Bixitor pills 60mg, 10pcs

Composition

1 tablet contains: Active ingredient: etoricoxib-60 mg; Excipients:  calcium hydrophosphate anhydrous, microcrystalline cellulose, povidone K 30, croscarmellose sodium, magnesium stearate; shell – hypromellose, lactose monohydrate, titanium dioxide, triacetin, indigo carmine aluminum varnish, iron oxide yellow.

Pharmacological action

Pharmacotherapy group: nonsteroidal anti-inflammatory drugs (NSAIDs)

ATX Code: M 01 AN 05

Pharmacological properties

Pharmacodynamics

Mechanism of action

Etoricoxib, when taken orally at therapeutic concentrations, is a selective cyclooxygenase-2 (COX-2) inhibitor. In clinical pharmacological studies, etoricoxib dose-dependently inhibited COX-2, without affecting COX-1 with a daily dose of up to 150 mg. The drug does not inhibit prostaglandin synthesis in the gastric mucosa and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase, COX – 1 and COX-2, have been identified. COX-2 is an isoenzyme that is induced by various pro-inflammatory mediators and is considered the main enzyme responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is involved in the processes of ovulation, implantation and closure of the ductus arteriosus, regulation of kidney and central nervous system function (fever induction, pain sensation, cognitive function), and may also play a role in the healing of ulcers. COX-2 has been found in the tissues surrounding gastric ulcers in humans, but its significance for ulcer healing has not been established.

Efficiency

In patients with osteoarthritis (OA), etoricoxib, when administered at a dose of 60 mg once a day, significantly reduced pain and improved the assessment of their condition by patients. These beneficial effects were observed on the second day of treatment and persisted for 52 weeks. Studies of etoricoxib administered at a dose of 30 mg once a day (using similar evaluation methods) demonstrated efficacy compared to placebo over a 12-week treatment period. In a study conducted to determine the optimal dose, etoricoxib at a dose of 60 mg showed significantly more pronounced improvement than at a dose of 30 mg for all three primary endpoints after 6 weeks of treatment. A dose of 30 mg has not been studied for osteoarthritis of the hand joints.

In patients with rheumatoid arthritis (RA), etoricoxib, when administered at a dose of 90 mg once a day, significantly reduced pain and inflammation and improved mobility. These beneficial effects persisted during the 12-week treatment period.

In patients with acute gouty arthritis, etoricoxib, when administered at a dose of 120 mg once daily for the entire eight-day treatment period, reduced moderate to severe joint pain and inflammation. The efficacy was comparable to that of Indometacin when administered at a dose of 50 mg three times a day. Pain reduction was noted as early as four hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib, when administered at a dose of 90 mg once a day, significantly reduced back pain, inflammation, stiffness, and improved function. Clinical efficacy of etoricoxib was observed as early as the second day of treatment and was maintained throughout the entire 52-week treatment period.

In a clinical study of pain after dental surgery, etoricoxib 90 mg was administered once daily for three days. In the subgroup of patients with moderate pain (at baseline), etoricoxib, when administered at a dose of 90 mg, had the same analgesic effect as ibuprofen at a dose of 600 mg (16.11 vs. 16.39; P=0.722), and was superior in effectiveness to the combination of paracetamol/codeine at a dose of 600 mg / 60 mg (11.00, P<0.001) and placebo (6.84, P The proportion of patients who required rapid-acting painkillers within the first 24 hours after taking the study drugs was 40.8% with etoricoxib at a dose of 90 mg,25.5% with ibuprofen at a dose of 600 mg every 6 hours and 46.7% with a combination of paracetamol/codeine at a dose of 600 mg/60 mg every 6 hours, compared with 76.2% in the placebo group. In this study, the median onset of action (measurable pain reduction) with etoricoxib 90 mg was 28 minutes after ingestion.

Security

MEDAL Program (Multinational Evaluation Program for Long-Term Use of Etoricoxib and Diclofenac for Arthritis)

The MEDAL program was a prospective safety assessment program based on cardiovascular (CV) events based on combined data from three randomized, double-blind, active-controlled trials: MEDAL, EDGE II, and EDGE.

The MEDAL study was a study whose duration was determined by the achievement of endpoints (SS events), which included 17,804 patients with OA and 5,700 patients with RA who received etoricoxib at a dose of 60 mg (OA) or 90 mg (OA and RA) 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 events and cases of withdrawal from the study due to any adverse events were recorded.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7,111 patients with OA who received etoricoxib 90 mg / day (1.5 times the recommended dose for OA) or diclofenac 150 mg / day for an average of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4,086 patients with RA who received either etoricoxib 90 mg / day or diclofenac 150 mg / day for an average of 19.2 months (maximum 33.1 months, median 24 months).

