Eksib

APPROVED WITH
Administrative Order of the Ministry of Health of Ukraine No. 1467 dated 16.08.2022
Registration certificate No. UA/19245/01/01, No. UA/19245/01/02, No. UA/19245/01/03

INSTRUCTIONS
for medical use of medicinal product
EKSIB

Composition:

Active ingredient: etoricoxib;

A film-coated tablet contains 60 mg, 90 mg or 120 mg of etoricoxib.

Excipients: calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium stearyl fumarate, talc, Opadry II 85F green - for 60 mg and 120 mg tablets, Opadry II 85F white - for 90 mg tablets.

Presentation. Film-coated tablets.

Basic physicochemical properties:

60 mg tablets: tablets of a round shape with a biconvex surface, covered with a film of dark green colour.

90 mg tablets: tablets of a round shape with a biconvex surface, covered with a film of white or almost white colour.

120 mg tablets: tablets of a round shape with a biconvex surface, covered with a film of light green colour.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Coxibs. ATC code M01A H05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Etoricoxib is a peroral selective cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range.

In the course of clinical pharmacological studies, etoricoxib has inhibited COX-2 dose-dependently without inhibition of cyclooxygenase-1 (COX-1) at doses up to 150 mg per day. Etoricoxib does not inhibit the synthesis of gastric prostaglandins 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 induced by a proinflammatory impulse and is considered to be 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 kidney function and central nervous system (induction of fever, sensation of pain, cognitive function). It can also participate in the healing process of ulcers. COX-2 has been identified in the tissue around gastric ulcers in humans, but the significance for ulcer healing has not been determined.

Efficiency

In patients with osteoarthritis, etoricoxib at a dose of 60 mg once daily significantly improved pain and patient assessment of their disease state. These positive effects were observed already on the second day of treatment and were maintained during the treatment period up to 52 weeks. In studies using etoricoxib at a dose of 30 mg once a day, the effectiveness of this medication exceeded placebo during 12 weeks of treatment (the same estimates as in other studies were used). In a dose-ranging study, etoricoxib 60 mg demonstrated significantly greater improvement than 30 mg for all three primary endpoints after six weeks of treatment. The use of a dose of 30 mg in osteoarthritis of the hand has not been studied.

In patients with rheumatoid arthritis, etoricoxib at a dose of 60 mg and 90 mg once daily significantly improved the condition in terms of the severity of pain, inflammation, and mobility. In studies evaluating doses of 60 mg and 90 mg, the positive effect was maintained during the 12-week treatment period. In a 60 mg versus 90 mg dose study, both doses of etoricoxib 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 Patient Total Pain Score (0–100 mm visual analogue 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 120 mg once daily for 8 days reduced moderate to severe joint pain and inflammation compared with indomethacin 50 mg three times daily. A decrease in the severity of pain is observed already 4 hours after the start of treatment.

In patients with ankylosing spondylitis, etoricoxib at a dose of 90 mg once a day provided significant improvement in spinal pain, inflammation, limitation of movement, and also improved functional capacity. The clinical benefits of etoricoxib were observed on the second day after initiation of therapy and were maintained throughout the 52-week treatment period. In a second study evaluating the 60 mg dose versus the 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 scores (0–100 mm visual analogue scale) as compared with continuing 60 mg daily, with a mean an improvement of -2.70 mm (95% CI: -4.88 mm, -0.52 mm).

During a clinical study of postoperative dental pain, etoricoxib at a dose of 90 mg was used once a day for up to three days. In the subgroup of patients with moderate pain at baseline, etoricoxib 90 mg had an analgesic effect similar to that of ibuprofen 600 mg (16.11 vs. 16.39; P = 0.722) and superior to that of paracetamol/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P < 0.001), as measured by total pain relief after 6 hours (TOPAR6). The number of patients reporting the use of emergency analgesics 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 group 600 mg/60 mg every 6 hours as compared to 76.2% of patients taking placebo. In this study, the onset of analgesic action (perceptible pain relief) of 90 mg etoricoxib was observed as early as 28 minutes after taking the medication.

