Bixitor, 90 mg 30 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 studies 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 results of the MEDAL liver safety assessment

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

Symptomatic therapy of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis.

Short-term therapy of moderate acute pain after dental surgery.

Active ingredient

Etoricoxib

Composition

1 tablet contains:

Active ingredient:

Etoricoxib – 90 mg;

Excipients: calcium hydrophosphate anhydrous, microcrystalline cellulose, povidone K 30, croscarmellose sodium, magnesium stearate; coating – hypromellose, lactose monohydrate, titanium dioxide, triacetin.

How to take, the dosage

Orally, regardless of meals, with a small amount of water.

Bixitor® should be used at the lowest effective dose for 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 conditions accompanied with acute pain, Bixitor® should be used only in acute symptomatic period.

Acute gouty arthritis

The recommended dose in the acute period is 120 mg once daily.
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 daily. When treating acute pain after dental surgery, Bixitor® should only be used for an acute period of not more than 3 days.

Doses higher than those recommended for each indication either have no additional efficacy or have not been studied.

Hence:
– the daily dose for osteoarthritis should not exceed 60 mg;
– the daily dose for rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg;
– Daily dose in acute gouty arthritis should not exceed 120 mg, for a period not exceeding 8 days;
– Daily dose for pain relief after dental surgery should not exceed 90 mg, for a period not exceeding 3 days.

Special patient groups

Elderly patients

Dose adjustment in elderly patients is not required. As with the use of other drugs in elderly patients, caution should be exercised when using Bixitor® (see “Cautionary Note”).

Patients with hepatic impairment

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

Patients with impaired renal function

Dose adjustment in patients with creatinine clearance ≥30 mL/min is not required (see section “Pharmacological properties”, subsection “Pharmacokinetics”). The use of etoricoxib in patients with creatinine clearance <30 ml/min is contraindicated (see sections “Contraindications” and “Special Precautions”).

Children

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

Because Bixitor® film-coated tablets are not intended to be split, other manufacturers’ etoricoxib tablets in the 30 mg dose should also be used when titrating the dose.

Interaction

Pharmacodynamic Interactions

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

Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., in patients with dehydration or elderly patients with impaired renal function), the simultaneous use of an ACE inhibitor or angiotensin II antagonist and cyclooxygenase inhibitor drugs may lead to additional deterioration of renal function, including possible development of acute renal failure, which is usually reversible. It should be remembered about the possibility of such interactions in patients who take etoricoxib simultaneously with ACE inhibitors or angiotensin II antagonists. Such combination should be administered with caution, especially in elderly patients. At the beginning of combined treatment, as well as at certain intervals thereafter, fluid replacement should be performed and renal function monitoring should be considered.

Acetylsalicylic acid. In a study with healthy volunteers, etoricoxib at a dose of 120 mg daily at equilibrium had no effect on the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Bixitor® can be used concomitantly with acetylsalicylic acid in low doses intended for prevention of SSs. However, concomitant administration of low doses of acetylsalicylic acid and etoricoxib may result in an increased incidence of gastrointestinal ulcers and other complications compared to etoricoxib alone. Concomitant use of etoricoxib with acetylsalicylic acid in doses higher than those recommended for the prevention of CC 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 concomitant use of etoricoxib with any of these drugs.

Pharmacokinetic interaction

The effect of etoricoxib on the pharmacokinetics of other drugs

Lithium. NSAIDs decrease renal excretion of lithium and therefore increase plasma lithium concentrations. If necessary, frequent monitoring of lithium concentration in blood is carried out and the dose of lithium is adjusted during concomitant use with NSAIDs, as well as during withdrawal of NSAIDs.

Methotrexate. Two studies examined the effects of etoricoxib in doses of 60, 90, and 120 mg once daily for seven days in patients who received once-weekly methotrexate in doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 and 90 mg had no effect on plasma concentrations and renal clearance of methotrexate. In one study, etoricoxib at a dose of 120 mg had no effect on the pharmacokinetic parameters of methotrexate. In another study, plasma concentrations of methotrexate were increased by 28% and renal clearance of methotrexate was decreased by 13%. When etoricoxib and methotrexate are prescribed concomitantly, monitoring should be conducted for possible toxic effects of methotrexate.