In the combined MEDAL Program,34,701 patients with OA or RA received treatment for an average of 17.9 months (maximum 42.3 months, median 16.3 months), and about 12,800 patients received treatment for more than 24 months. A wide range of SS and gastrointestinal risk factors were registered in patients enrolled in the MEDAL Program at the initial assessment. Patients with a recent myocardial infarction, as well as those with coronary artery bypass grafting or percutaneous coronary intervention for 6 months prior to inclusion in the study were excluded. Studies allowed the use of gastroprotectors and low-dose aspirin.

General security

There were no significant differences between etoricoxib and diclofenac in the frequency of thrombotic SS events. Cardiorenal adverse events were more frequently observed with etoricoxib than with diclofenac: this effect was dose-dependent (individual results are presented below). Adverse events from the gastrointestinal tract (GIT) and liver were significantly more often observed with the appointment of diclofenac than with the appointment of etoricoxib. The incidence of adverse events in the EDGE and EDGE II trials, as well as adverse events considered serious or requiring discontinuation of treatment, in the MEDAL study was higher with etoricoxib than with diclofenac.

Results of the cardiovascular safety assessment

The incidence of confirmed serious thrombotic SS adverse events (including cardiac, cerebrovascular, and peripheral vascular events) was comparable between the groups receiving etoricoxib or diclofenac (see the table below). In terms of the frequency of thrombotic events, there were no statistically significant differences between etoricoxib and diclofenac in all analyzed subgroups, including categories of patients in the range of initial CV risk. The relative risk for confirmed serious thrombotic SS adverse events was similar for etoricoxib (when taken at a dose of 60 mg or 90 mg) and diclofenac (when taken at a dose of 150 mg).

Table ” Frequency of confirmed SS thrombotic events (MEDAL Program)”

	Etoricoxib (N=16,819) 25,836 patient-years	Diclofenac (N=16483) 24766 patient-years	Comparison between treatments
	Frequency 1 (95% CI)	Frequency 1 (95% CI)	Relative risk (95% CI)
Confirmed thrombotic SS serious adverse events
When meeting protocol requirements	1,24(1,11,1,38)	1,30 (1,17,1,45)	0,95 (0,81,1,11)
Depending on the prescribed treatment	1.25 (1.14,1.36)	1,19 (1,08,1,30)	1,05 (0,93,1,19)
Confirmed cardiac events
If the protocol requirements	are met 0.71 (0.61,0,82)	0,78 (0,68,0,90)	0,90 (0,74,1,10)
Depending on the prescribed treatment	0.69 (0.61,0,78)	0,70 (0,62,0,79)	0,99 (0,84,1,17)
Confirmed cerebrovascular events
If the protocol requirements	are met 0.34 (0.28,0.42)	0,32 (0,25,0,40)	1,08 (0,80,1,46)
Depending on the prescribed treatment	0,33 (0,28,0,39)	0,29 (0,24,0,35)	1,12 (0,87,1,44)
Confirmed peripheral vascular events
When meeting protocol requirements	0,20 (0,15,0,27)	0,22 (0,17,0,29)	0,92 (0,63,1,35)
Depending on the prescribed treatment	0,24 (0,20,0,30)	0,23 (0,18,0,28)	1,08 (0,81,1,44)
1 Number of events per 100 patient-years; CI=confidence interval; N=total number of patients included in the population of patients who met the protocol requirements. If the protocol requirements are met, all events that developed during the study therapy or within 14 days of its discontinuation (excluding patients who received <75% of the study drug, and patients who took NSAIDs not included in the study >10% of the time). Depending on the prescribed treatment – all confirmed events that developed before the end of the study (including patients who may have been exposed to non – included interventions after discontinuation of the study drug). Total number of randomized patients: n=17,412 for etoricoxib and n=17,289 for diclofenac.

CV mortality and overall mortality were comparable between the etoricoxib and diclofenac treatment groups.

Cardiorenal phenomena

Approximately 50% of the patients included in the MEDAL study had a history of hypertension at baseline. The rate of withdrawal due to adverse events associated with hypertension was statistically significantly higher for etoricoxib than for diclofenac. The incidence of adverse events associated with chronic heart failure (cases of withdrawal from the study and serious events) was similar for etoricoxib 60 mg and diclofenac 150 mg, but was higher for etoricoxib 90 mg compared to diclofenac 150 mg (and statistically significantly higher for etoricoxib 90 mg compared to diclofenac 150 mg in the OA group of the MEDAL study). The incidence of confirmed adverse events associated with chronic heart failure (events that were serious and resulted in hospitalization or emergency department visits) was slightly higher for etoricoxib compared to diclofenac at a dose of 150 mg; this effect was dose-dependent. The rate of withdrawal from the study due to edema-related adverse events was higher for etoricoxib compared to diclofenac at a dose of 150 mg; this effect was dose-dependent (statistically significant for etoricoxib at a dose of 90 mg, but not for etoricoxib at a dose of 60 mg).

