Tosibiya
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOSIBIA (TOSIBIA)
Composition:
Active substance: etoricoxib;
One tablet contains etoricoxib (calculated as 100 % dry substance) 30 mg, 60 mg, 90 mg, or 120 mg;
Excipients: calcium hydrogen phosphate anhydrous, microcrystalline cellulose, sodium croscarmellose, hypromellose, magnesium stearate;
Film coating:
30 mg, 60 mg, 120 mg: hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin, indigo carmine (E 132), iron oxide yellow (E 172);
90 mg: hypromellose, lactose monohydrate, titanium dioxide (E 171), triacetin.
Dosage form. Film-coated tablets.
Main physicochemical properties:
30 mg: round-shaped, film-coated tablets, blue-green in color, with a biconvex surface;
60 mg: round-shaped, film-coated tablets, dark green in color, with a biconvex surface;
90 mg: round-shaped, film-coated tablets, white in color, with a biconvex surface;
120 mg: round-shaped, film-coated tablets, grey-green, blue-green, or green in color, with a biconvex surface.
Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01AH05.
Pharmacological Properties.
Pharmacodynamics
Mechanism of Action
Etoricoxib is an oral selective inhibitor of cyclooxygenase-2 (COX-2) within the clinical dose range.
In clinical pharmacological studies, etoricoxib dose-dependently inhibited COX-2 without inhibiting COX-1 when administered at doses up to 150 mg daily. 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 the inducible isoform of the enzyme, activated by inflammatory stimuli, and is considered the main factor responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation, and closure of the ductus arteriosus, as well as in the regulation of kidney function and the central nervous system (fever induction, pain perception, cognitive function). It may also participate in the process of ulcer healing. COX-2 has been identified in perilesional gastric tissue in humans, but its significance for ulcer healing has not been established.
Efficacy
In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improved pain symptoms and patient assessment of disease status. These positive effects were observed as early as the second day of treatment and persisted throughout the 52-week treatment period. In studies using etoricoxib at a dose of 30 mg once daily, the drug's efficacy exceeded that of placebo over a 12-week treatment period (using endpoints applied in other studies). In a dose-ranging study, etoricoxib at 60 mg demonstrated significantly greater improvement compared to 30 mg across all three primary endpoints after 6 weeks of treatment. The 30 mg dose has not been studied in hand osteoarthritis.
In patients with rheumatoid arthritis, etoricoxib at doses of 60 mg and 90 mg once daily significantly improved pain intensity, inflammation, and joint mobility. In trials evaluating the 60 mg and 90 mg doses, positive effects were maintained throughout the 12-week treatment period. In a study comparing the 60 mg and 90 mg doses, both etoricoxib regimens – 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 according to the method of patients’ Global Pain Assessment (0–100 mm visual analog scale), with a mean improvement of -2.71 mm (95% CI: -4.98 mm, -0.45 mm).
In patients with acute gouty arthritis attacks, etoricoxib at a dose of 120 mg once daily for 8 days reduced moderate to severe joint pain and inflammation compared to indomethacin 50 mg three times daily. Reduction in pain intensity was observed as early as 4 hours after initiation of treatment.
In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once daily provided significant improvement in spinal pain, inflammation, restricted mobility, and enhanced functional capacity. Clinical benefits of etoricoxib were observed on the second day after initiation of therapy and persisted throughout the 52-week treatment period. In a second dose-comparison study evaluating 60 mg versus 90 mg, etoricoxib at 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg daily. In patients who did not show an adequate response to the 60 mg daily dose over 6 weeks, increasing the dose to 90 mg daily improved assessment of back pain intensity (0–100 mm visual analog scale) compared to continuing 60 mg daily, with a mean improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).
In a clinical study of postoperative dental pain, etoricoxib 90 mg was administered once daily for up to three days. In the subgroup of patients with moderate baseline pain, etoricoxib 90 mg demonstrated an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P=0.722) and superior to that of acetaminophen/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001), as measured by the Total Pain Relief over 6 hours (TOTPAR6). The proportion of patients reporting use of rescue analgesic 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 acetaminophen/codeine 600 mg/60 mg every 6 hours group, compared to 76.2% of patients receiving placebo. In this study, onset of analgesic effect (perceived pain relief) with 90 mg etoricoxib was observed as early as 28 minutes after dosing.
Safety
Medications for the Evaluation of the Long-term Safety of Etoricoxib and Diclofenac in Arthritis (MEDAL) Program
The MEDAL program was a prospectively designed safety outcomes program analyzing cardiovascular safety data pooled from three randomized, double-blind, active-comparator controlled trials (the MEDAL, EDGE II, and EDGE studies).
In the MEDAL study, designed to assess cardiovascular effects, 17,804 patients with osteoarthritis (OA) and 5,700 with rheumatoid arthritis (RA) received etoricoxib 60 mg (OA) or 90 mg (OA and RA), or diclofenac 150 mg daily for a median of 20.3 months (maximum 42.3 months, median 21.3 months). In this study, only serious adverse reactions and discontinuations due to any adverse reactions were recorded.
