Bixitor, 120 mg 10 pcs.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory drugs (NSAIDs) ATX code: M01AN05 Pharmacological properties

Pharmacodynamics

Mechanism of action

Etoricoxib is a selective cyclooxygenase-2 (COX-2) inhibitor when administered orally in therapeutic concentrations. In clinical pharmacological studies, etoricoxib inhibited COX-2 in a dose-dependent manner, with no effect on COX-1 at a daily dose up to 150 mg. The drug does not inhibit the synthesis of prostaglandins 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 isolated. COX-2 is an isoenzyme that is induced by various proinflammatory 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 arterial duct, regulation of kidney function and the central nervous system (induction of fever, sensation of pain, cognitive function), and may also play a certain role in the process of ulcer healing. COX-2 has been detected in the tissues surrounding gastric ulcers in humans, but its importance in ulcer healing has not been established.

Efficacy

In patients with osteoarthritis (OA), etoricoxib, administered at a dose of 60 mg once daily, provided a significant reduction in pain and improvement in patients’ assessment of their condition. These favorable effects were observed on the second day of treatment and persisted for 52 weeks. Studies of etoricoxib at a dose of 30 mg once daily (using similar evaluation methods) demonstrated efficacy compared to placebo during the treatment period of 12 weeks. In a study conducted to determine the optimal dose, etoricoxib at a dose of 60 mg demonstrated significantly greater improvement than at a dose of 30 mg for all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of the hand joints.

In patients with rheumatoid arthritis (RA), etoricoxib at a dose of 90 mg once daily provided a significant reduction in pain and inflammation and improved mobility. These favorable effects persisted for a treatment period of 12 weeks.

In patients with acute gouty arthritis, etoricoxib, administered at a dose of 120 mg once daily for an eight-day treatment period, reduced moderate to severe joint pain and inflammation. The efficacy was comparable to that of indomethacin when used in 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 at a dose of 90 mg once daily provided a significant reduction in back pain, inflammation, stiffness, and improved function. The clinical efficacy of etoricoxib was observed on the second day of treatment and was sustained for the entire treatment period of 52 weeks.

In a clinical study of pain after dental surgery, etoricoxib at a dose of 90 mg was administered once daily for three days. In a subgroup of patients with moderate pain (at baseline assessment), etoricoxib had the same analgesic effect as ibuprofen at a dose of 600 mg (16.11 vs. 16.39 P=0.722), and was superior to the paracetamol/codeine combination at a dose of 600 mg/60 mg (11.00, P<0.001) and placebo (6.84, P<0.001) according to the overall assessment of pain reduction during the first 6 hours (TOPAR6). The proportion of patients who required rapid-acting pain medication within the first 24 hours of taking the study drugs was 40.8% with etoricoxib at 90 mg, 25.5% with ibuprofen at 600 mg every 6 hours, and 46.7% with the paracetamol/codein combination at 600 mg/60 mg every 6 hours, compared with 76.2% in the placebo group. In this study, the median onset of action (tangible pain reduction) with etoricoxib at a dose of 90 mg was 28 minutes after taking the drug.

Safety

The MEDAL (Multinational Evaluation of Long-Term Prescribing of Etoricoxib and Diclofenac in Arthritis) Program

The MEDAL Program was a multinational program that evaluated the long-term use of etoricoxib and diclofenac in arthritis. The MEDAL program was a prospective safety assessment program based on cardiovascular (CV) events from pooled data from three randomized, double-blind, active-controlled trials: MEDAL, EDGE II and EDGE.

The MEDAL study was a trial, the duration of which was determined by achieving endpoints (CC events), that 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 daily for an average of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse events and dropouts due to any adverse events were reported in this study.

The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7111 patients with OA who received etoricoxib at a dose of 90 mg daily (1.5 times the recommended dose for OA) or diclofenac at a dose of 150 mg daily 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 etoricoxib at a dose of 90 mg daily or diclofenac at a dose of 150 mg daily 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 were treated for an average of 17.9 months (maximum 42.3 months, median 16.3 months); about 1,800 patients were treated for more than 24 months. Patients included in the MEDAL Program had a wide range of CV and gastrointestinal risk factors at baseline assessment. Patients with recent myocardial infarction, as well as those with aortocoronary bypass or percutaneous coronary intervention within 6 months before study inclusion were excluded. Gastroprotectants and low-dose aspirin were allowed in the studies.

The cardiovascular safety results

The incidence of confirmed serious thrombotic CC adverse events (which included cardiac, cerebrovascular, and peripheral vascular events) was comparable between the groups receiving etoricoxib or diclofenac (data are shown in the table below). There were no statistically significant differences in the incidence of thrombotic events between etoricoxib and diclofenac in all subgroups analyzed, including patient categories in the baseline CC risk range. The relative risk for confirmed serious thrombotic CC adverse events was similar for etoricoxib (when administered at 60 mg or 90 mg) and diclofenac (when administered at 150 mg).