The oral contraceptives. Taking etoricoxib for 21 days at a dose of 60 mg with an oral contraceptive containing 35 mcg ethinylestradiol (EE) and 0.5 to 1 mg norethindrone increases the AUC0-24h for EE by 37%. Taking etoricoxib at a dose of 120 mg with the above oral contraceptives (simultaneously or 12 hours apart) increases the equilibrium AUC0-24h for EE by 50-60%. This increase in EE concentration should be taken into account when choosing an appropriate oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increased incidence of adverse events associated with the use of oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of etoricoxib at a dose of 120 mg concomitantly with drugs for hormone replacement therapy containing conjugated estrogens at a dose of 0.625 mg. for 28 days increases the average equilibrium AUC0-24h of unconjugated estrone (41%), equiline (76%) and 17-β-estradiol (22%). The effects of the doses of etoricoxib 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 less than twice as much as monotherapy with the conjugated estrogen-containing drug, with an increase in the dose of the latter 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. Elevated estrogen concentrations should be considered when choosing a hormone medication for use in the postmenopause when concomitantly prescribed with etoricoxib because increased estrogen exposure may increase the risk of adverse events associated with MHT.

Prednisone/prednisolone. In drug interaction studies, etoricoxib had no clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. When using etoricoxib at a dose of 120 mg once daily for 10 days in healthy volunteers there was no change in AUC0-24h at equilibrium or effect on the renal excretion of digoxin. There was an increase in the Cmax of digoxin (approximately 33%). This increase is generally not significant in most patients. However, concomitant use of etoricoxib and digoxin should be monitored in patients at high risk of digoxin toxicity.

The effect of etoricoxib on drugs metabolized by sulfotransferases. Etoricoxib is an inhibitor of human sulfotransferase (specifically SULT1E1) and can increase serum EE concentrations. Due to the fact that there are currently insufficient data on the effects of various sulfotransferases and their clinical relevance to the use of many drugs is still being studied, it is advisable to prescribe etoricoxib with caution simultaneously with other drugs that are metabolized primarily by human sulfotransferases (e.g., oral salbutamol and minoxidil).

The effect of etoricoxib on drugs metabolized by isoenzymes of the cytochrome system. Based on 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 had no effect on the activity of the CYP WA4 isoenzyme in the liver, according to the erythromycin breath test.

The effect of other drugs on the pharmacokinetics of etoricoxib

The main route of metabolism of etoricoxib depends on enzymes of the cytochrome system. The CYP3A4 isoenzyme contributes to the metabolism of etoricoxib in vivo. In vitro studies suggest that the CYP2D6, CYP2C9, CYP1A2, and CYP2C19 isoenzymes may also catalyze the major metabolic pathway, but their quantitative characteristics in vivo have not been studied.
Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4 isoenzyme. When administered in healthy volunteers at a dose of 400 mg once daily for 11 days ketoconazole had no clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (increased AUC by 43%).

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

Rifampicin. Concomitant administration of etoricoxib and rifampicin (a potent inducer of the cytochrome system) resulted in a 65% decrease in plasma concentration of etoricoxib. This interaction may be accompanied by relapse of symptoms when concomitant use of etoricoxib with rifampicin. These data may indicate the need to increase the dose, but etoricoxib should not be used in doses that exceed those recommended for each indication (see section “Dosage and administration”), since the combined use of rifampicin and etoricoxib in such doses has not been studied.

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

Special Instructions

Impact on the gastrointestinal tract

There have been cases of upper gastrointestinal complications (perforations, ulcers or bleeding), sometimes with fatal outcome, in patients who received etoricoxib. It is recommended to exercise caution when treating patients with a high risk of GI complications when using NSAIDs, particularly in the elderly, patients who simultaneously use other NSAIDs, including acetylsalicylic acid, as well as in patients with such GI diseases in the history as ulceration or gastrointestinal bleeding.

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

Indications on the cardiovascular system

The results of clinical studies suggest 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 SS disease with 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. The patient’s need for symptomatic treatment in response to therapy should be periodically evaluated, especially for patients with osteoarthritis.

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

The selective COX-2 inhibitors are not a substitute for acetylsalicylic acid in the prevention of SS because they have no effect on platelets. Therefore, the use of antiplatelet agents should not be discontinued.