The results of the cardiorenal safety assessment in the EDGE and EDGE II studies are consistent with the results in the MEDAL study

In individual MEDAL studies, the absolute dropout rate for either treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% due to hypertension, up to 1.9% due to edema, and up to 1.1% due to chronic heart failure. Patients treated with 90 mg of etoricoxib had a higher dropout rate than patients treated with 60 mg of etoricoxib.

Results of the open study of gastrointestinal tolerance in the MEDAL Program

In each of the three trials included in the MEDAL Program, the dropout rate for any clinical gastrointestinal adverse event (e. g., dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared to diclofenac. The rate of withdrawal from the study due to gastrointestinal adverse events per 100 patient-years over the entire study period was as follows: 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, and 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Results of the GIT safety assessment in the MEDAL Program

In general, adverse events from the upper gastrointestinal tract were identified as perforations, ulcers and bleeding. Complicated upper gastrointestinal adverse events included perforation, obstruction, and complicated bleeding; uncomplicated upper gastrointestinal adverse events included uncomplicated bleeding and uncomplicated ulcers. The overall incidence of upper gastrointestinal adverse events was significantly lower for etoricoxib compared to diclofenac. There were no significant differences in the incidence of complications between etoricoxib and diclofenac. No significant differences were found between etoricoxib and diclofenac for upper gastrointestinal hemorrhagic events (complicated and uncomplicated in the aggregate). The upper gastrointestinal benefit of etoricoxib compared to diclofenac in patients taking low-dose aspirin concomitantly (approximately 33% of patients) was not statistically significant.

The frequency of confirmed complicated and uncomplicated clinical adverse events from the upper gastrointestinal tract per 100 patient-years (perforation, ulcers and bleeding) was 0.67 (95% CI 0.57 percent, to 0.77) for etoricoxib and 0.97 (95% CI of 0.85 to 1.10) for diclofenac, based on which the relative risk was 0.69 (95% CI of 0.57,0,83).

The frequency of confirmed upper gastrointestinal adverse events in elderly patients was studied; the maximum reduction in the frequency was observed in patients aged ≥75 years-1.35 (95% CI 0.94,1.87) compared with 2.78 (95% CI 2.14,3.56) events per 100 patient-years for etoricoxib and diclofenac, respectively.

The incidence of confirmed lower gastrointestinal adverse events (perforation of the small or large intestine, obstruction or bleeding) did not significantly differ between the groups receiving etoricoxib and diclofenac.

Results of the liver safety assessment in the MEDAL Program

Etoricoxib was characterized by a statistically significantly lower rate of withdrawal from the study due to adverse liver events compared to diclofenac. In the combined MEDAL Program,0.3% of patients treated with etoricoxib and 2.7% of patients treated with diclofenac dropped out of the study due to liver adverse events. The incidence of adverse events per 100 patient-years was 0.22 for etoricoxib and 1.84 for diclofenac (p Most of the liver adverse events in the MEDAL Program were not serious.

Additional safety data related to thrombotic SS events

In clinical trials, with the exception of the MEDAL Program, approximately 3,100 patients received etoricoxib at a dose of ≥60 mg per day for 12 weeks or longer. There were no significant differences in the incidence of confirmed serious SS thrombotic events in patients treated with etoricoxib ≥60 mg, placebo, or non-naproxen-containing NSAIDs. However, compared to patients receiving naproxen 500 mg twice daily, the incidence of these events was higher in patients receiving etoricoxib. The difference in antiplatelet activity between some COX-1 inhibiting PPAs and selective COX-2 inhibitors may have clinical significance in patients at risk of developing thromboembolic events. Selective COX-2 inhibitors inhibit the formation of systemic (and possibly endothelial) prostacyclin without affecting platelet-derived thromboxane. The clinical significance of these observations has not been established.

Additional information on gastrointestinal safety

In two double-blind endoscopic studies lasting 12 weeks, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients treated with etoricoxib at a dose of 120 mg once a day than in patients treated with naproxen at a dose of 500 mg twice a day or ibuprofen at a dose of 800 mg three times a day. The incidence of ulcers with etoricoxib was higher than with placebo.

Study of renal function in the elderly

A randomized, double-blind, placebo-controlled study in parallel groups evaluated the effects of 15-day therapy with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on renal sodium excretion, blood pressure (BP), and other parameters of renal function in patients aged 60 to 85 years who received a 200 meq/day sodium diet. Etoricoxib, celecoxib, and naproxen had similar effects on renal sodium excretion after 2 weeks of treatment.All active comparison drugs resulted in an increase in systolic blood pressure relative to placebo, but etoricoxib therapy resulted in a statistically significant increase in systolic blood pressure on day 14 compared to celecoxib and naproxen (mean change for systolic blood pressure compared to baseline: etoricoxib-7.7 mm Hg, celecoxib-2.4 mm Hg, naproxen-3.6 mm Hg).