Table “Frequency of Confirmed Thrombotic CC Events (MEDAL Program)”

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

Cardiorenal events

Approximately 50% of patients included in the MEDAL study had a history of arterial hypertension at baseline assessment. The dropout rate due to adverse events associated with arterial hypertension was statistically significantly higher for etoricoxib than for diclofenac. The frequency of adverse events related to chronic heart failure (dropouts and serious events) was similar for etoricoxib in 60 mg dose and diclofenac in 150 mg dose, but was higher for etoricoxib in 90 mg dose compared to diclofenac in 150 mg dose (and statistically significantly higher for etoricoxib in 90 mg dose compared to diclofenac in 150 mg dose in the MEDAL trial OA group). The frequency of confirmed adverse events related to chronic heart failure (events that were serious and resulted in hospitalization or emergency department visits) was slightly higher for etoricoxib compared to diclofenac in the 150 mg dose; this effect was dose-dependent. Study dropout rates due to adverse events related to edema were higher for etoricoxib compared with 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 EDGE and EDGE II cardiorenal safety assessments are consistent with the results in the MEDAL study

. In individual MEDAL studies, the absolute dropout rate in any treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% for arterial hypertension, up to 1.9% for edema, and up to 1.1% for chronic heart failure. Patients taking etoricoxib at the 90-mg dose had a higher dropout rate than patients taking etoricoxib at the 60-mg dose.

The MEDAL gastrointestinal tolerability results

In each of the three MEDAL studies, the study dropout rate for any clinical GI adverse event (e.g., dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared to diclofenac. The dropout rate due to GI adverse clinical events per 100 patient-years for 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.

The MEDAL Gastrointestinal Safety Assessment Results

In general, upper GI adverse events were defined as perforations, ulcers and bleeding. Complicated upper GI adverse events included perforations, obstruction and complicated bleeding; uncomplicated upper GI adverse events included uncomplicated bleeding and uncomplicated ulcers. The overall incidence of upper gastrointestinal adverse events was significantly lower for etoricoxib compared with diclofenac. No significant differences between etoricoxib and diclofenac were found in the incidence of complications. No significant differences between etoricoxib and diclofenac were found for hemorrhagic adverse events from the upper gastrointestinal tract (complicated and uncomplicated in the aggregate). The advantage of etoricoxib in the upper GI tract compared with diclofenac in patients simultaneously taking low-dose aspirin (about 33% of patients) was not statistically significant.

The incidence of confirmed complicated and uncomplicated upper GI clinical adverse events per 100 patient-years (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57, 0.77) for etoricoxib and 0.97 (95% CI 0.85, 1.10) for diclofenac, based on which the relative risk was 0.69 (95% CI 0.57, 0.83).

The incidence of confirmed upper gastrointestinal adverse events in older patients was examined; the maximum reduction 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 GI adverse events (small or large bowel perforation, obstruction, or bleeding) did not differ significantly between the groups receiving etoricoxib and diclofenac.

The MEDAL liver safety results

Etoricoxib had a statistically significantly lower dropout rate due to liver adverse events compared to diclofenac. In the combined MEDAL Program, 0.3% of patients receiving etoricoxib and 2.7% of patients receiving 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<0.001 for etoricoxib versus diclofenac). Most liver adverse events in the MEDAL Program were not serious.

Additional safety data related to thrombotic CC events

In clinical trials other than the MEDAL Program trials, approximately 3,100 patients received etoricoxib at a dose of ≥60 mg daily for 12 weeks or longer. There were no notable differences in the incidence of confirmed serious thrombotic CC events in patients receiving etoricoxib ≥60 mg, placebo, or naproxen-free NSAIDs. However, compared with patients receiving naproxen at a dose of 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 DAAs and COX-2 selective inhibitors may be of clinical significance in patients at risk for thromboembolic events. Selective COX-2 inhibitors inhibit systemic (and possibly endothelial) prostacyclin formation without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional Gastrointestinal Safety Data

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

The study of renal function in the elderly

. A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days of 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 measures of renal function in patients aged 60 to 85 years who received a sodium diet of 200 mEq/day. Etoricoxib, celecoxib, and naproxen had similar effects on renal sodium excretion after 2 weeks of treatment. All active comparison drugs increased systolic BP relative to placebo, but etoricoxib therapy resulted in a statistically significant increase in systolic BP at day 14 compared with celecoxib and naproxen (mean change for systolic BP compared with baseline: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, naproxen 3.6 mmHg).

