Etoricoxib-Vista film-coated tablets 60 mg No. 7

Instructions for Etoricoxib-Vista film-coated tablets 60 mg No. 7

Composition

active ingredient: etoricoxib;

1 tablet contains 30 mg, 60 mg, 90 mg or 120 mg of etoricoxib;

excipients: calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate;

tablet shell: Opadry II white 31K28459 (titanium dioxide (E171), lactose monohydrate, hypromellose, triacetin).

Dosage form

Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, embossed with “Е9ОХ” on one side and “30” or “60” or “90” or “120” on the other side.

Pharmacotherapeutic group

Nonsteroidal anti-inflammatory and antirheumatic drugs. Coxibs. ATX code M01A H05.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

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

In clinical pharmacology studies, etoricoxib dose-dependently inhibited COX-2 without inhibiting COX-1 at doses up to 150 mg/day. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function. Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms have been identified, COX-1 and COX-2. COX-2 is an isoform of the enzyme that is induced by a proinflammatory impulse and is considered the main factor responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is also involved in the processes of ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and the central nervous system (induction of fever, pain perception, cognitive function). It may also participate in the healing process of ulcers. COX-2 has been identified in the tissue surrounding gastric ulcers in humans, but its significance for ulcer healing has not been established.

Efficiency.

In patients with osteoarthritis, etoricoxib 60 mg once daily significantly improved pain and patient self-reported disease status. These positive effects were observed as early as the second day of treatment and were maintained for up to 52 weeks. In studies with etoricoxib 30 mg once daily, the efficacy of this drug was superior to placebo for 12 weeks of treatment (using assessments used in other studies). In a dose-finding study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg in all 3 primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in osteoarthritis of the hand. In patients with rheumatoid arthritis, etoricoxib 60 mg and 90 mg once daily significantly improved pain, inflammation, and mobility. In studies evaluating the 60 mg and 90 mg doses, the beneficial effects were maintained over the 12-week treatment period. Both etoricoxib doses, 60 mg once daily and 90 mg once daily, were more effective than placebo. The 90 mg dose was more effective than the 60 mg dose in terms of patients' global pain assessment (0–100 mm visual analogue scale), with a mean improvement of -2.71 mm (95% CI [confidence interval]: -4.98 mm, -0.45 mm).

In patients with acute gouty arthritis, etoricoxib 120 mg once daily for 8 days provided relief of moderate to severe joint pain and inflammation compared with indomethacin 50 mg three times daily. Pain relief was observed as early as 4 hours after initiation of treatment. In patients with ankylosing spondylitis, etoricoxib 90 mg once daily provided significant improvements in spinal pain, inflammation, and limitation of movement, as well as improved functional capacity. The clinical benefits of etoricoxib were observed on the second day after initiation of therapy and were maintained through a 52-week treatment period. In a second study evaluating the 60 mg versus 90 mg dose, etoricoxib 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared with naproxen 1000 mg daily. In patients who did not respond adequately to 60 mg daily for 6 weeks, increasing the dose to 90 mg daily improved back pain intensity (0-100 mm visual analogue scale) compared with continuing 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

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

International research program on the long-term use of etoricoxib and diclofenac in arthritis (MEDAL).

The MEDAL program was a prospectively designed cardiovascular safety outcome program based on pooled data from three randomized, double-blind, active-controlled trials (MEDAL, EDGE II, and EDGE studies).

The MEDAL study, which was designed to determine the effects on the cardiovascular system, included 17,804 patients with osteoarthritis (OA) and 5,700 with rheumatoid arthritis (RA) who received etoricoxib 60 mg (OA) or 90 mg (OA and RA) or diclofenac 150 mg daily for a mean of 20.3 months (maximum 42.3 months, median 21.3 months). Only serious adverse reactions and discontinuation of the drug due to any adverse reactions were recorded 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 either etoricoxib 90 mg/day (1.5 times the recommended dose for the treatment of OA) or diclofenac 150 mg/day for a mean of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II study included 4086 patients with RA who received either etoricoxib 90 mg/day or diclofenac 150 mg/day for a mean of 19.2 months (maximum 33.1 months, median 24 months).