The EDGE and EDGE II studies compared gastrointestinal tolerability of etoricoxib and diclofenac. In the EDGE study, 7,111 OA patients received etoricoxib 90 mg daily (1.5 times higher than the recommended OA dose) or diclofenac 150 mg daily for a median of 9.1 months (maximum 16.6 months, median 11.4 months). In the EDGE II study, 4,086 RA patients received etoricoxib 90 mg daily or diclofenac 150 mg daily for a median of 19.2 months (maximum 33.1 months, median 24 months).
The combined MEDAL program included 34,701 patients with OA and RA treated for a median 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 varying baseline cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass grafting, or percutaneous coronary intervention within 6 months prior to study enrollment were excluded. Concomitant use of gastroprotective agents and low-dose acetylsalicylic acid was permitted in the studies.
Overall Safety
There were no significant differences in the incidence of thrombotic cardiovascular complications between etoricoxib and diclofenac. Cardiorenal adverse reactions were more frequently observed with etoricoxib than with diclofenac; this effect was dose-dependent (see detailed results below). Gastrointestinal and hepatic adverse reactions occurred significantly more frequently with diclofenac than with etoricoxib. The incidence of adverse reactions in the EDGE and EDGE II studies, as well as serious adverse reactions or those leading to drug discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.
Cardiovascular Safety
The incidence of confirmed serious thrombotic cardiovascular adverse reactions (including cardiac events, cerebrovascular events, and peripheral vascular events) was comparable between etoricoxib and diclofenac (data summarized in Table 1). There were no significant differences in the rates of thrombotic complications between etoricoxib and diclofenac across all analyzed subgroups, including patients with cardiovascular risk. When analyzed separately, the relative risk of confirmed serious thrombotic cardiovascular adverse reactions with etoricoxib 60 mg or 90 mg versus diclofenac 150 mg was similar.
Incidence of confirmed cardiovascular thrombotic complications (combined MEDAL program)
Table 1
| Complications |
Etoricoxib (N=16819) 25836 patient-years |
Diclofenac (N=16483) 24766 patient-years |
Comparison between treatment groups |
|||
| Incidence† (95% CI) |
Incidence† (95% CI) |
Relative risk (95% CI) |
||||
| Confirmed serious thrombotic cardiovascular adverse reactions |
||||||
| Per-protocol |
1.24 (1.11; 1.38) |
1.30 (1.17; 1.45) |
0.95 (0.81; 1.11) |
|||
| Intention-to-treat |
1.25 (1.14; 1.36) |
1.19 (1.08; 1.30) |
1.05 (0.93; 1.19) |
|||
| Confirmed cardiac complications |
||||||
| Per-protocol |
0.71 (0.61; 0.82) |
0.78 (0.68; 0.90) |
0.90 (0.74; 1.10) |
|||
| Intention-to-treat |
0.69 (0.61; 0.78) |
0.70 (0.62; 0.79) |
0.99 (0.84; 1.17) |
|||
| Confirmed cerebrovascular complications |
||||||
| Per-protocol |
0.34 (0.28; 0.42) |
0.32 (0.25; 0.40) |
1.08 (0.80; 1.46) |
|||
| Intention-to-treat |
0.33 (0.28; 0.39) |
0.29 (0.24; 0.35) |
1.12 (0.87; 1.44) |
|||
| Confirmed peripheral vascular complications |
||||||
| Per-protocol |
0.20 (0.15; 0.27) |
0.22 (0.17; 0.29) |
0.92 (0.63; 1.35) |
|||
| Intention-to-treat |
0.24 (0.20; 0.30) |
0.23 (0.18; 0.28) |
1.08 (0.81; 1.44) |
|||
| †Events per 100 patient-years; CI – confidence interval. N – total number of patients in the per-protocol population. Per-protocol: all complications during the study treatment or within 14 days after its discontinuation (except patients who took <75% of the study drug or used non-study nonsteroidal anti-inflammatory drugs for >10% of the total period). Intention-to-treat: all confirmed complications up to the end of the study (including patients who may have received interventions unrelated to the study, followed by discontinuation of the study drug). Total number of randomized patients: 17412 in the etoricoxib group and 17289 in the diclofenac group. |
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The cardiovascular mortality rate, as well as overall 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 arterial hypertension at baseline. In this study, the rate of treatment discontinuation due to adverse reactions related to arterial hypertension was statistically significantly higher in the etoricoxib group than in the diclofenac group. The frequency of the adverse reaction of congestive heart failure (treatment discontinuation and serious events) was similar with etoricoxib 60 mg and diclofenac 150 mg, but the frequency of these events was higher with etoricoxib 90 mg compared to diclofenac 150 mg (statistically significant difference with etoricoxib 90 mg compared to diclofenac 150 mg in the OA MEDAL group). The frequency 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 rate of treatment discontinuation 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 with etoricoxib 60 mg).