Pharmacokinetics

Absorption rate

Etoricoxib is rapidly absorbed when taken orally. Absolute oral bioavailability is about 100%. When using the drug in adults on an empty stomach at a dose of 120 mg once a day until the equilibrium state is reached, the maximum concentration (Cmax) is 3.6 mcg/ml. The time to reach the maximum concentration (TMAX) in blood plasma is 1 hour after taking the drug. Geometric mean AUC0-24-37.8 mcg-h / ml. The pharmacokinetics of etoricoxib within therapeutic doses are linear. When taking etoricoxib 120 mg with a meal (high-fat food), there was no clinically significant effect on the degree of absorption. The rate of absorption changed, which led to a decrease in Cmax by 36% and an increase in TCmax by 2 h. These results are not considered clinically significant. In clinical trials, etoricoxib was used regardless of food intake.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 mcg / ml. The volume of distribution (Vdss) at steady state is about 120 liters. Etoricoxib penetrates the placental and blood-brain barriers.

Metabolism

Etoricoxib is extensively metabolized. Less than 1% of etoricoxib is excreted unchanged by the kidneys. The main pathway of metabolism is the formation of 6 ‘ – hydroxymethylethoricoxib, which is catalyzed by enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes etoricoxib metabolism in vivo. In vitro studies indicate that the isoenzymes CYP2D6, CYP2C9, CYP1A2, and CYP2C19 can also catalyze the main pathway of metabolism, but their quantitative effects in vivo have not been studied.

5 metabolites of etoricoxib were detected in humans. The main metabolite is 6′ – carboxyacetylethoricoxib, which is formed by additional oxidation of 6′ – hydroxymethylethoricoxib. These major metabolites do not have significant activity, or are weak COX-2 inhibitors. None of these metabolites inhibit COX-1.

Deduction

In a single intravenous dose of 25 mg labeled radioactive etoricoxib,70% of etoricoxib was excreted via the kidneys,20% – via the intestines, mainly in the form of metabolites. Less than 2% were found unchanged.

Elimination of etoricoxib occurs mainly through metabolism, followed by elimination through the kidneys.

The steady-state concentration is reached with a daily intake of 120 mg of etoricoxib after 7 days with a cumulative coefficient of about 2, which corresponds to a half-life of about 22 hours. Plasma clearance after intravenous use of 25 mg is approximately 50 ml / min

. Pharmacokinetics in selected groups of patients

Elderly patients

The pharmacokinetics in the elderly (65 years and older) are comparable to the pharmacokinetics in the young.

The

pharmacokinetics of etoricoxib are similar in men and women.

Liver function disorders

In patients with mild hepatic impairment (Child-Pugh score 5-6), taking etoricoxib at a dose of 60 mg once a day was accompanied by an increase in AUC by 16% compared to healthy individuals taking the drug at the same dose.

In patients with moderate hepatic impairment (Child-Pugh score 7-9) who received etoricoxib at a dose of 60 mg every other day, the average AUC value was the same as in healthy individuals who took etoricoxib daily at the same dose. Etoricoxib 30 mg once daily has not been studied in this population. Data from clinical and pharmacokinetic studies in patients with severe hepatic impairment (≥10 points on the Child-Pugh scale) are not available.

Renal impairment

The pharmacokinetic parameters of a single 120 mg dose of etoricoxib in patients with moderate to severe renal impairment and end-stage chronic renal failure (CRF) undergoing hemodialysis did not differ significantly from those in healthy subjects. Hemodialysis had little effect on elimination (dialysis clearance was about 50 ml / min).

The detipharmacokinetic parameters 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, the pharmacokinetics in adolescents with a body weight of 40 to 60 kg when taking etoricoxib at a dose of 60 mg once a day and in adolescents with a body weight of more than 60 kg when taking etoricoxib at a dose of 90 mg once a day were similar to the pharmacokinetics in adults when taking etoricoxib at a dose of 90 mg once a day.

The safety and efficacy of etoricoxib in children has not been established.

Indications

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis. Short-term treatment of moderate acute pain after dental surgery.

Use during pregnancy and lactation

Pregnancyclinical data on the use of etoricoxib during pregnancy are not available. Toxic effects on the reproductive system have been observed in animal studies. The potential risk in women during pregnancy is unknown. Application of etoricoxib. as with other drugs that inhibit prostaglandin synthesis, during the last trimester of pregnancy, it can lead to suppression of uterine contractions and premature closure of the ductus arteriosus. Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib should be discontinued. Breast-feeding In lactating rats, etoricoxib is excreted in milk. Studies confirming the release of etoricoxib in breast milk in women have not been conducted. Women who take etoricoxib should stop breastfeeding. Fectilityapplication of etoricoxib. as with other drugs that inhibit COX-2 and prostaglandin synthesis, it is not recommended for women who are planning pregnancy.