Impact on renal function

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. In the presence of conditions that adversely affect renal perfusion, administration of etoricoxib may cause decreased formation of prostaglandins and decreased renal blood flow, and thereby reduce 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, renal function should be monitored.

Fluid retention, edema and arterial hypertension

As with other prostaglandin synthesis inhibiting drugs, fluid retention, edema and arterial hypertension have been observed in patients using etoricoxib. The use of all NSAIDs, including etoricoxib, may be associated with the occurrence or recurrence of chronic heart failure. Caution should be exercised when prescribing Bixitor® in patients with a history of heart failure, left ventricular dysfunction or arterial hypertension, as well as in patients with pre-existing edema due to any other cause. If clinical signs of deterioration appear in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.
The use of etoricoxib. especially in high doses may be associated with more frequent and severe arterial hypertension than with some other NSAIDs and COX-2 selective inhibitors. During treatment with etoricoxib special attention should be paid to BP control (see section “Contraindications”), which should be monitored for 2 weeks after the start of treatment and periodically thereafter. Alternative treatment should be considered if there is a significant increase in BP.

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 (ACT) activity (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 parameters should be monitored. In case of detection of permanent liver function abnormalities (three times the upper limit of normal) the use of Bixitor® should be discontinued.

General Effects

If any of the organ systems listed above deteriorate during treatment, appropriate measures should be taken and etoricoxib discontinuation should be considered. Appropriate medical monitoring is necessary when using etoricoxib in elderly patients and in patients with impaired renal, hepatic or cardiac function.

With caution, treatment with etoricoxib should be initiated in patients who are dehydrated. Rehydration is recommended before starting etoricoxib.

During postmarketing surveillance, serious skin reactions have very rarely been reported 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 receiving etoricoxib. The use of some selective COX-2 inhibitors was accompanied by an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Use of etoricoxib may mask fever or other signs of inflammation. Caution should be exercised when etoricoxib is concomitantly prescribed 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 to become pregnant.

Influence on driving, operating machinery

Patients who have experienced dizziness, drowsiness or weakness while using etoricoxib should refrain from driving and operating machinery.

Contraindications

• High sensitivity to any component of the drug;
• Gastric and duodenal ulcer in the acute stage, active gastrointestinal bleeding;
• pregnancy, breastfeeding;
• severe hepatic dysfunction (serum albumin <25 g/L or ≥10 points on the Child-Pugh scale);severe renal impairment (creatinine clearance less than 30 ml/min);
• children under 16 years of age;
• inflammatory bowel disease;
• chronic heart failure (NYHA functional class II-IV);
• uncontrolled arterial hypertension in which BP is persistently above 140/90 mmHg.
• Confirmed coronary heart disease, peripheral artery disease and/or cerebrovascular disease.
• lactose intolerance, lactase deficiency, glucose-galactose malabsorption (the drug contains lactose)
• confirmed hyperkalemia;
• progressive renal disease.

Cautions

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

• Patients with an increased risk of gastrointestinal complications due to taking NSAIDs; the elderly; concomitantly taking other NSAIDs, including acetylsalicylic acid; or patients with a history of gastrointestinal diseases, such as peptic ulcer disease and gastrointestinal bleeding:
• Patients with a history of cardiovascular risk factors such as dyslipidemia/hyperlipidemia, diabetes mellitus, arterial hypertension, smoking, heart failure, left ventricular dysfunction, edema and fluid retention:
• Patients with mild liver dysfunction (Child-Pugh score 5-6) should not exceed a dose of 60 mg once daily, patients with moderate liver dysfunction (Child-Pugh score 7-9) 30 mg once daily:
• 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 with concomitant therapy with the following drugs:

• anticoagulants (e.g., warfarin),
• anti-aggregants (e.g., acetylsalicylic acid, clopidogrel),
• drugs metabolized by sulfotransferases.

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Side effects

The frequency of adverse reactions has been defined as:

Very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1000 to < 1/100): rare (≥1/10000 to < 1/1000); very rare (< 1/10000).

Infectious and parasitic diseases: Frequently – alveolar ostitis; infrequently – gastroenteritis, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders: Infrequent – anemia (mainly due to gastrointestinal bleeding), leukopenia, thrombocytopenia.