Pharmacokinetics

Absorption

Etoricoxib is rapidly absorbed when administered orally. Absolute bioavailability when taken orally is about 100%. Administration in adults on an empty stomach in a dose of 120 mg once a day until reaching equilibrium state the maximum concentration (Cmax) is 3.6 µg/ml. Time of reaching maximum concentration (TCmax) in blood plasma is 1 h after drug administration. Geometric mean AUC0-24 is 37.8 µg/h/ml. Pharmacokinetics of etoricoxib within therapeutic doses is linear.
When taking etoricoxib at a dose of 120 mg with meals (high-fat meals) there was no clinically significant effect on the degree of absorption. The rate of absorption was altered, resulting in a 36% decrease in Cmax and a 2 h increase in TCmax. These results are not considered clinically significant. In clinical trials etoricoxib was used independently from food intake.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 µg/ml. The volume of distribution (Vdss) in equilibrium is about 120 l.
Etoricoxib penetrates through the placental and blood-brain barriers.

Metabolism

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

In humans, 5 metabolites of etoricoxib have been identified. The main metabolite is 6′-carboxyacetyl etoricoxib, which is formed by additional oxidation of 6′-hydroxymethyl etoricoxib. These major metabolites have no appreciable activity or are weak COX-2 inhibitors. None of these metabolites inhibits COX-1.

On single intravenous administration of labeled radioactive etoricoxib to healthy volunteers at a dose of 25 mg, 70% of etoricoxib was excreted through the kidneys, 20% – through the intestine, mostly as metabolites. Less than 2% was found unchanged.

The excretion of etoricoxib is mainly by metabolism, followed by excretion through the kidneys.

The equilibrium concentration is reached when 120 mg of etoricoxib is taken daily after 7 days with a cumulation coefficient of about 2, which corresponds to a half-life of about 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 ml/min.

Pharmacokinetics in selected patient groups

Elderly patients

Pharmacokinetics in the elderly (65 years and older) are comparable with those in the young.

Paul

The pharmacokinetics of etoricoxib are similar in men and women.

Hepatic disorders

In patients with mild hepatic impairment (Child-Pugh score of 5-6), administration of etoricoxib in a dose of 60 mg once daily was associated with a 16% increase in AUC compared to healthy subjects taking the drug in the same dose.

In patients with moderate hepatic dysfunction (Child-Pugh score 7-9) taking etoricoxib 60 mg once daily, the average AUC was the same as in healthy subjects taking etoricoxib daily in the same dose. Etoricoxib in a dose of 30 mg once daily has not been studied in this population.
No data from clinical and pharmacokinetic studies in patients with severe hepatic impairment (≥10 Child-Pugh score) are available.

Renal dysfunction

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

Children
Pharmacokinetic 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 weighing 40 to 60 kg when taking etoricoxib at a dose of 60 mg once daily and in those weighing more than 60 kg when taking etoricoxib at a dose of 90 mg once daily were similar to the pharmacokinetics in adults when taking etoricoxib at a dose of 90 mg once daily.

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

Indications

Treatment of chronic low back pain.
Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis.
Short-term therapy for moderate acute pain after dental surgery.
The decision to prescribe a selective COX-2 inhibitor should be justified taking into account the general risks for each individual patient (see sections “Contraindications” and “Special instructions”).

Pharmacological effect

Pharmacotherapeutic group: non-steroidal anti-inflammatory drugs (NSAIDs)
ATX code: M01AH05

Pharmacological properties

Pharmacodynamics

Mechanism of action
Etoricoxib, when administered 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 when using a daily dose of up to 150 mg. The drug does not inhibit the synthesis of prostaglandins in the gastric mucosa and does not affect platelet function.
Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase have been isolated: COX-1 and COX-2. COX-2 is an isoenzyme that is induced by various proinflammatory mediators and
is considered as 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 renal and central function.
nervous system (induction of fever, pain sensations, cognitive function), and may also play a role in the healing process of ulcers. COX-2 has been found in the tissue surrounding human gastric ulcers, but its significance for ulcer healing is unclear.
installed.