Contraindications

• Hypersensitivity to any component of the drug;
• gastric ulcer and 12 duodenal ulcer in the acute stage, active gastrointestinal bleeding;
• complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance of acetylsalicylic acid or other NSAIDs (including in the anamnesis);
• pregnancy, lactation;
• severe disturbances of liver function (serum albumin <25 g/l or ≥10 points on a scale child-Pugh);
• severe renal insufficiency (creatinine clearance less than 30 ml/min);
• children up to age 16;
• inflammatory bowel disease;
• chronic heart failure (II-IV functional class NYHA);
• uncontrolled hypertension in which blood pressure parameters consistently over 140/90 mm Hg. article;
• confirmed coronary heart disease, peripheral arterial disease and/or cerebrovascular disease.
• lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the drug contains lactose);
• confirmed hyperkalemia;
• progressive kidney disease.

With caution

Caution should be exercised when using the drug in the following groups of patients:

• patients with an increased risk of gastrointestinal complications due to NSAIDs; the elderly who are taking other NSAIDs at the same time, including acetylsalicylic acid; or patients with a history of gastrointestinal diseases, such as peptic ulcer disease and gastrointestinal bleeding:
• patients with a history of risk factors for cardiovascular events, such as dyslipidemia/hyperlipidemia, diabetes mellitus, hypertension, smoking, heart failure, left ventricular dysfunction, edema, and fluid retention:
• patients with mild hepatic impairment (Child-Pugh score 5-6) should not exceed the dose of 60 mg once a day, patients with moderate hepatic impairment (Child-Pugh score 7-9) – 30 mg once a day:
• patients with dehydration:
• patients with impaired renal function, concomitantly using ACE inhibitors, diuretics, angiotensin II receptor antagonists, especially the elderly;
• patients with creatinine clearance < 60 ml / min;
• patients with a previous significant decrease in renal function, with impaired renal function, decompensated heart failure or cirrhosis of the liver, who are at risk for long-term use of NSAIDs.

Caution should be exercised when concomitant therapy with the following medications::

• anticoagulants (for example, warfarin),
• antiplatelet agents (for example, acetylsalicylic acid, clopidogrel),
• drugs that are metabolized by sulfotransferases.

Side effects

The frequency of adverse reactions is defined as:Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100): rare (≥1/10000 to <1/1000); very rare (Infectious and parasitic diseases: Often – alveolar ostitis; infrequently-gastroenteritis, upper respiratory tract infections, urinary tract infections.Disorders of the blood and lymphatic system: Infrequently-anemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia. Immune system disorders: Infrequently-hypersensitivity reactions*, **; rarely-angioedema, anaphylactic / anaphylactoid reactions, including shock*. Metabolic and nutritional disorders: Often – edema/fluid retention; infrequently-decreased or increased appetite, weight gain. Mental disorders: Infrequently-anxiety, depression, concentration disorders, hallucinations*; rarely-confusion*, anxiety*. Nervous system disorders: Often – headache, dizziness; infrequently – taste disorders, insomnia, drowsiness, paresthesia/hypesthesia. Visual disturbances: Infrequently – blurred vision, conjunctivitis. Hearing disorders and labyrinth disorders: Infrequently-tinnitus, vertigo. Cardiac disorders: Often-palpitation, arrhythmia*; infrequently-atrial fibrillation, tachycardia*, chronic heart failure, non-specific ECG changes, angina pectoris*, myocardial infarction***. Vascular disorders: Often-arterial hypertension; infrequently-hot flashes, impaired cerebral circulation***, transient ischemic attack, hypertensive crisis*, vasculitis*. Respiratory, thoracic and mediastinal disorders: Often-bronchospasm*; infrequently-cough, shortness of breath, nosebleeds. Disorders of the gastrointestinal tract: Very often-abdominal pain; often – constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, ulcers of the oral mucosa; infrequently – bloating, changes in peristalsis, dryness of the oral mucosa, gastroduodenal ulcer, ulcer stomach disorders, including gastrointestinal perforations and bleeding, irritable bowel syndrome, and pancreatitis*. Liver and biliary tract disorders: Often-increased ALT activity, increased ACT activity; rarely-hepatitis*, liver failure*, jaundice*. Skin and subcutaneous tissue disorders: Often-ecchymosis; infrequently-facial swelling, pruritus, rash, erythema*, urticaria*; rarely-Stevens-Johnson syndrome*, toxic epidermal necrolysis*, fixed drug erythema*. Musculoskeletal and connective tissue disorders: Infrequently-muscle cramps/ spasms, myalgia, musculoskeletal pain/stiffness. Kidney and urinary tract disorders: Infrequently-proteinuria, increased serum creatinine, renal failure*. General disorders and disorders at the injection site: Often-asthenia/weakness, flu-like syndrome; infrequently-chest pain. Laboratory and instrumental data: Infrequently-increased blood urea nitrogen, increased creatine phosphokinase activity, hyperkalemia, increased uric acid; rarely-decreased blood sodium. * This adverse reaction was reported during post-marketing surveillance. The frequency of reports for it is estimated based on the highest frequency observed in clinical studies combined depending on the dose and indication. ** Hypersensitivity includes the terms “allergy”, “drug allergy”, “drug hypersensitivity”, “hypersensitivity”, “unspecified hypersensitivity”, “hypersensitivity reaction” and “non-specific allergy”. *** Based on data from long-term placebo-controlled and actively controlled clinical trials, the use of selective COX-2 inhibitors increases the risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on the available data, it is unlikely that the absolute risk of these events exceeds 1% per year (infrequently). The following serious adverse events have been reported with NSAIDs and cannot be excluded for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Interaction