Cardiorenal outcomes from the EDGE and EDGE II studies were consistent with the data reported in the MEDAL study.
In individual studies of the MEDAL program, the absolute frequency of treatment discontinuation in any etoricoxib treatment group (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 congestive heart failure, with a higher discontinuation rate observed with etoricoxib 90 mg compared to 60 mg.
Gastrointestinal tolerability results in the MEDAL program
A significantly lower rate of treatment discontinuation due to any gastrointestinal (GI) clinical complications (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib compared to diclofenac in each of the three MEDAL studies. The rates of treatment discontinuation due to GI clinical events per 100 patient-years over the entire study period were: 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; 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.
Gastrointestinal safety results from the MEDAL program
Upper gastrointestinal events were defined as perforations, ulcers, and bleeding. A subgroup of upper gastrointestinal events considered complicated included perforations, obstructions, and complicated bleeding; a subgroup of upper gastrointestinal events considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of overall upper gastrointestinal events was observed with etoricoxib compared to diclofenac. There was no significant difference between etoricoxib and diclofenac in the rate of complicated events. For the subgroup of upper gastrointestinal bleeding events (combined complicated and uncomplicated), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib over diclofenac regarding upper gastrointestinal effects was not statistically significant in patients concurrently taking low-dose aspirin (approximately 33% of patients).
The rate per 100 patient-years of confirmed complicated and uncomplicated clinical upper gastrointestinal events (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57, 0.77) with etoricoxib and 0.97 (95% CI 0.85, 1.10) with diclofenac, with a relative risk of 0.69 (95% CI 0.57, 0.83).
The rate of confirmed upper gastrointestinal events was assessed in elderly patients; the greatest reduction was observed in patients aged ≥75 years (1.35 [95% CI 0.94, 1.87] events per 100 patient-years with etoricoxib compared to 2.78 [95% CI 2.14, 3.56] with diclofenac).
Rates of confirmed clinical lower gastrointestinal events (perforation of the small or large intestine, obstruction, or bleeding) did not differ statistically between etoricoxib and diclofenac.
Hepatic safety results from the MEDAL program
Etoricoxib was associated with a statistically significantly lower rate of treatment discontinuation due to hepatic adverse reactions compared to diclofenac. In the combined MEDAL program, 0.3% of patients taking etoricoxib and 2.7% of patients taking diclofenac discontinued treatment due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 with etoricoxib and 1.84 with diclofenac (p-value < 0.001 for etoricoxib compared to diclofenac). However, in the MEDAL program, most hepatic adverse reactions were non-serious.
Additional cardiovascular safety data regarding thrombotic complications
During clinical trials, excluding the MEDAL program studies, approximately 3100 patients received etoricoxib at doses ≥ 60 mg daily for 12 weeks or longer. There was no significant difference in the rates of confirmed serious thrombotic cardiovascular complications among patients taking etoricoxib at doses ≥ 60 mg, placebo, or other NSAIDs (except naproxen). However, the frequency of such events was higher in patients receiving etoricoxib compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between some COX-1 inhibiting NSAIDs and selective COX-2 inhibitors may be clinically significant in patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce systemic (and thus possibly endothelial) prostacyclin formation without affecting platelet thromboxane. The clinical significance of these data is unknown.
Additional gastrointestinal safety data
During two 12-week double-blind endoscopic studies, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving etoricoxib 120 mg once daily compared to patients receiving naproxen 500 mg twice daily or ibuprofen 800 mg three times daily. The incidence of ulcers was higher with etoricoxib than with placebo.
Renal function study in elderly patients
A randomized, double-blind, placebo-controlled parallel-group study evaluated the effects of 15-day 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 renal function parameters in patients aged 60 to 85 years on a diet containing 200 mEq/day of salt. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after two weeks of treatment. All active comparator drugs showed an increase in systolic blood pressure relative to placebo; however, etoricoxib was associated with a statistically significant increase on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: etoricoxib 7.7 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).
Pharmacokinetics.
Absorption.
Etoricoxib is well absorbed following oral administration. Absolute bioavailability is approximately 100%. After administration of 120 mg once daily to steady state, peak plasma concentration (geometric mean Cmax = 3.6 µg/mL) is observed at approximately 1 hour (Tmax) after dosing in fasting adults. The geometric mean AUC0–24 hr is 37.8 µg×hr/mL. Within the clinical dosing range, the pharmacokinetics of etoricoxib are linear.
Administration of 120 mg with food (high-fat meal) did not affect the extent of etoricoxib absorption. The rate of absorption was altered, characterized by a 36% reduction in Cmax and a 2-hour increase in Tmax. These findings are not considered clinically significant. During clinical trials, etoricoxib was administered without regard to food intake.
Distribution.
Etoricoxib is approximately 92% bound to human plasma proteins at 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 unchanged in urine. The primary metabolic pathway is the formation of the 6'-hydroxymethyl derivative, catalyzed by cytochrome enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway, but their quantitative contributions have not been studied in vivo.