The combined MEDAL program enrolled 34,701 patients with OA and RA who were treated for a mean of 17.9 months (maximum 42.3 months, median 16.3 months); approximately 12,800 patients were treated for more than 24 months. Patients enrolled in this program had a variety of baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary angioplasty within 6 months prior to study enrollment were excluded. Gastroprotective medications and low-dose acetylsalicylic acid were permitted in the studies.

General safety.

There were no significant differences in the incidence of thrombotic cardiovascular events between etoricoxib and diclofenac. Cardiorenal adverse events were more common with etoricoxib than with diclofenac; this effect was dose-dependent (see below for details of the results). Gastrointestinal and hepatic adverse events were significantly more common with diclofenac than with etoricoxib. The incidence of adverse events in the EDGE and EDGE II studies, as well as adverse events considered serious or leading to discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Safety regarding the cardiovascular system.

The incidence of confirmed thrombotic cardiovascular serious adverse reactions (including cardiac reactions, cerebrovascular reactions, and peripheral vascular reactions) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the incidence of thrombotic complications between etoricoxib and diclofenac in all subgroups analyzed, including patients with cardiovascular risk. When considered separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions was similar between etoricoxib 60 mg or 90 mg and diclofenac 150 mg.

Table 1

Indicators of confirmed thrombotic cardiovascular complications (joint MEDAL program)

†Complications per 100 patient-years.

CI — confidence interval.

Per protocol: all complications during study therapy or within 14 days after its discontinuation (excluding patients who took < 75% of the study drug or took non-study non-steroidal anti-inflammatory drugs > 10% of the total period).

Intention-to-treat: all confirmed complications before the end of the study (including in patients who may have undergone an intervention unrelated to the study, with subsequent discontinuation of the study drug).

Total number of patients randomized: 17,412 in the etoricoxib group and 17,289 in the diclofenac group.

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

Cardiorenal complications.

Approximately 50% of patients enrolled in the MEDAL study had a history of hypertension at baseline. In this study, the incidence of discontinuation due to adverse reactions related to hypertension was statistically significantly higher in the etoricoxib group than in the diclofenac group. The incidence of adverse reactions such as congestive heart failure (discontinuation and serious reactions) was similar for etoricoxib 60 mg and diclofenac 150 mg, but the incidence of these reactions was higher for etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference for etoricoxib 90 mg compared to diclofenac 150 mg in the MEDAL OA group). The incidence of confirmed adverse reactions related to congestive heart failure (events that were serious and required hospitalization or emergency care) was slightly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent. The incidence of discontinuation of treatment due to adverse reactions related to edema was significantly higher with etoricoxib compared to diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference with etoricoxib 90 mg, but not etoricoxib 60 mg).

Cardiorenal outcomes obtained in the EDGE and EDGE II studies were consistent with those reported in the MEDAL study.

In individual MEDAL trials, the absolute incidence of discontinuation in any etoricoxib treatment group (60 mg or 90 mg) was up to 2.6% in hypertension, up to 1.9% in edema, and up to 1.1% in congestive heart failure, with a higher incidence of discontinuation observed with etoricoxib 90 mg than with 60 mg.

Gastrointestinal tolerability results in the MEDAL program.

A significantly lower rate of discontinuation due to any clinical GI complication (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib than with diclofenac in each of the three MEDAL trials. The rates of discontinuation due to GI clinical reactions per 100 patient-years over the entire study period were as follows: 3.23 for etoricoxib and 4.96 for diclofenac in MEDAL; 9.12 for etoricoxib and 12.28 for diclofenac in EDGE; and 3.71 for etoricoxib and 4.81 for diclofenac in EDGE II.

Results of the MEDAL program regarding gastrointestinal safety.

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

The rate per 100 patient-years of confirmed complicated and uncomplicated upper GI clinical events (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, with a relative risk of 0.69 (95% CI 0.57, 0.83). The rate of confirmed upper GI events in elderly patients was determined; the greatest reduction was observed in patients ≥75 years of age (1.35 [95% CI 0.94, 1.87] reactions per 100 patient-years with etoricoxib compared with 2.78 [95% CI 2.14, 3.56] with diclofenac).

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

Etoricoxib was associated with a statistically significantly lower rate of discontinuation due to hepatic adverse reactions than diclofenac. In the pooled MEDAL program, 0.3% of etoricoxib-treated patients and 2.7% of diclofenac-treated patients discontinued due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 for etoricoxib and 1.84 for diclofenac (p-value < 0.001 for etoricoxib versus diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.