Pharmacodynamic interaction

Oral anticoagulants (warfarin): In patients receiving warfarin, etoricoxib 120 mg / day was associated with an increase in the International Normalized Ratio (INR) of prothrombin time by approximately 13%. In patients receiving oral anticoagulants, prothrombin time and INR should be monitored at the beginning of treatment or when changing treatment with etoricoxib, especially in the first days of taking the drug.

Diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin II antagonists: NSAIDs may weaken the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (for example, patients with dehydration or elderly patients with impaired renal function), the simultaneous use of an ACE inhibitor or angiotensin II antagonist and drugs that inhibit cyclooxygenase may lead to additional deterioration of renal function, including the possible development of acute renal failure, which is usually reversible. Patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists should be aware of the possibility of such interactions. This combination should be used with caution, especially in elderly patients. At the beginning of combined treatment, as well as at certain intervals in the future, fluid deficiency should be replenished and monitoring of renal function should be considered.

Acetylsalicylic acid. In a study involving healthy volunteers, etoricoxib 120 mg daily at steady state did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). The drug Bixitor® can be used simultaneously with acetylsalicylic acid in low doses intended for the prevention of SS diseases. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulceration and other complications compared to etoricoxib alone. Concomitant use of etoricoxib with acetylsalicylic acid in doses exceeding those recommended for the prevention of SS complications, as well as with other NSAIDs, is not recommended. Cyclosporine and tacrolimus. The interaction of etoricoxib with these drugs has not been studied, but the simultaneous use of NSAIDs with cyclosporine and tacrolimus may increase the nephrotoxic effect of these drugs. Renal function should be monitored when etoricoxib is co-administered with any of these medications.

Pharmacokinetic interaction

Effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs reduce the excretion of lithium by the kidneys and, consequently, increase the concentration of lithium in the blood plasma. If necessary, frequent monitoring of blood lithium concentrations is performed and the dose of lithium is adjusted during concomitant use with NSAIDs, as well as when NSAIDs are discontinued.

Methotrexate. Two studies examined the effects of etoricoxib at doses of 60,90, and 120 mg once daily for seven days in patients treated with 7.5 to 20 mg methotrexate once weekly for rheumatoid arthritis. Etoricoxib at doses of 60 and 90 mg had no effect on the plasma concentration and renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on the pharmacokinetic parameters of methotrexate. In another study, the concentration of methotrexate in plasma increased by 28%, and the renal clearance of methotrexate decreased by 13%. Co-use of etoricoxib and methotrexate should be monitored for possible toxic effects of methotrexate.

Oral contraceptives. Taking etoricoxib for 21 days at a dose of 60 mg with an oral contraceptive containing 35 mcg of ethinyl estradiol (EE) and 0.5 to 1 mg of norethindrone increases the AUC0-24 hours for EE by 37%. Taking etoricoxib 120 mg with the above-mentioned oral contraceptives (simultaneously or at 12-hour intervals) increases the steady-state AUC0-24 hours for EE by 50-60%. This increase in EE concentration should be taken into account when selecting an appropriate oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increase in the incidence of adverse events associated with the use of oral contraceptives (for example, venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). use of etoricoxib at a dose of 120 mg concomitantly with hormone replacement therapy containing conjugated estrogens at a dose of 0.625 mg for 28 days increases the mean steady-state AUC0-24 hours of unconjugated estrone (41%), equilin (76%) and 17-β-estradiol (22%). The effect of the recommended long-term doses of etoricoxib (30,60, and 90 mg) has not been studied. Etoricoxib at a dose of 120 mg changed the exposure (AUC0-24 h) of these estrogenic components by less than half compared to monotherapy with a drug containing conjugated estrogens, with an increase in the latter’s dose from 0.625 to 1.25 mg. The clinical significance of such increases is unknown. The use of a combination of etoricoxib and a drug containing higher doses of conjugated estrogens has not been studied. Increased estrogen concentrations should be taken into account when choosing a hormone preparation for use in the postmenopausal period when administered concomitantly with etoricoxib, since increased estrogen exposure may increase the risk of HRT-related adverse events.

Prednisone/prednisone. In drug 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 a day for 10 days in healthy volunteers, there was no change in AUC0-24 hours at steady state or effect on the excretion of digoxin by the kidneys. There was an increase in digoxin Cmax (approximately 33%). Such an increase, as a rule, is not significant in most patients. However, patients at high risk of developing 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 (in particular SULT1E1) and can increase the concentration of EE in the blood serum. Due to the current lack of data on the effects of various sulfotransferases, and their clinical significance for the use of many drugs is still being studied, it is advisable to prescribe etoricoxib with caution simultaneously with other drugs that are mainly metabolized by human sulfotransferases (for example, oral salbutamol and minoxidil).