Security

International research programme of long-term use of etoricoxib and diclofenac in arthritis (MEDAL)

The MEDAL programme was a prospectively designed programme of cardiovascular safety outcomes from consolidated data from three randomized, double blind, active-controlled, comparative studies (the MEDAL, EDGE II, and EDGE studies).

In the MEDAL study aimed at determination of the impact over the cardiovascular system, 17,804 patients with osteoarthritis and 5,700 patients with rheumatoid arthritis received etoricoxib 60 mg (osteoarthritis) or 90 mg (osteoarthritis and rheumatoid arthritis) or diclofenac, at a dose of 150 mg per day for an average of 20.3 months (maximum ‒ 42.3 months, median ‒ 21.3 months). Only serious adverse reactions and discontinuation of the medication in this study due to the occurrence of any adverse reactions were recorded.

Gastrointestinal tolerability of etoricoxib and diclofenac was compared in EDGE and EDGE II studies. The EDGE study enrolled 7,111 patients with osteoarthritis who received etoricoxib 90 mg daily (1.5 times the recommended dose for osteoarthritis) or diclofenac 150 mg daily for an average of 9.1 months (maximum ‒ 16.6 months, median ‒ 11.4 months). The EDGE II study enrolled 4,086 patients with rheumatoid arthritis who received etoricoxib 90 mg daily or diclofenac 150 mg daily for a mean duration of 19.2 months (maximum 33.1 months, median 24 months).

In the consolidated MEDAL programme, 34,701 patients with osteoarthritis and rheumatoid arthritis were treated for an average 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 programme had various initial cardiovascular and gastrointestinal (GI) risk factors. Patients with recent myocardial infarction, coronary artery bypass surgery, or percutaneous coronary angioplasty within 6 months prior to study enrolment were excluded from the study. Use of gastroprotective medications and acetylsalicylic acid in low doses was allowed during the studies.

General safety

No significant differences in the frequency of thrombotic cardiovascular complications were noted when using etoricoxib and diclofenac. Cardiorenal adverse reactions were more common with etoricoxib than with diclofenac; this effect was dose-dependent (see results below for details). Adverse reactions from the gastrointestinal tract and liver occurred significantly more often with the use of diclofenac than with etoricoxib. The incidence of adverse reactions in the EDGE and EDGE II studies, as well as adverse reactions considered serious or leading to discontinuation in the MEDAL study, was higher with etoricoxib than with diclofenac.

Safety in relation to the cardiovascular system

The incidence of confirmed thrombotic cardiovascular serious adverse reactions (including cardiac, cerebrovascular, and peripheral vascular events) was compared between etoricoxib and diclofenac (data are summarized in Table 1). No significant differences in the frequency of thrombotic complications when were noted using etoricoxib and diclofenac in all analysed subgroups, including patients with cardiovascular risk. When considered separately, the relative risk of occurrence of confirmed serious thrombotic adverse reactions from the cardiovascular system with the use of etoricoxib at a dose of 60 mg or 90 mg and diclofenac at a dose of 150 mg was the same.

Table 1

Indicators of confirmed thrombotic complications from the cardiovascular system (consolidated MEDAL programme)

Complications

Etoricoxib

(N=16819)

25836 patient-years

Diclofenac

(N=16483)

24766 patient-years

Comparison between treatment groups

Indicator†

(95 % CI)

Indicator†

(95 % CI)

Relative risk

(95 % CI)

Confirmed serious thrombotic adverse reactions from in cardiovascular system

According to the protocol

1.24 (1.11; 1.38)

1.30 (1.17; 1.45)

0.95 (0.81; 1.11)

By intention to be treated

1.25 (1.14; 1.36)

1.19 (1.08; 1.30)

1.05 (0.93; 1.19)

Confirmed heart complications

According to the protocol

0.71 (0.61; 0.82)

0.78 (0.68; 0.90)

0.90 (0.74; 1.10)

By intention to be treated

0.69 (0.61; 0.78)

0.70 (0.62; 0.79)

0.99 (0.84; 1.17)

Confirmed cerebrovascular complications

According to the protocol

0.34 (0.28; 0.42)

0.32 (0.25; 0.40)

1.08 (0.80; 1.46)

By intention to be treated

0.33 (0.28; 0.39)

0.29 (0.24; 0.35)

1.12 (0.87; 1.44)

Confirmed complications on the part of peripheral vessels

According to the protocol

0.20 (0.15; 0.27)

0.22 (0.17; 0.29)

0.92 (0.63; 1.35)

By intention to be treated

0.24 (0.20; 0.30)

0.23 (0.18; 0.28)

1.08 (0.81; 1.44)

†Complications per 100 patient-years; CI – Confidence interval.