Five metabolites have been identified in humans. The major metabolite is the 6'-carboxylic acid derivative of etoricoxib, formed by further oxidation of the 6'-hydroxymethyl derivative. These primary metabolites are either inactive or weakly active COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination.
Following a single intravenous dose of 25 mg radiolabeled etoricoxib to healthy volunteers, 70% of the radioactive drug was excreted in urine and 20% in feces, primarily as metabolites. Less than 2% was excreted unchanged.
Elimination of etoricoxib occurs almost entirely via metabolism, followed by renal excretion. Steady-state concentrations of etoricoxib are reached within 7 days with 120 mg once daily, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 mL/min.
Special patient populations.
Elderly patients. Pharmacokinetics in elderly patients (aged 65 years and older) are similar to those in younger patients.
Gender. Pharmacokinetics of etoricoxib are similar in men and women.
Hepatic impairment. In patients with mild hepatic impairment (Child-Pugh score 5–6), administration of etoricoxib 60 mg once daily resulted in a mean AUC approximately 16% higher than in healthy volunteers receiving the same dose. In patients with moderate hepatic impairment (Child-Pugh score 7–9), administration of etoricoxib 60 mg every other day resulted in a mean AUC similar to that in healthy volunteers receiving 60 mg once daily; administration of etoricoxib 30 mg once daily has not been studied in this patient group. There are no clinical or pharmacokinetic data available for 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 and severe renal impairment, as well as in patients with end-stage renal disease undergoing hemodialysis, do not differ significantly from those in healthy volunteers. Etoricoxib is minimally removed during hemodialysis (dialysis clearance approximately 50 mL/min).
Pediatrics. The pharmacokinetics of etoricoxib in children (under 12 years of age) have not been studied.
In pharmacokinetic studies (n=16) involving adolescents (aged 12 to 17 years), pharmacokinetics in patients with body weight 40–60 kg receiving etoricoxib 60 mg once daily and in patients with body weight over 60 kg receiving etoricoxib 90 mg once daily were similar to those in adults receiving etoricoxib 90 mg once daily. The safety and efficacy of etoricoxib in pediatric patients have not been established.
Clinical characteristics.
Indications.
Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, as well as pain and signs of inflammation associated with acute gouty arthritis.
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 patient risks.
Contraindications.
The medicinal product Tosibia is contraindicated:
- in patients with hypersensitivity to the active substance or to any of the excipients;
- in active peptic ulcer or active gastrointestinal bleeding;
- in patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors (cyclooxygenase-2);
- during pregnancy or breastfeeding;
- in severe hepatic impairment (serum albumin <25 g/L or ≥10 points on the Child-Pugh scale);
- when the calculated creatinine clearance is <30 mL/min;
- in children under 16 years of age;
- in inflammatory bowel diseases;
- in congestive heart failure (NYHA II–IV);
- in patients with arterial hypertension whose blood pressure values are consistently above 140/90 mm Hg and are insufficiently controlled;
- in diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions
Oral anticoagulants. In patients whose condition is stabilized on long-term warfarin therapy, administration of etoricoxib at a dose of 120 mg daily is associated with an increase of approximately 13% in the international normalized ratio (INR). Therefore, in patients receiving oral anticoagulants, INR values should be monitored frequently, especially during the first days of etoricoxib treatment or when changing its dosage.
Diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Nonsteroidal anti-inflammatory drugs may reduce the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with reduced renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist with drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients receiving etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, particularly in elderly patients. Adequate hydration should be ensured, and monitoring of renal function should be considered at the start of combination therapy and periodically thereafter.
Acetylsalicylic acid. In a study involving healthy volunteers at steady state, administration of etoricoxib 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib may be administered concomitantly with low-dose acetylsalicylic acid used for cardiovascular prophylaxis. However, concomitant use of low-dose acetylsalicylic acid and etoricoxib may increase the frequency of gastrointestinal ulceration and other complications compared to monotherapy with etoricoxib. Concomitant use of etoricoxib with acetylsalicylic acid doses higher than those used for prophylaxis, as well as with other nonsteroidal anti-inflammatory drugs, is not recommended.
Cyclosporine and tacrolimus. Although interactions between etoricoxib and these drugs have not been studied, concomitant use of any nonsteroidal anti-inflammatory drug with cyclosporine or tacrolimus may enhance the nephrotoxic effects of the latter. Renal function should be monitored when etoricoxib is used concomitantly with either of these agents.
Pharmacokinetic interactions
Effect of etoricoxib on the pharmacokinetics of other drugs.
Lithium. Nonsteroidal anti-inflammatory drugs reduce renal excretion of lithium, thereby increasing plasma lithium levels. Careful monitoring of plasma lithium levels and dose adjustment of lithium may be necessary during concomitant use of these drugs, as well as after discontinuation of nonsteroidal anti-inflammatory drugs.