Effect of etoricoxib on drugs metabolized by cytochrome isoenzymes. Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P450 isoenzymes 1A2,2C9,209,2D6,2E1, and 3A4. In a study involving healthy volunteers, daily use of etoricoxib at a dose of 120 mg did not affect the activity of the CYP-4 isoenzyme in the liver, according to the results of an erythromycin breath test.

Effect of other drugs on the pharmacokinetics of etoricoxib

The main pathway of etoricoxib metabolism depends on enzymes of the cytochrome system. The CYP3A4 isoenzyme promotes etoricoxib metabolism in vivo. In vitro studies suggest that the isoenzymes CYP2D6, CYP2C9, CYP1A2, and CYP2C19 can also catalyze the main pathway of metabolism, but their quantitative characteristics in vivo have not been studied. Ketoconazole. Ketoconazole is a potent inhibitor of the CYP3A4 isoenzyme. When ketoconazole was administered to healthy volunteers at a dose of 400 mg once a day for 11 days, it did not have a clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (an increase in AUC by 43%).

Voriconazole and miconazole. Concomitant use of strong inhibitors of the CYP3A4 isoenzyme (voriconazole for oral use or topically miconazole, oral gel) and etoricoxib caused a slight increase in etoricoxib exposure, which, based on published data, was not considered clinically significant.

Rifampicin. Concomitant use of etoricoxib and rifampicin (a potent inducer of the cytochrome system) resulted in a 65% reduction in etoricoxib plasma concentrations. This interaction may be accompanied by a relapse of symptoms when etoricoxib is co-administered with rifampicin. These data may indicate the need to increase the dose, but etoricoxib should not be used at doses that exceed the recommended dose for each indication (see section “Dosage and use”), since the combined 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.

How to take, course of use and dosage

Inside, regardless of food intake, with a small amount of water.

Bixitor® should be administered at the lowest effective dose in the shortest possible course.

Osteoarthritis

The recommended dose is 30 mg once daily or 60 mg once daily. Rheumatoid arthritis and ankylosing spondylitis The recommended dose is 90 mg once daily. In cases of acute pain, Bixitor should only be used during the acute symptomatic period.

Acute gouty arthritis

The recommended dose in the acute period is 120 mg once a day. The duration of use of the drug in a dose of 120 mg is no more than 8 days.

Acute pain after dental surgery

The recommended dose is 90 mg once a day. In the treatment of acute pain after dental surgery, Bixitor® should be used only in the acute period of no more than 3 days.

Doses that exceed the recommended values for each indication either have no additional efficacy or have not been studied.

Thus:- the daily dose for osteoarthritis should not exceed 60 mg; – the daily dose for rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg; – the daily dose for acute gouty arthritis should not exceed 120 mg, for a period of no more than 8 days; – the daily dose for pain relief after dental operations should not exceed 90 mg, for a period of no more than 3 days.

Special patient groups

Elderly patients

No dose adjustment is required in elderly patients. As with other medications used in elderly patients, caution should be exercised when using Bixitor® (see section “Special instructions”).

Patients with impaired liver function

Regardless of the indication, patients with mild hepatic impairment (Child-Pugh score 5-6) should not exceed the dose of 60 mg once a day, and patients with moderate hepatic impairment (Child-Pugh score 7-9) should not exceed the dose of 30 mg once a day. Caution is recommended when using Bixitor® in patients with moderate hepatic impairment, as the clinical experience of using etoricoxib in this group of patients is limited. Due to the lack of clinical experience with the use of etoricoxib in patients with severe hepatic impairment (≥10 points on the Child-Pugh scale), the drug is contraindicated for this group of patients (see the section “Pharmacological properties”, subsection “Pharmacokinetics”, as well as the sections” Contraindications “and”Special Instructions”).

Patients with impaired renal function

No dose adjustment is required in patients with creatinine clearance ≥30 ml / min (see section “Pharmacological properties”, subsection”Pharmacokinetics”). Use of etoricoxib in patients with creatinine clearance

Children

Etoricoxib is contraindicated in children and adolescents under 16 years of age (see section “Contraindications”).

Since Bixitor ® film-coated tablets are not intended for separation, other manufacturers ‘ 30 mg etoricoxib tablets should also be used when titrating the dose.

Overdose

In clinical studies, taking etoricoxib at a single dose of up to 500 mg and repeated use at a dose of up to 150 mg / day for 21 days did not cause significant toxic effects. Acute overdose with etoricoxib has been reported, but no adverse reactions have been reported in most cases. The most frequent adverse reactions were consistent with the safety profile of etoricoxib (for example, gastrointestinal disorders, cardiorenal events). In case of overdose, it is advisable to use the usual supportive measures, such as removing the unabsorbed drug from the gastrointestinal tract. clinical observation and, if necessary, maintenance therapy. Etoricoxib is not eliminated by hemodialysis, and the elimination of etoricoxib by peritoneal dialysis has not been studied.