Efficiency
In patients with osteoarthritis (OA), etoricoxib, when administered at a dose of 60 mg once daily, provided a significant reduction in pain and improved patient assessment of their condition. These beneficial effects were observed already on the second day of treatment and
persisted for 52 weeks. Studies of etoricoxib at a dose of 30 mg once daily (using similar assessment methods) demonstrated efficacy compared with placebo over a treatment period of
12 weeks. In a dose-finding study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg for all three primary endpoints across
6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of the hand joints.
In patients with rheumatoid arthritis (RA), etoricoxib 60 mg and 90 mg once daily provided both significant reductions in pain and inflammation and improvements in mobility. In studies evaluating etoricoxib doses of 60 mg and 90 mg, these beneficial effects were maintained over a 12-week treatment period.
In patients with acute gouty arthritis attacks, etoricoxib 120 mg once daily for an eight-day treatment period reduced moderate to severe joint pain and inflammation. The effectiveness was comparable to that of indomethacin when administered at a dose of 50 mg three times a day. A decrease in pain was noted within four hours after the start of treatment.
In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant improvements in back pain, inflammation, stiffness, and function. Clinical efficacy of etoricoxib
was observed already on the second day of treatment and persisted throughout the entire treatment period of 52 weeks. In a second study comparing a 60 mg dose of etoricoxib with a 90 mg dose, etoricoxib 60 mg once daily and 90 mg once daily
once daily demonstrated similar efficacy to naproxen 1000 mg once daily.
In a clinical trial examining 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 at a dose of
90 mg had the same analgesic effect as ibuprofen 600 mg (16.11 versus 16.39; P = 0.722), and was superior to paracetamol/codeine 600 mg/60 mg (11.00, P < 0.001) and placebo (6.84, P < 0.001) in the overall pain reduction score. during the first 6 hours (TOPAR6). The proportion of patients who required rapid-acting pain medications within the first 24 hours of study medication was 40.8% with etoricoxib 90 mg, 25.5% with ibuprofen 600 mg every 6 hours, and 46.7% with paracetamol/codeine
600 mg/60 mg every 6 hours versus 76.2% in the placebo group. In this study, the median onset of action (perceived pain relief) with etoricoxib 90 mg was 28 minutes after dosing.

Security
Multinational Program for the Evaluation of Long-Term Administration of Etoricoxib and Diclofenac in Arthritis (MEDAL)
The MEDAL program was a prospective safety assessment program based on cardiovascular (CV) events based on pooled data from three randomized, double-blind, active-controlled trials: MEDAL,
EDGE II and EDGE.
The MEDAL study was a duration-of-endpoint (SS) study that included 17,804 patients with OA and 5,700 patients with RA who received etoricoxib 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 dropouts due to any
were recorded.
adverse events.
The EDGE and EDGE II studies compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE study included 7111 patients with OA who received etoricoxib at a dose of 90 mg per day (1.5 times the dose recommended for
OA) or diclofenac 150 mg daily for an average of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4086 patients with RA who received etoricoxib 90 mg daily or diclofenac 150 mg daily in
on average for 19.2 months (maximum 33.1 months, median 24 months).
In the combined MEDAL Program, 34,701 patients with OA or RA were treated for an average of 17.9 months (maximum 42.3 months, median 16.3 months), and approximately 12,800 patients were treated for more than 24 months. Patients enrolled in the MEDAL Program had a wide range of cardiovascular and gastrointestinal risk factors at baseline assessment. Patients with a recent myocardial infarction, as well as coronary artery bypass grafting or percutaneous coronary intervention within 6 months before inclusion in the study were excluded. The studies allowed the use of gastroprotectors and low-dose aspirin.

General safety
There were no significant differences between etoricoxib and diclofenac in the incidence of thrombotic cardiovascular events. Cardiorenal adverse events were observed more frequently with etoricoxib than with
prescription of diclofenac; this effect was dose-dependent (selected results are presented below). Adverse events from the gastrointestinal tract and liver were significantly more often observed when prescribing diclofenac than when prescribing
etoricoxib. The incidence of adverse events in the EDGE and EDGE II studies, as well as adverse events considered serious or requiring treatment discontinuation in the MEDAL study, was higher with etoricoxib than with
diclofenac.

Results of the cardiovascular safety assessment
The incidence of confirmed serious thrombotic cardiovascular adverse events (including cardiac, cerebrovascular and peripheral vascular events) was comparable between the groups receiving etoricoxib or diclofenac (data are shown in the table below). There were no statistically significant differences in the incidence of thrombotic events between etoricoxib and diclofenac in all analyzed subgroups, including categories of patients in the range
baseline cardiovascular risk. When considered individually, the relative risk for confirmed serious thrombotic cardiovascular adverse events was similar for etoricoxib (at a dose of 60 mg or
90 mg) and diclofenac (when taken at a dose of 150 mg).

Special instructions

Effect on the gastrointestinal tract
Cases of upper gastrointestinal complications (perforation, ulceration or bleeding), sometimes fatal, have been reported in patients receiving etoricoxib.
It is recommended to exercise caution 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, incl. acetylsalicylic
acid, as well as in patients with a history of gastrointestinal diseases such as ulcers or gastrointestinal bleeding.
There is an additional increase in the risk of developing GI adverse events (gastrointestinal ulcers or other GI complications) with concomitant use of etoricoxib and acetylsalicylic acid (even at low
doses). In long-term clinical studies, there were no significant differences in gastrointestinal safety when using selective COX-2 inhibitors + acetylsalicylic acid compared with the use of NSAIDs + acetylsalicylic acid (see section “Pharmacological properties”, subsection “Pharmacodynamics”).