Additional cardiovascular safety data regarding thrombotic events. In clinical trials, excluding the MEDAL trials, approximately 3,100 patients received etoricoxib at doses ≥ 60 mg/day for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular events in patients receiving etoricoxib at doses ≥ 60 mg, placebo, or other NSAIDs [nonsteroidal anti-inflammatory drugs] (excluding naproxen). However, the incidence of such reactions was higher in patients receiving etoricoxib compared with those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between some COX-1-inhibiting NSAIDs and selective COX-2 inhibitors may be clinically relevant in patients at risk for thromboembolic events. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of this finding is unknown.

Additional safety data for the gastrointestinal tract.

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

Study of kidney function in elderly patients.

A randomized, double-blind, placebo-controlled, parallel-group study evaluated the effects of 15 days of treatment with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on urinary sodium excretion, blood pressure, and other measures of renal function in patients 60 to 85 years of age on a 200 mEq/day salt diet. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion over 2 weeks of treatment. All active comparators showed increases relative to placebo in systolic blood pressure; however, etoricoxib was associated with a statistically significant increase at day 14 compared with celecoxib and naproxen (mean change from baseline in systolic blood pressure: etoricoxib 7.7 mmHg, celecoxib 2.4 mmHg, naproxen 3.6 mmHg).

Pharmacokinetics.

Absorption.

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

When etoricoxib was administered at a dose of 120 mg with food (high-fat meal), there was no effect on the extent of etoricoxib absorption. The rate of absorption was altered, with a 36% decrease in Cmax and a 2-hour increase in Tmax. These findings are not considered clinically significant. In clinical studies, etoricoxib was administered without regard to food intake.

Distribution.

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

Etoricoxib crosses the placental barrier in rats and rabbits, and the blood-brain barrier in rats.

Metabolism.

Etoricoxib is extensively metabolized, with less than 1% of the dose excreted in the urine as unchanged drug. The primary route of metabolism is the formation of a 6'-hydroxymethyl derivative catalyzed by cytochrome enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway, but their quantitative characteristics have not been studied in vivo.

Five metabolites have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, which is formed by further oxidation of the 6'-hydroxymethyl derivative. These major metabolites are either inactive or weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

Breeding.

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

Certain groups of patients.

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

Gender: The pharmacokinetics of etoricoxib are similar in men and women.

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

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

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

In a pharmacokinetic study (n = 16) conducted in adolescents (aged 12 to 17 years), the pharmacokinetics in patients weighing 40–60 kg receiving etoricoxib 60 mg once daily and in patients weighing more than 60 kg receiving 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in children have not been established.

Indication

For symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and signs of inflammation associated with acute gouty arthritis.

For the short-term treatment of moderate postoperative pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of all individual risks in the patient.

Contraindication

• Hypersensitivity to the active substance or any excipient of the medicinal product;
• Active peptic ulcer or active gastrointestinal bleeding;
• Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 (cyclooxyhexanase-2) inhibitors;
• Pregnancy and breastfeeding;
• Severe liver dysfunction (serum albumin < 25 g/l or ≥ 10 points on the Child-Pugh scale);
• Patients with estimated renal creatinine clearance < 30 mL/min;
• Children under 16 years of age;
• Inflammatory bowel diseases;
• Congestive heart failure (functional class II–IV according to the NYHA [New York Heart Association] classification);
• Patients with arterial hypertension whose blood pressure is consistently higher than 140/90 mm Hg and is not adequately controlled;
• Diagnosed with ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the concomitant use of an ACE inhibitor or angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase may result in further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be borne in mind in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be maintained and consideration should be given to monitoring renal function at the start of combination therapy and periodically thereafter.

Acetylsalicylic acid. In a study in healthy volunteers under steady-state conditions, etoricoxib 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be administered concomitantly with acetylsalicylic acid at doses used for the prevention of cardiovascular disease (low-dose acetylsalicylic acid). However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the incidence of gastrointestinal ulcers and other complications compared with etoricoxib monotherapy. Concomitant use of etoricoxib with acetylsalicylic acid at doses higher than prophylactic doses and with other nonsteroidal anti-inflammatory drugs is not recommended.