N – total number of patients in the population by the protocol.

According to the protocol: all complications during the study therapy or within 14 days after its discontinuation (except for patients who took <75% of the study medication or took non-study nonsteroidal anti-inflammatory medications (NSAIDs) >10% of the entire period).

By intention to be treated: all confirmed complications before the end of the study (including in patients who may have undergone an intervention not related to the study, with subsequent discontinuation of the study medication). Total number of patients randomized: 17,412 in the etoricoxib group and 17,289 in the diclofenac group.

Cardiovascular mortality, as well as total mortality, was similar to that in etoricoxib and diclofenac treatment groups.

Cardiorenal complications

Approximately 50% of patients enrolled in MEDAL study had a history of hypertension in anamnesis at baseline. In this study, the rate of discontinuation due to hypertension-related adverse events was statistically significantly higher in the etoricoxib group as compared to the diclofenac group. The frequency of adverse reactions such as congestive heart failure (discontinuation of the medication and serious reactions) was similar both with etoricoxib 60 mg and with diclofenac 150 mg, but the frequency of these reactions was higher with etoricoxib 90 mg as compared with diclofenac 150 mg (statistically significant difference when taking etoricoxib 90 mg as compared to diclofenac 150 mg in the OA MEDAL 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 as compared with diclofenac 150 mg, and this effect was dose-dependent. The rate of discontinuation due to oedema-related adverse reactions was significantly higher with etoricoxib as compared with diclofenac 150 mg, and this effect was dose-dependent (statistically significant difference with etoricoxib 90 mg but not with etoricoxib 60 mg).

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

In individual MEDAL studies, absolute discontinuation rates in either etoricoxib (60 mg or 90 mg) treatment group were up to 2.6% for hypertension, up to 1.9% for oedema, and up to 1.1% for congestive heart failure, while a higher frequency of withdrawal was observed with etoricoxib 90 mg than 60 mg.

Gastrointestinal tolerability results in the MEDAL programme

A significantly lower rate of the preparation withdrawal due to any clinical GI complication (e.g., dyspepsia, abdominal pain, ulcer) was observed with etoricoxib rather than with diclofenac in each of the three MEDAL studies. Discontinuation rates due to clinical gastrointestinal reactions per 100 patient-years over the entire study period were 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 trial; 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II trial.

Results of the MEDAL programme regarding GI safety

Common reactions from the upper gastrointestinal tract section were defined as perforations, ulcers, and bleeding. A subset of common upper gastrointestinal section reactions considered as complicated included perforations, obstructions, and complicated bleeding; a subset of common upper gastrointestinal reactions that were considered uncomplicated included uncomplicated bleeding and uncomplicated ulcers. A significantly lower rate of general reactions from the upper part of the gastrointestinal tract was observed rather with the use of etoricoxib than with diclofenac. There was no significant difference between etoricoxib and diclofenac in terms of the frequency of complicated reactions. For the subgroup of upper gastrointestinal section bleeding (complicated and uncomplicated combined), there was no significant difference between etoricoxib and diclofenac. The advantage of etoricoxib with regard to the effect on the upper part of the gastrointestinal tract compared to diclofenac was not statistically significant in patients who simultaneously used acetylsalicylic acid in low doses (approximately 33% of patients).

The frequency rate per 100 patient-years of confirmed complicated and uncomplicated clinical reactions from the upper gastrointestinal tract section (perforations, ulcers and bleeding) was 0.67 (95% CI 0.57, 0.77) with etoricoxib and 0.97 (95 % CI 0.85, 1.10) when taking diclofenac, while the relative risk was 0.69 (95 % CI 0.57, 0.83).

The rate of confirmed reactions from the upper section of the gastrointestinal tract in elderly patients was determined; the greatest reduction was observed in patients aged ≥75 years (1.35 [95% CI 0.94, 1.87] reactions per 100 patient-years with etoricoxib as compared with 2.78 [95% CI 2.14, 3.56] when taking diclofenac).