Effect on the cardiovascular system
Clinical trial results suggest that the use of selective COX-2 inhibitor drugs may be associated with a risk of thrombotic events (especially myocardial infarction (MI) and stroke)
relative to placebo and some NSAIDs. Because the risk of developing cardiovascular disease with etoricoxib 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 (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as sections “Contraindications”, “Dosage and Administration” and “Side effects”).
Patients with significant risk factors for cardiovascular complications (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed etoricoxib only after careful evaluation of benefit (see section “Pharmacological properties”,
subsection “Pharmacodynamics”).
Selective COX-2 inhibitors are not a replacement for acetylsalicylic acid in the prevention of cardiovascular thromboembolic diseases due to their insufficient effect on platelets. Therefore, you should not stop using
antiplatelet drugs (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as section “Interaction with other drugs”).

Effect on kidney function
Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in the presence of conditions that adversely affect renal perfusion, the use of etoricoxib may cause a decrease in prostaglandin formation and, secondarily, a decrease in renal blood flow, and thus impair renal function. The greatest risk of developing this reaction is in 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, fluid retention, edema, and hypertension have been reported in patients treated with etoricoxib.
All NSAIDs, including etoricoxib, may be associated with the onset or recurrence of chronic heart failure. Information on the dose dependence of the effect of etoricoxib is given in the section “Pharmacological properties”,
subsection “Pharmacodynamics”. Caution should be exercised in patients with a history of heart failure, left ventricular dysfunction or hypertension, as well as in patients with pre-existing edema due to any
another reason. If clinical signs of deterioration occur in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.
The use of etoricoxib, especially at high doses, may be associated with more frequent and severe hypertension than with some other NSAIDs and selective COX-2 inhibitors. Special attention should be paid during treatment with etoricoxib
to control blood pressure (see section “Contraindications”). Blood pressure should be monitored for two weeks after starting treatment and periodically thereafter. If there is a significant increase in blood pressure, alternative treatment should be considered.

Effect on liver function
In clinical studies lasting up to one year, approximately 1% of patients treated with etoricoxib at doses of 30 mg, 60 mg and 90 mg per day experienced increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal).
All patients with symptoms and/or signs of liver dysfunction, as well as patients with abnormal liver function tests, should be monitored.
If there are signs of liver failure or persistent liver function abnormalities (three times the upper limit of normal), use of Bixitor® should be discontinued.

General instructions
If the patient experiences deterioration in the function of any of the organ systems listed above during treatment, appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered. When using etoricoxib in
Elderly patients and patients with impaired renal, hepatic or cardiac function require appropriate medical supervision.
Caution should be exercised when initiating treatment with etoricoxib in patients with dehydration.
Rehydration is recommended before starting etoricoxib therapy.
During post-marketing surveillance, the development of serious skin reactions was very rarely reported with the use of NSAIDs and some selective COX-2 inhibitors, some of them (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) were fatal (see section “Side effects”). The risk of developing such reactions in patients 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 receiving etoricoxib (see section “Side effects”). The use of some selective COX-2 inhibitors has been associated with an increased risk of skin reactions in patients with a history of any drug allergies. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Etoricoxib may mask fever or other signs of inflammation.
Caution should be exercised when concomitantly prescribing etoricoxib with warfarin or other oral anticoagulants (see section “Interactions with other drugs”).
The use of etoricoxib, like other drugs that inhibit the synthesis of cyclooxygenase/prostaglandins, is not recommended for women who are planning pregnancy (see section “Pharmacological properties”, subsection “Pharmacodynamics”
and section “Use during pregnancy and breastfeeding, effects on fertility”).
Bixitor® contains lactose monohydrate. Patients with rare congenital diseases such as lactose intolerance, congenital lactase deficiency and glucose-galactose malabsorption should not use this drug.

Impact on the ability to drive vehicles and machinery
Patients who experience spatial disorientation, dizziness, or drowsiness while taking etoricoxib should refrain from driving or operating machinery.

Active ingredient

Etoricoxib

Composition

1 tablet contains:
Active ingredient: etoricoxib – 60 mg / or 90 mg / or 120 mg;
Excipients: anhydrous calcium hydrogen phosphate, microcrystalline cellulose, povidone K 30, croscarmellose sodium, magnesium stearate; shell – hypromellose, lactose monohydrate, titanium dioxide, triacetin, indigo carmine aluminum varnish (for dosage 60 mg and 120 mg), iron oxide yellow (for dosage 60 mg and 120 mg).