Methotrexate. Two studies evaluated the effects of etoricoxib administered at doses of 60, 90, or 120 mg once daily for 7 days in patients receiving weekly methotrexate at doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at doses of 60 and 90 mg did not affect plasma concentrations or renal clearance of methotrexate. In one study, administration of etoricoxib 120 mg had no effect on plasma concentration or renal clearance of methotrexate, whereas in another study, etoricoxib 120 mg increased methotrexate plasma concentration by 28% and decreased its renal clearance by 13%. Appropriate monitoring for signs of methotrexate toxicity should be performed when etoricoxib and methotrexate are used concomitantly.
Oral contraceptives. Etoricoxib 60 mg administered concomitantly with oral contraceptives containing 35 mcg ethinylestradiol and 0.5–1 mg norethindrone for 21 days increased the steady-state AUC0–24 hr of ethinylestradiol by 37%. Etoricoxib 120 mg administered concomitantly with the same oral contraceptives, either simultaneously or 12 hours apart, increased the steady-state AUC0–24 hr of ethinylestradiol by 50–60%. This increase in ethinylestradiol concentration should be considered when selecting an oral contraceptive with varying ethinylestradiol content for concomitant use with etoricoxib. Increased ethinylestradiol exposure may increase the incidence of adverse reactions associated with oral contraceptives (e.g., venous thromboembolism in women at risk).
Hormone replacement therapy (HRT). Administration of 120 mg etoricoxib with hormone replacement therapy containing conjugated estrogens for 28 days increased the mean steady-state AUC0–24 hr of unconjugated estrone (by 41%), equilin (by 76%), and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (30, 60, and 90 mg) has not been studied. Compared to increasing the dose from 0.625 to 1.25 mg in monotherapy with conjugated estrogens, the effect of 120 mg etoricoxib on exposure (AUC0–24 hr) of estrogenic components was less than half. The clinical significance of this increase is unknown, and the use of high doses of conjugated estrogens concomitantly with etoricoxib has not been studied. This increased estrogen concentration should be considered when selecting a hormonal preparation for postmenopausal use in combination with etoricoxib, as increased estrogen exposure may elevate the risk of adverse reactions associated with hormone replacement therapy.
Prednisone/prednisolone. In interaction studies, etoricoxib did not show clinically significant effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin. Administration of etoricoxib 120 mg once daily for 10 days to healthy volunteers did not affect steady-state AUC0–24 hr or renal digoxin excretion. However, an increase in digoxin Cmax (by approximately 33%) was observed. This increase is generally not significant in most patients. Nevertheless, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are prescribed concomitantly.
Effect of etoricoxib on drugs metabolized by sulfotransferases
Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum concentrations of ethinylestradiol. Since information on the effects of numerous sulfotransferases is currently limited and the clinical effects of many drugs are still under investigation, etoricoxib should be used with caution when coadministered with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).
Effect of etoricoxib on drugs metabolized by CYP isoenzymes
Based on in vitro studies, inhibition of cytochrome P450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 is not expected. In studies involving healthy volunteers, daily administration of etoricoxib 120 mg did not affect hepatic CYP3A4 activity, as determined by the erythromycin breath test.
Effect of other drugs on the pharmacokinetics of etoricoxib
The primary metabolic pathway of etoricoxib depends on CYP enzymes. CYP3A4 contributes to etoricoxib metabolism in vivo. In vitro studies suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyze the primary metabolic pathway of etoricoxib, although their quantitative contributions have not been studied in vivo.
Ketoconazole. Ketoconazole is a potent inhibitor of CYP3A4. When administered at 400 mg once daily for 11 days to healthy volunteers, ketoconazole had no clinically significant effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (a 43% increase in AUC).
Voriconazole and miconazole. Concomitant administration of oral voriconazole or miconazole in the form of an oral gel for local use (potent CYP3A4 inhibitors) with etoricoxib resulted in a slight increase in etoricoxib exposure, which, however, was not considered clinically significant according to published data.
Rifampicin. Concomitant administration of etoricoxib and rifampicin (a potent CYP enzyme inducer) resulted in a 65% decrease in etoricoxib plasma concentration. This may lead to recurrence of symptoms when used concomitantly with etoricoxib. While these data may suggest the need for dose adjustment, it is not recommended to use etoricoxib at doses exceeding those specified for each indication, as the combined use of rifampicin and etoricoxib at such doses has not been studied.
Antacids. Antacid agents do not have a clinically significant effect on the pharmacokinetics of etoricoxib.
Special precautions for use.
Gastrointestinal effects
Complications of the upper gastrointestinal tract (perforations, ulcers, or bleeding), sometimes fatal, have been reported in patients receiving etoricoxib.
Nonsteroidal anti-inflammatory drugs should be prescribed with caution in patients at increased risk of gastrointestinal complications: elderly patients, patients taking any other nonsteroidal anti-inflammatory drug or acetylsalicylic acid concomitantly, and patients with a history of gastrointestinal disorders, specifically peptic ulcers and gastrointestinal bleeding.