Special instructions

Effect on the gastrointestinal tract

Upper gastrointestinal complications (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients treated with etoricoxib. Caution is recommended when treating patients at high risk of developing gastrointestinal complications when using NSAIDs, in particular in the elderly, patients who are simultaneously using other NSAIDs, including acetylsalicylic acid, as well as in patients with a history of gastrointestinal diseases such as ulcers or gastrointestinal bleeding.

There is an additional risk of gastrointestinal adverse reactions (gastrointestinal ulcers or other gastrointestinal complications) when etoricoxib and acetylsalicylic acid are co-administered (even at low doses). In long-term clinical studies, there were no significant differences in gastrointestinal safety when using selective COX-2 inhibitors in combination with acetylsalicylic acid compared to the use of NSAIDs in combination with acetylsalicylic acid.

Impact on the cardiovascular system

The results of clinical studies indicate that the use of drugs of the class of selective COX-2 inhibitors is associated with an increased risk of thrombotic events (especially myocardial infarction and stroke) relative to placebo and some NSAIDs. Since the risk of developing SS diseases when taking selective COX-2 inhibitors may increase with increasing dose and duration of use, it is necessary to choose the shortest possible duration of use and the lowest effective daily dose. It is necessary to periodically assess the patient’s need for symptomatic treatment in response to therapy, especially for patients with osteoarthritis.

Patients with known risk factors for the development of SS complications (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed etoricoxib only after careful assessment of the benefit and risk.

Selective COX-2 inhibitors are not a substitute for acetylsalicylic acid in the prevention of SS diseases, since they do not affect platelets. Therefore, the use of antiplatelet drugs should not be discontinued.

Effects on kidney function

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. In the presence of conditions that negatively affect renal perfusion, the use of etoricoxib may cause a decrease in prostaglandin formation and a decrease in renal blood flow, and thus reduce renal function. The greatest risk of developing this reaction exists for patients with a significant decrease in renal function, decompensated heart failure, or a history of cirrhosis. In such patients, it is necessary to monitor renal function.

Fluid retention, edema, and hypertension

As with other drugs that inhibit prostaglandin synthesis in patients receiving etoricoxib. fluid retention, edema and hypertension were observed. Use of all NSAIDs, including etoricoxib. it may be associated with the occurrence or relapse of chronic heart failure. Caution should be exercised when prescribing Bixitor® to patients with a history of heart failure, left ventricular dysfunction, or hypertension, as well as to patients with pre-existing edema that has occurred for any other reason. If there are clinical signs of deterioration in these patients, appropriate measures should be taken, including discontinuation of etoricoxib. Application of etoricoxib. especially in high doses, it may be associated with more frequent and severe arterial hypertension than with certain other NSAIDs and selective COX-2 inhibitors. During treatment with etoricoxib, special attention should be paid to blood pressure control (see section “Contraindications”), which should be monitored for 2 weeks after the start of treatment and periodically thereafter. If there is a significant increase in blood pressure, alternative treatment should be considered.

Effects on liver function

In clinical trials lasting up to one year, approximately 1% of patients treated with etoricoxib at doses of 30 mg,60 mg and 90 mg per day showed an increase in the activity of alanine aminotransferase (ALT) and/or aspartate aminotransferase (ACT) (approximately three or more times relative to the upper limit of normal).

All patients with symptoms and/or signs of liver dysfunction, as well as patients with abnormal liver function indicators, should be monitored. If permanent abnormalities in liver function parameters are detected (three times higher than the upper limit of normal), the use of Bixitor® should be discontinued.

Common influences

If the patient experiences a deterioration in the function of any of the organ systems listed above during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. When using etoricoxib in elderly patients and in patients with impaired renal, liver or heart function, appropriate medical supervision is necessary.

Caution should be exercised when starting treatment with etoricoxib in patients with dehydration. Rehydration is recommended before starting the use of etoricoxib.

Serious skin reactions have been reported very rarely during post-marketing surveillance with NSAIDs and some selective COX-2 inhibitors. Some of them (including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) were fatal. The risk of developing such reactions is highest at the beginning of therapy, in most cases during the first month of treatment. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported in patients treated with etoricoxib. The use of some selective COX-2 inhibitors was associated with an increased risk of skin reactions in patients with a history of drug allergies. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. The use of etoricoxib may mask fever or other signs of inflammation. Caution should be exercised when etoricoxib is co-administered with warfarin or other oral anticoagulants.

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

Influence on the ability to drive vehicles and mechanisms

Patients who have experienced dizziness, drowsiness or weakness during the use of etoricoxib should refrain from driving vehicles and working with mechanisms.

Storage conditions

At a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package.

Active ingredient

Etoricoxib

Conditions of release from pharmacies

By prescription

Dosage form

Tablets