children under 16 years of age.

Overdose.

Single doses of etoricoxib up to 500 mg or multiple daily doses up to 150 mg for 21 days have not resulted in significant toxic effects. Acute overdosage has been reported, although adverse reactions were not commonly reported in most cases. The adverse reactions observed were consistent with the safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal events).

In case of overdose, standard supportive measures are recommended, 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

Adverse reactions are classified by frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Infections and infestations

Common: alveolar osteitis

Uncommon: gastroenteritis, upper respiratory tract infections, urinary tract infections

Blood and lymphatic system disorders

Uncommon: anaemia (mainly due to gastrointestinal bleeding), leucopenia, thrombocytopenia

Immune system disorders

Uncommon: hypersensitivity‡ ß

Rare: angioneurotic oedema/anaphylactic/anaphylactoid reactions, including shock ‡

Metabolism and nutrition disorders

Common: oedema/fluid retention

Uncommon: decreased or increased appetite, weight gain

Psychiatric disorders

Uncommon: anxiety, depression, impaired mental function, hallucinations‡

Rare: confusion‡, restlessness‡

Nervous system disorders

Common: dizziness, headache

Uncommon: dysgeusia, insomnia, paraesthesia/hypoesthesia, somnolence

Eye disorders

Uncommon: blurred vision, conjunctivitis

Ear and labyrinth disorders

Uncommon: tinnitus, vertigo

Cardiac disorders

Common: palpitations, arrhythmia‡, hypertension

Uncommon: atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§, flushing, stroke§, transient ischaemic attack, hypertensive crisis‡, vasculitis‡

Respiratory, thoracic and mediastinal disorders

Common: bronchospasm‡

Uncommon: cough, dyspnoea, epistaxis

Gastrointestinal disorders

Very common: abdominal pain

Common: constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcers

Uncommon: abdominal distension, changes in bowel motility, dry mouth, gastroduodenal ulcers, peptic ulcers, including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis‡

Hepatobiliary disorders

Common: increased ALT levels, increased AST levels

Rare: hepatitis‡, hepatic failure‡, jaundice‡

Skin and subcutaneous tissue disorders

Common: ecchymosis

Uncommon: facial swelling, pruritus, rash, erythema‡, urticaria‡

Rare †: Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, persistent drug erythema‡

Musculoskeletal and connective tissue disorders

Uncommon: muscle spasms/cramps, musculoskeletal pain/stiffness

Renal and urinary disorders

Uncommon: proteinuria, increased serum creatinine, renal failure/dysfunction‡

General disorders and administration site conditions

Common: asthenia/fatigue, influenza-like symptoms

Uncommon: chest pain

Investigations

Uncommon: increased blood urea nitrogen, increased creatine phosphokinase, hyperkalaemia, increased uric acid

Rare: decreased blood sodium levels

‡ This adverse reaction was identified during post-marketing use of etoricoxib. The frequency was determined based on the highest frequency observed in clinical trials (data pooled by indication and approved dose).

† The frequency category "rare" was defined in accordance with the requirements of the 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 etoricoxib in the pooled Phase III data analysis, combined by dose and indication (n = 15,470).

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

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

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

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

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

30 mg tablets: 7 tablets in a blister. Carton containing 4 blisters.

60 mg tablets: 4, 7, or 10 tablets in a blister. Carton containing 1 blister with 4 tablets, or 4 blisters with 7 tablets each, or 10 blisters with 10 tablets each.

90 mg tablets: 7 or 10 tablets in a blister. Carton containing 1 or 4 blisters with 7 tablets each, or 10 blisters with 10 tablets each.

120 mg tablets: 7 tablets in a blister. Carton containing 1 or 4 blisters.

Prescription status. Prescription only.

Manufacturer.

SALUTAS Pharma GmbH (batch release).

Manufacturer's address and place of business.

Otto-von-Guericke-Allee 1, 39179 Barleben, Saxony-Anhalt, Germany

Costarox