There is an increased risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) with concomitant use of etoricoxib and acetylsalicylic acid (even at low doses). In long-term clinical trials, no significant difference in gastrointestinal safety was observed between selective COX-2 inhibitors + acetylsalicylic acid and nonsteroidal anti-inflammatory drugs + acetylsalicylic acid.
Cardiovascular effects
Clinical studies indicate that the use of selective COX-2 inhibitors may be associated with an increased risk of thrombotic complications (particularly myocardial infarction and stroke) compared to placebo and some nonsteroidal anti-inflammatory drugs. Since the risk of cardiovascular complications increases with higher doses and longer duration of etoricoxib treatment, the drug should be prescribed at the shortest possible duration and at the lowest effective daily dose. The need for symptomatic pain relief and the patient's response to treatment should be periodically reassessed, especially in patients with osteoarthritis.
Etoricoxib should be prescribed to patients with significant cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking) only after careful assessment of the risk of complications.
Selective COX-2 inhibitors do not replace acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they lack antiplatelet effects. Therefore, antiplatelet agents should not be discontinued.
Renal effects
Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions associated with impaired renal perfusion, the use of etoricoxib may lead to reduced prostaglandin synthesis and, consequently, decreased renal blood flow, thereby worsening renal function. Patients with pre-existing severe renal impairment, decompensated heart failure, or cirrhosis are at high risk of such reactions. Renal function should be monitored in these patients.
Fluid retention, edema, and arterial hypertension
As with other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and arterial hypertension have been observed in patients receiving etoricoxib. All nonsteroidal anti-inflammatory drugs, including etoricoxib, may lead to the development or exacerbation of congestive heart failure. Dose-dependent effects are described in the section "Pharmacological properties. Pharmacodynamics." The drug should be used with caution in patients with heart failure, left ventricular dysfunction, or a history of arterial hypertension, as well as in patients with edema due to any other causes. If clinical signs of worsening condition occur, appropriate measures should be taken, including discontinuation of etoricoxib.
Etoricoxib, particularly at high doses, may lead to more frequent and severe arterial hypertension compared to some other nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors. Therefore, arterial hypertension should be controlled before initiating etoricoxib treatment, and particular attention should be paid to monitoring blood pressure during therapy. Blood pressure should be monitored within the first 2 weeks of treatment and periodically thereafter. If blood pressure increases significantly, alternative treatment should be considered.
Hepatic effects
Elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels (approximately 3 times or more above the upper limit of normal) have been observed in approximately 1% of patients participating in clinical trials and receiving etoricoxib at doses of 30, 60, and 90 mg daily for up to 1 year.
All patients with symptoms of hepatic dysfunction or abnormal liver function tests should be monitored. Etoricoxib should be discontinued if signs of liver dysfunction occur or if persistent abnormal liver function test results (3 times above the upper limit of normal) are observed.
General instructions
If deterioration in the function of any of the organ systems mentioned above occurs during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. Appropriate medical monitoring should be ensured when etoricoxib is administered to elderly patients and patients with renal, hepatic, or cardiac impairment.
Initiation of etoricoxib therapy should be done with caution in dehydrated patients. Rehydration is recommended prior to starting etoricoxib.
Serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported during post-marketing surveillance with nonsteroidal anti-inflammatory drugs and some selective COX-2 inhibitors, sometimes with fatal outcomes (see section "Adverse reactions"). The highest risk of such reactions occurs early in therapy, with most cases beginning within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been observed in patients receiving etoricoxib. Some selective COX-2 inhibitors increase the risk of skin reactions in patients with a history of allergic reactions to any drug. Etoricoxib should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.
Etoricoxib may mask signs of fever and other symptoms of inflammatory processes.
Concomitant use of etoricoxib and warfarin or other oral anticoagulants should be done with caution.
The use of etoricoxib, as with other drugs that inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women planning pregnancy. The medicinal product Tosibia, film-coated tablets, contains lactose. If a patient has been diagnosed with carbohydrate intolerance, consultation with a physician is recommended before taking this medicinal product.
This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
Use during pregnancy or breastfeeding.
Pregnancy
There are no clinical data on the use of etoricoxib during pregnancy. Animal studies have demonstrated reproductive toxicity. The potential risk to pregnant women is unknown. The use of etoricoxib during the third trimester of pregnancy, as with other drugs that inhibit prostaglandin synthesis, may lead to uterine inertia and premature closure of the ductus arteriosus. Cases of impaired fetal renal function leading to reduced amniotic fluid volume (oligohydramnios) have been reported in pregnant women taking nonsteroidal anti-inflammatory drugs (NSAIDs) from the 20th week of gestation onward. In some cases, this may lead to impaired renal function in newborns. These effects may occur soon after initiating NSAID therapy; oligohydramnios is usually reversible upon discontinuation of treatment. Etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant while taking etoricoxib, the drug should be discontinued immediately.