Cyclosporine and tacrolimus: Although the interaction of etoricoxib with these drugs has not been studied, concomitant use of any nonsteroidal anti-inflammatory drug with cyclosporine or tacrolimus may potentiate the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is administered concomitantly with any of these drugs.

Pharmacokinetic interactions.

Effect of etoricoxib on the pharmacokinetics of other drugs.

Lithium. Nonsteroidal anti-inflammatory drugs reduce the renal excretion of lithium, thereby increasing the level of lithium in the blood plasma. If necessary, carefully monitor the level of lithium in the blood and adjust the dose of lithium during the simultaneous use of these drugs, as well as when discontinuing the use of nonsteroidal anti-inflammatory drugs.

Methotrexate. Two studies examined the effects of etoricoxib 60 mg, 90 mg, or 120 mg once daily for 7 days in patients receiving methotrexate 7.5 to 20 mg once weekly for rheumatoid arthritis. Etoricoxib 60 and 90 mg did not affect the plasma concentration or renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on the plasma concentration or renal clearance of methotrexate, while in another study, etoricoxib 120 mg increased plasma methotrexate concentrations by 28% and decreased renal clearance of methotrexate by 13%. When etoricoxib and methotrexate are co-administered, appropriate monitoring for methotrexate toxicity should be performed.

Hormone Replacement Therapy (HRT). Coadministration of 120 mg of etoricoxib with a hormone replacement therapy containing conjugated estrogens (0.625 mg of Premarin™) for 28 days increased the mean steady-state AUC0–24hr of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effects of etoricoxib doses recommended for long-term use (30 mg, 60 mg, and 90 mg) have not been studied. Compared with increasing doses from 0.625 mg to 1.25 mg with Premarin™ monotherapy, the effect of etoricoxib at doses of 120 mg on the exposure (AUC0–24hr) of the estrogenic components of Premarin™ was less than half that of the placebo. The clinical significance of this increase is unknown, and high doses of Premarin™ have not been studied with etoricoxib. This increase in estrogen levels should be considered when selecting a hormonal agent for use in postmenopausal women when used with etoricoxib, as increased estrogen exposure increases the risk of adverse reactions to hormone replacement therapy.

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

Digoxin. Etoricoxib 120 mg once daily for 10 days in healthy volunteers had no effect on steady-state AUC0-24hr or renal clearance of digoxin. An increase in digoxin Cmax (approximately 33%) was observed. This increase is generally not significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are co-administered.

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

Effects of etoricoxib on medicinal products metabolised by CYP isoenzymes. In vitro studies do not indicate that inhibition of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4 is expected. In studies in healthy volunteers, daily administration of etoricoxib at a dose of 120 mg did not affect hepatic CYP3A4 activity as measured by the erythromycin breath test.

Effects of other medicinal products on the pharmacokinetics of etoricoxib. The major metabolic pathway of etoricoxib is mediated by CYP enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 may also catalyze the major metabolic pathway of etoricoxib, but their quantitative characteristics have not been studied in vivo.

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

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

Rifampicin: Co-administration of etoricoxib with rifampicin (a potent inducer of CYP enzymes) resulted in a 65% decrease in etoricoxib plasma concentrations. This may be associated with a recurrence of symptoms when co-administered with etoricoxib. While these data may indicate the need for dose escalation, it is not recommended to use etoricoxib at doses higher than those indicated for each indication, as the combined use of rifampicin and etoricoxib at these doses has not been studied.

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

Application features

Effect on the gastrointestinal tract.

Upper gastrointestinal complications (perforation, ulceration or bleeding), sometimes fatal, have been reported in patients receiving etoricoxib.

Nonsteroidal anti-inflammatory drugs should be prescribed with caution to patients at increased risk of gastrointestinal complications; elderly patients, patients taking any other nonsteroidal anti-inflammatory drug or acetylsalicylic acid concomitantly, or patients with a history of gastrointestinal disease, namely ulcers and gastrointestinal bleeding.

There is an additional risk of gastrointestinal adverse events (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is co-administered with acetylsalicylic acid (even at low doses). In long-term clinical trials, no significant difference in gastrointestinal safety was observed between a selective COX-2 inhibitor with acetylsalicylic acid and a nonsteroidal anti-inflammatory drug with acetylsalicylic acid.