Immune system disorders: Infrequent – hypersensitivity reactions *,**, rarely – angioedema, anaphylactic/anaphylactoid reactions, including shock *.

Metabolic and nutrition disorders: Often – edema/ fluid retention, infrequent – decreased or increased appetite, increased body weight.

Mental disorders: Infrequent – anxiety, depression, concentration disorders, hallucinations*; rare – confusion*, anxiety*.

Nervous system disorders: Often – headache, dizziness; infrequent – taste disorders, insomnia, somnolence, paresthesia/hypoesthesia.

Visual organ disorders: Infrequent – blurred vision, conjunctivitis.

Hearing organ and labyrinth disorders: Infrequent – tinnitus, vertigo.

Cardiac disorders: Often – palpitations, arrhythmia*; infrequent – atrial fibrillation, tachycardia*, chronic heart failure, non-specific changes on ECG, angina pectoris*, myocardial infarction***.

Vascular disorders: Often – arterial hypertension; infrequent – “hot flashes”, cerebral arrhythmia***, transient ischemic attack, hypertensive crisis*, vasculitis*.

Respiratory, chest and mediastinal disorders: Often – bronchospasm*; infrequent – cough, dyspnea, nasal bleeding.

Gastrointestinal tract disorders: Very common – abdominal pain; common – constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/discomfort in epigastrium, nausea, vomiting, esophagitis, oral mucosal ulcers; infrequent – bloating, altered peristalsis, dry oral mucosa, gastroduodenal ulcer, peptic ulcer, including gastrointestinal perforations and bleeding, irritable bowel syndrome, 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; infrequent – facial edema, skin itching, rash, erythema*, urticaria*; rare – Stevens-Johnson syndrome*, toxic epidermal necrolysis*, fixed erythema drug*.

Musculoskeletal and connective tissue disorders: Infrequent – muscle cramps/spasms, myalgia, musculoskeletal pain/shortness.

Renal and urinary tract disorders: Infrequent – proteinuria, increased serum creatinine, renal failure*.

General disorders and disorders at the site of administration: Often – asthenia/weakness, flu-like syndrome; infrequently – pain in the chest.

Laboratory and instrumental data: Infrequent – increase of blood urea nitrogen, increased creatine phosphokinase activity, hyperkalemia, increased uric acid; rare – decrease of sodium in blood.

* This adverse reaction has been reported during the post-marketing monitoring. The frequency of reports for it is estimated based on the highest frequency observed in clinical trials combined by dose and indication.

** Hypersensitivity includes the terms “allergy”, “drug allergy”, “hypersensitivity to the drug”, “hypersensitivity”, “hypersensitivity unspecified”, “hypersensitivity reaction” and “non-specific allergy”.

*** According to the results of the analysis of 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 (infrequent).

The following serious adverse events have been reported in connection with administration of NSAIDs and cannot be excluded for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

Overdose

In clinical trials, administration of etoricoxib at a single dose of up to 500 mg and multiple doses of up to 150 mg/day over 21 days caused no significant toxic effects. Acute overdose with etoricoxib has been reported, but in most cases no adverse reactions have been reported.

The most common adverse reactions were consistent with the safety profile of etoricoxib (e.g., GI disorders, cardiorenal events).

In the event of an overdose, the usual supportive measures such as removal of the unabsorbed drug from the GI tract are appropriate. clinical observation and, if necessary, supportive therapy. Etoricoxib is not excreted by hemodialysis; excretion of etoricoxib by peritoneal dialysis has not been studied.

Pregnancy use

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy. Toxic effects on the reproductive system have 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 the synthesis of prostaglandins, during the last trimester of pregnancy may lead to suppression of uterine contractions and premature closure of the arterial duct.
Etoricoxib is contraindicated during pregnancy. If pregnancy occurs during treatment, etoricoxib should be discontinued.

Breastfeeding

In lactating rats, etoricoxib is excreted with milk. There have been no studies confirming excretion of etoricoxib with breast milk in women. Women who take etoricoxib should stop breastfeeding.
Fertility

The use of etoricoxib as well as other drugs that inhibit COX-2 and prostaglandin synthesis is not recommended for women who plan to become pregnant.

Similarities

Arcoxia, Kostarox, Atorika tablets, Etoricoxib-Teva