Lactation
It is unknown whether etoricoxib passes into breast milk. In rats, etoricoxib is excreted in milk. Women taking etoricoxib should not breastfeed.
Fertility
The use of etoricoxib, as with other drugs that inhibit COX-2, is not recommended in women attempting to conceive.
Ability to influence reactions while driving or operating machinery.
Patients who experience dizziness, vertigo, or somnolence during etoricoxib treatment should avoid driving or operating machinery.
Method of administration and dosage.
The medicinal product Tosebia should be administered orally. The drug can be taken regardless of food intake. The onset of the drug's effect occurs faster when taken before meals. This should be considered if rapid symptom relief is required.
Since the risk of cardiovascular adverse events with etoricoxib increases with higher doses and longer duration of exposure, the shortest duration of treatment and the lowest effective daily dose should be used. The need for symptom relief and response to treatment should be periodically reassessed, especially in patients with osteoarthritis.
Osteoarthritis
The recommended dose is 30 mg once daily. In some patients, if symptoms are not adequately relieved, increasing the dose to 60 mg once daily may improve efficacy. If no improvement is observed, alternative treatment options should be considered.
Rheumatoid arthritis
The recommended dose is 60 mg once daily. In some patients, if symptoms are not adequately relieved, increasing the dose to 90 mg once daily may enhance therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.
Ankylosing spondylitis
The recommended dose is 60 mg once daily. In some patients, if symptoms are not adequately relieved, increasing the dose to 90 mg once daily may enhance therapeutic effect. Once clinical stability is achieved, the dose should be reduced to 60 mg once daily. If no improvement is observed, alternative treatment options should be considered.
Acute pain
In the case of acute pain, etoricoxib should be used only during the acute symptomatic period.
Acute gouty arthritis
The recommended dose is 120 mg once daily. In clinical trials of acute gouty arthritis, etoricoxib was administered for 8 days.
Postoperative dental pain
The recommended dose is 90 mg once daily for up to 3 days. Some patients may require additional postoperative analgesia.
Doses exceeding those recommended for each indication have not demonstrated additional efficacy or have not been studied. Therefore:
- The dose in osteoarthritis should not exceed 60 mg per day;
- The dose in rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg per day;
- The dose in acute gout should not exceed 120 mg per day for a maximum treatment duration of 8 days;
- The dose for acute pain following dental surgery should not exceed 90 mg per day for a maximum of 3 days.
Elderly patients
No dose adjustment is necessary for elderly patients. As with other medicinal products, Tosebia should be prescribed with caution in elderly patients.
Hepatic impairment
Regardless of the indication, the dose should not exceed 60 mg once daily in patients with mild hepatic impairment (5–6 points on the Child–Pugh scale). In patients with moderate hepatic impairment (7–9 points on the Child–Pugh scale), the dose should not exceed 30 mg once daily, regardless of the indication.
Clinical experience is limited, particularly in patients with moderate hepatic impairment; therefore, the drug should be used with caution. There is no clinical experience with the use of the drug in patients with severe hepatic impairment (≥10 points on the Child–Pugh scale); therefore, the drug is contraindicated in such patients.
Renal impairment
Dose adjustment is not required in patients with creatinine clearance ≥30 mL/min. The use of etoricoxib is contraindicated in patients with creatinine clearance <30 mL/min.
Children
The medicinal product Tosebia is contraindicated in children under 16 years of age.
Overdose.
In clinical studies, single doses of etoricoxib up to 500 mg or multiple doses up to 150 mg daily for 21 days did not cause significant toxic effects. Cases of acute overdose have been reported, although adverse reactions were not reported in most cases. The adverse reactions observed most frequently were consistent with the safety profile of etoricoxib (such as gastrointestinal, cardiac, and renal events).
In the event of overdose, standard supportive measures should be taken, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and, if necessary, supportive treatment.
Etoricoxib is not eliminated by hemodialysis; it is unknown whether the drug is eliminated by peritoneal dialysis.
Adverse reactions
The safety of etoricoxib was evaluated in clinical studies involving 9295 patients, including 6757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis received treatment for 1 year or longer).
During clinical studies, the adverse event profile was consistent among patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.
In a clinical study involving patients with acute gouty arthritis, etoricoxib was administered at a dose of 120 mg once daily for 8 days. The adverse event profile in this study was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.
In the cardiovascular safety assessment program, data from three active-comparator-controlled trials included 17,412 patients with osteoarthritis or rheumatoid arthritis who received etoricoxib (at doses of 60 mg or 90 mg) for a mean duration of approximately 18 months. Safety data and further details on this program are provided in the section "Pharmacological properties".
In clinical studies involving patients with acute postoperative dental pain, including 614 patients who received etoricoxib (at doses of 90 mg or 120 mg), the adverse event profile was generally similar to that observed in studies involving patients with osteoarthritis, rheumatoid arthritis, and chronic low back pain.