Pregnancy

Pregnancy
There are no clinical data on the use of etoricoxib during pregnancy. Reproductive toxicity has been observed in animal studies. The potential risk in women during pregnancy is unknown. The use of etoricoxib, as well as other drugs that inhibit prostaglandin synthesis, can lead to suppression of uterine contractions in the last trimester of pregnancy – to premature closure of the ductus arteriosus in the fetus.
Etoricoxib is contraindicated during pregnancy (see section “Contraindications”).
If a woman becomes pregnant during treatment, etoricoxib should be discontinued.

Breastfeeding
It is unknown whether etoricoxib is excreted into human milk. In lactating rats, etoricoxib is excreted in milk. Women taking etoricoxib should stop breastfeeding (see Contraindications section).

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

Contraindications

Hypersensitivity to any component of the drug;
peptic ulcer of the stomach and duodenum in the acute stage, active gastrointestinal bleeding;
complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including a history);
pregnancy, breastfeeding period;
severe liver dysfunction (serum albumin <25 g/l or ≥10 points on the Child-Pugh scale); severe renal failure (creatinine clearance less than 30 ml/min); children under 16 years of age; inflammatory bowel diseases; chronic heart failure (NYHA functional class II-IV); uncontrolled arterial hypertension, in which blood pressure levels consistently exceed 140/90 mm Hg. Art.; 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 diseases. With caution

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

patients with an increased risk of developing complications from the gastrointestinal tract due to taking NSAIDs; elderly patients concomitantly taking other NSAIDs, including acetylsalicylic acid, or patients with a history of gastrointestinal diseases such as peptic ulcers and gastrointestinal bleeding:
patients with a history of risk factors for cardiovascular complications, such as dyslipidemia/hyperlipidemia, diabetes mellitus, hypertension, smoking, heart failure, left ventricular dysfunction, edema and fluid retention:
patients with mild liver dysfunction (5-6 points on the Child-Pugh scale) should not exceed a dose of 60 mg once a day, patients with moderate liver dysfunction (7-9 points on the Child-Pugh scale) should not exceed 30 mg once a day:
patients with dehydration:
patients with impaired renal function who are simultaneously 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 weakened renal function, decompensated heart failure or cirrhosis, who are at risk with long-term use of NSAIDs.

Caution should be exercised during concomitant therapy with the following drugs:

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

Side Effects

Security Profile Summary
The safety of etoricoxib was assessed in clinical studies that included 9295 participants, including 6757 patients with OA, RA, chronic low back pain and ankylosing spondylitis (approximately 600 patients with
OA or RA have been treated for one year or longer).
In clinical studies, the adverse effect profile was similar in patients with OA or RA who took etoricoxib for one year or longer.
In a clinical trial of acute gouty arthritis, patients received etoricoxib 120 mg once daily for eight days. The adverse effect profile in this study was generally similar to that in the pooled studies of OA, RA, and chronic low back pain.
In a cardiovascular safety program combining data from three active-controlled studies, 17,412 patients with OA or RA received etoricoxib (60 mg or 90 mg) for an average of 18 months (see Pharmacological Properties, Pharmacodynamics subsection).
In clinical studies of acute postoperative pain associated with dental surgery, in which 614 patients received etoricoxib at a dose of 90 mg or 120 mg, the adverse effect profile in these studies was generally
similar to the profile in pooled studies of OA, RA and chronic low back pain.

List of adverse reactions in table form
The following adverse reactions were reported at a higher frequency with the drug than with placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing
spondylitis who received etoricoxib 30 mg, 60 mg, or 90 mg escalated to the recommended dose over 12 weeks, in the MEDAL Program studies of up to 3.5 years, in short-term acute pain studies of up to 7 days, and in post-marketing use.
The incidence of adverse reactions is given in accordance with the World Health Organization classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare
(< 1/10000); unknown (frequency cannot be estimated from available data).Infectious and parasitic diseases: Often – alveolar osteitis; uncommon – gastroenteritis, upper respiratory tract infections, urinary tract infections.Blood and lymphatic system disorders: Uncommon – anemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia.Immune system disorders: Uncommon – hypersensitivity reactions*,**; rarely – angioedema, anaphylactic/anaphylactoid reactions, including shock*.Metabolic and nutritional disorders: Often – swelling/fluid retention; uncommon – decreased or increased appetite, weight gain.Mental disorders: Uncommon – anxiety, depression, concentration problems, hallucinations*; rarely – confusion*, anxiety*.Nervous system disorders: Often – headache, dizziness; uncommon – taste disturbance, insomnia, drowsiness, paresthesia/hypoesthesia.Visual disorders: Uncommon – blurred vision, conjunctivitis.Hearing and labyrinthine disorders: Uncommon – tinnitus, vertigo.Cardiac disorders: Often – palpitations, arrhythmia*; uncommon – atrial fibrillation, tachycardia*, chronic heart failure, nonspecific ECG changes, angina*, myocardial infarction***.Vascular disorders: Often – arterial hypertension; uncommon – “hot flashes”, cerebrovascular accident***, transient ischemic attack, hypertensive crisis*, vasculitis*.Disorders of the respiratory system, chest and mediastinal organs: Often – bronchospasm*; uncommon – cough, shortness of breath, nosebleeds.Gastrointestinal disorders: Very often – abdominal pain; often – constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, ulcers of the oral mucosa; uncommon – abdominal bloating, changes in peristalsis, dry oral mucosa, gastroduodenal ulcer, stomach ulcer, including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis*.Disorders of the liver and biliary tract: Often – increased ALT activity, increased AST activity; rarely – hepatitis*, liver failure*, jaundice*.Disorders of the skin and subcutaneous tissues: Often – ecchymosis; uncommon – swelling of the face, itching, rash, erythema*, urticaria*; rarely – Stevens-Johnson syndrome*, toxic epidermal necrolysis*, fixed drug-induced erythema*.Musculoskeletal and connective tissue disorders: Uncommon – muscle cramps/spasms, myalgia, musculoskeletal pain/stiffness.Renal and urinary tract disorders: Uncommon – proteinuria, increased serum creatinine, renal failure*.General disorders and disorders at the injection site: Often – asthenia/weakness, flu-like syndrome; uncommon – chest pain.Laboratory and instrumental data: Uncommon – increased blood urea nitrogen, increased creatine phosphokinase activity, hyperkalemia, increased uric acid; rarely – decreased sodium in the blood.* This adverse reaction was reported during post-marketing surveillance. The reported frequency for it is estimated based on the highest frequency observed in clinical studies pooled by dose and indication.** Hypersensitivity includes the terms “allergy”, “drug allergy”, “drug hypersensitivity”, “hypersensitivity”, “unspecified hypersensitivity”, “hypersensitivity reaction” and “non-specific allergy”.*** According to the results of an analysis of long-term placebo-controlled and actively controlled clinical studies, the use of selective COX-2 inhibitors increases the risk of developing serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk of developing these events exceeds 1% per year (infrequent).The following serious adverse events have been reported in association with NSAIDs and cannot be excluded for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Interaction

Pharmacodynamic interaction
Oral anticoagulants (warfarin). In patients stabilized on long-term warfarin therapy, etoricoxib 120 mg once daily was associated with an approximately 13% increase in international normalized ratio (INR) prothrombin time. Therefore, INR prothrombin time values ​​should be closely monitored in patients receiving oral anticoagulants, particularly in the first few days of starting treatment with etoricoxib or when the dose of etoricoxib is changed.
Diuretics, ACE inhibitors and angiotensin II antagonists. NSAIDs may reduce 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), concomitant use of an ACE inhibitor or angiotensin II antagonist and drugs that inhibit cyclooxygenase may lead to a further deterioration of renal function, including the possible development of acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. In this regard, this combination should be prescribed 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 the issue of monitoring renal function should be considered.
Acetylsalicylic acid. In a study in healthy volunteers, etoricoxib 120 mg once daily at steady state did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily).
Etoricoxib can be used simultaneously with acetylsalicylic acid in doses intended for the prevention of cardiovascular diseases (low doses of acetylsalicylic acid). However, simultaneous administration of low doses of acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared to taking etoricoxib alone. The simultaneous use of etoricoxib with acetylsalicylic acid in doses exceeding those recommended for the prevention of cardiovascular diseases, as well as with other NSAIDs, is not recommended (see section “Pharmacological properties”, subsection “Pharmacodynamics”, as well as section “Special instructions”).
Cyclosporine and tacrolimus. Although this interaction with etoricoxib has not been studied, concomitant use of cyclosporine or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporine or tacrolimus. With simultaneous
If etoricoxib is used with any of these drugs, renal function should be monitored.