The adverse reactions listed below were reported more frequently with etoricoxib than with placebo in clinical studies involving patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis who received etoricoxib at doses of 30 mg, 60 mg, or 90 mg for 12 weeks (MEDAL program studies, short-term acute pain studies, and post-marketing experience).
Table 2
| System organ class |
Adverse reactions |
Frequency category* |
| Infections and infestations |
alveolar osteitis |
common |
| gastroenteritis, upper respiratory tract infections, urinary tract infections |
uncommon |
|
| Blood and lymphatic system disorders |
anaemia (mainly due to gastrointestinal haemorrhage), leucopenia, thrombocytopenia |
uncommon |
| Immune system disorders |
hypersensitivity‡ ß |
uncommon |
| angioneurotic oedema, anaphylactic/anaphylactoid reactions, including shock‡ |
rare |
|
| Metabolism and nutrition disorders |
oedema/fluid retention |
common |
| decreased or increased appetite, weight gain |
uncommon |
|
| Psychiatric disorders |
anxiety, depression, impaired intellectual performance, hallucinations‡ |
uncommon |
| confusional state‡, restlessness‡ |
rare |
|
| Nervous system disorders |
dizziness, headache |
common |
| dysgeusia, insomnia, paraesthesia/hypoaesthesia, somnolence |
uncommon |
|
| intracranial haemorrhage¶ |
unknown |
|
| Eye disorders |
blurred vision, conjunctivitis |
uncommon |
| Ear and labyrinth disorders |
tinnitus, dizziness |
uncommon |
| Cardiac disorders |
palpitations, arrhythmia‡ |
common |
| atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§ |
uncommon |
|
| Vascular disorders |
hypertension |
common |
| flushing, cerebral ischaemia§, transient ischaemic attack, hypertensive crisis‡, vasculitis‡ |
uncommon |
|
| deep vein thrombosis |
unknown |
|
| Respiratory, thoracic and mediastinal disorders |
bronchospasm‡ |
common |
| cough, dyspnoea, epistaxis |
uncommon |
|
| pulmonary embolism |
unknown |
|
| Gastrointestinal disorders |
abdominal pain |
very common |
| constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcers |
common |
|
| abdominal distension, altered bowel habit, dry mouth, gastroduodenal ulcers, peptic ulcers including gastrointestinal perforation and haemorrhage, irritable bowel syndrome, pancreatitis‡ |
uncommon |
|
| Hepatobiliary disorders |
elevated ALT, elevated AST |
common |
| hepatitis‡ |
rare |
|
| hepatic failure‡, jaundice‡ |
rare† |
|
| Skin and subcutaneous tissue disorders |
ecchymosis |
common |
| facial swelling, pruritus, rash, erythema‡, urticaria‡ |
uncommon |
|
| Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, persistent drug erythema‡ |
rare† |
|
| Musculoskeletal and connective tissue disorders |
muscle cramps/spasms, musculoskeletal pain/stiffness |
uncommon |
| Renal and urinary disorders |
proteinuria, increased serum creatinine, renal failure/dysfunction‡ (see section "Special precautions") |
uncommon |
| General disorders and administration site conditions |
asthenia/fatigue, influenza-like symptoms |
common |
| chest pain |
uncommon |
|
| Investigations |
increased blood urea nitrogen, increased creatine phosphokinase, hyperkalaemia, increased uric acid |
uncommon |
| decreased blood sodium |
rare |
* The frequency category is defined for each adverse reaction term according to its frequency in the clinical trial database: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000).
‡ Adverse reaction identified during post-marketing surveillance. The frequency was determined based on the highest frequency observed in clinical trials (data collected for approved indications and doses).
† The "rare" frequency category was defined in accordance with the Guideline on summary of product characteristics (SmPC) (2nd revision, September 2009), based on the calculated upper limit of the 95% confidence interval for 0 events, taking into account the number of participants who received etoricoxib in the pooled Phase III data analysis by dose and indication (n=15,470).
ß Hypersensitivity includes the following terms: allergy, drug allergy, drug hypersensitivity, hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction, and unspecified allergy.
¶ Intracranial hemorrhage was observed in patients with additional risk factors, such as arterial hypertension, thrombocytopenia, and concomitant warfarin use.
§ Based on results from long-term, placebo- and active comparator-controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk increase for such events exceeds 1% per year (uncommon).
Serious adverse reactions reported with NSAID use include nephrotoxicity, such as interstitial nephritis and nephrotic syndrome; therefore, occurrence of these events cannot be excluded with etoricoxib use.
Reporting of adverse reactions after medicinal product authorization is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
No special storage conditions are required for this medicinal product.
Keep out of reach and sight of children.
Packaging.
7 tablets in a blister. 1 or 4 blisters per cardboard pack.
10 tablets in a blister. 1 or 3 blisters per cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".
Manufacturer's address and location of its business activity.
17, Miru Street, Kyiv, 03134, Ukraine.