Pharmacokinetic interaction
Effect of etoricoxib on the pharmacokinetics of other drugs Lithium. NSAIDs reduce the renal excretion of lithium and, therefore, increase the concentration of lithium in the blood plasma. If necessary, frequently monitor the concentration of lithium in the blood and adjust the dose of lithium during simultaneous 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 given once daily for seven days in patients receiving 7.5 to 20 mg of methotrexate once weekly for rheumatoid arthritis.
Etoricoxib at doses of 60 and 90 mg had no effect on plasma concentrations or renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on plasma concentrations (as measured by AUC) or renal clearance
methotrexate, and in another study, etoricoxib 120 mg increased plasma methotrexate concentrations by 28% and decreased the renal clearance of methotrexate by 13%. If etoricoxib is co-administered with methotrexate, adequate monitoring should be carried out for possible toxic effects of methotrexate.
Oral contraceptives. Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady-state AUC0-24h for EE by 37%.
Etoricoxib 120 mg, administered with these oral contraceptives concomitantly or 12 hours apart, increased the steady-state AUC0-24h for EE by 50-60%. This increase in EE concentration should be taken into account when selecting
appropriate oral contraceptive for use with etoricoxib.
Increased exposure to EE may increase the incidence of adverse events associated with the use of oral contraceptives (for example, venous thromboembolism in women at risk).
Hormone replacement therapy (HRT). Administration of etoricoxib 120 mg with hormone replacement therapy containing 0.625 mg conjugated estrogens for 28 days increased the mean steady-state AUC0-24h of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%).
The effects of etoricoxib doses recommended for long-term use (30, 60 and 90 mg) have not been studied. Etoricoxib at a dose of 120 mg changed the exposure (AUC0-24h) of these estrogenic components to less than half compared with drug monotherapy,
containing conjugated estrogens, increasing the dose of the latter from 0.625 to 1.25 mg. The clinical significance of such increases is unknown. The combination of etoricoxib and a product containing higher doses of conjugated estrogens has not been studied. Increased estrogen concentrations should be taken into account when choosing a hormonal drug for postmenopausal use when coadministered with etoricoxib, since increased estrogen exposure may increase the risk of HRT-related adverse events.
Prednisone/prednisolone. In drug interaction studies, etoricoxib did not have a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.
Digoxin. Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers had no effect on steady-state plasma AUC0-24h or renal excretion of digoxin. An increase in digoxin Cmax was noted
(by approximately 33%). This increase is usually not significant in most patients. However, when using etoricoxib and digoxin concomitantly, the condition of patients at high risk of developing
toxic effects of digoxin.
Effect of etoricoxib on drugs metabolized by sulfotransferases
Etoricoxib is an inhibitor of human sulfotransferases (specifically SULT1E1) and may increase serum EE concentrations. Due to the fact that currently limited data have been obtained on the influence of various sulfotransferases, and their
The clinical relevance for the use of many drugs is still being studied, it is advisable to use caution when prescribing etoricoxib with other drugs that are metabolized primarily by human sulfotransferases (for example, oral salbutamol and minoxidil).
Effect of etoricoxib on drugs metabolized by CYP isoenzymes
Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4. In a study of healthy volunteers, daily use of etoricoxib 120 mg had no effect on hepatic CYP3A4 activity as measured by the erythromycin breath test.
Effect of other drugs on the pharmacokinetics of etoricoxib
The main route of metabolism of etoricoxib is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies suggest that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyze
the main metabolic pathway, but their quantitative characteristics in vivo have not been studied.
Ketoconazole. Ketoconazole, a potent CYP3A4 inhibitor, when administered to healthy volunteers at a dose of 400 mg once daily for 11 days did not have any clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (43% increase in AUC).
Voriconazole and miconazole. Concomitant administration of etoricoxib and oral voriconazole or miconazole oral gel, strong CYP3A4 inhibitors, resulted in a small increase in etoricoxib exposure that was not considered to be clinically significant based on published data.
Rifampicin. Co-administration of etoricoxib with rifampicin, a strong inducer of CYP enzymes, resulted in a 65% decrease in etoricoxib plasma concentrations. This interaction may result in relapse of symptoms when etoricoxib is used concomitantly with rifampicin. Although these data may indicate a need for dose escalation, use of etoricoxib in doses higher than those recommended for each indication has not been studied and is therefore not recommended (see Dosage and Administration).
Antacids. Antacids do not have a clinically significant effect on the pharmacokinetics of etoricoxib.

Overdose

In clinical studies, single doses of etoricoxib up to 500 mg or multiple doses of up to 150 mg/day for 21 days did not cause significant toxic effects. There have been reports of acute overdose with etoricoxib, but in most cases no adverse reactions were reported.
The most commonly observed adverse reactions were consistent with the safety profile of etoricoxib (eg, gastrointestinal disorders, cardiorenal events).
In case of overdose, it is advisable to apply the usual supportive measures, such as removal of unabsorbed drug from the gastrointestinal tract, clinical observation and, if necessary, supportive therapy.
Etoricoxib is not eliminated by hemodialysis, and elimination of etoricoxib by peritoneal dialysis has not been studied.

Storage conditions

At a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

3 years. Do not use after the expiration date stated on the package.

Manufacturer

AET Laboratories Private Limited/Hemofarm LLC, India