Indicators of the frequency of confirmed clinical reactions from the lower part of the gastrointestinal tract (perforation of the small or large intestine, obstruction or bleeding) were not statistically different from those when etoricoxib and diclofenac was used.

Results of the MEDAL programme regarding liver safety

Etoricoxib was associated with a statistically significantly lower rate of withdrawal due to hepatic adverse reactions as compared with diclofenac. In the consolidated MEDAL programme, 0.3% of etoricoxib-treated patients and 2.7% of diclofenac-treated patients discontinued the treatment due to hepatic adverse reactions. The rate per 100 patient-years was 0.22 with etoricoxib and 1.84 with diclofenac (p value was < 0.001 for etoricoxib versus diclofenac). However, in the MEDAL programme, most adverse liver reactions were minor.

Additional cardiovascular safety data on thrombotic complications

In clinical trials, excluding MEDAL studies, approximately 3,100 patients received etoricoxib at doses ≥60 mg daily for 12 weeks or longer. There was no significant difference in rates of confirmed serious thrombotic cardiovascular events in patients receiving etoricoxib ≥60 mg, placebo, or other NSAIDs (except naproxen). However, the incidence of such reactions was higher in patients receiving etoricoxib as compared to those receiving naproxen 500 mg twice daily. The difference in antithrombotic activity between some NSAIDs that inhibit COX-1 and selective COX-2 inhibitors may be clinically significant in patients at risk of thromboembolic complications. Selective COX-2 inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these data is unknown.

Additional gastrointestinal safety data

In two 12-week double-blind endoscopic studies, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving etoricoxib 120 mg once daily than in patients receiving naproxen 500 mg twice daily or ibuprofen in a dose of 800 mg 3 times a day. The incidence of ulcers was higher with etoricoxib than with placebo.

Study of kidney function in elderly patients

Effects of 15-days 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 parameters of kidney function in patients aged 60 to 85 years who followed a 200 mEq/day salt diet were evaluated in a randomized, double-blind, parallel-group, placebo-controlled study. Etoricoxib, celecoxib, and naproxen had similar effects on urinary sodium excretion after 2 weeks of treatment. All active comparators showed an increase relative to placebo in systolic blood pressure, but 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 mm Hg, celecoxib 2.4 mm Hg, naproxen 3.6 mm Hg).

Pharmacokinetics

Absorption

Etoricoxib is well absorbed when taken orally. Absolute bioavailability is approximately 100%. After taking 120 mg once a day until the equilibrium state is reached, the maximum concentration in the blood plasma (geometric mean value of Cmax=3.6 μg/ml) is observed approximately 1 hour (Tmax) after taking in adults on an empty stomach. The geometric mean value of AUC0-24h is 37.8 μg×h/ml. Within the clinical dosage range, the pharmacokinetics of etoricoxib is linear.

When taking the medication at a dose of 120 mg during a meal (food with a high fat content), no effect on the degree of absorption of etoricoxib was observed. The rate of absorption changed, which was characterized by a decrease in Cmax by 36% and an increase in Tmax by 2 hours. Such data 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 actively metabolized with less than 1% of the dose being excreted in the urine as an unchanged medicinal product. The main metabolic pathway is the formation of the 6'-hydroxymethyl derivative due to catalysis by cytochrome enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyse the major metabolic pathway, but their quantitative characteristics have not been studied in vivo.

Five metabolites have been identified in humans. The main metabolite is the 6'-carboxylic acid derivative of etoricoxib, which is formed during further oxidation of the 6'-hydroxymethyl derivative. These major metabolites either show no activity or are weakly active COX-2 inhibitors. None of these metabolites inhibits COX-1.

Excretion

After a single intravenous administration of 25 mg of radioisotope-labelled etoricoxib to healthy volunteers, 70% of the radioactive preparation shall be excreted in urine and 20% in faeces, mostly in the form of metabolites. Less than 2% is excreted in the form of an unchanged medicinal product.

Elimination of etoricoxib occurs almost entirely by metabolism with subsequent excretion by the kidneys. Steady-state concentrations of etoricoxib are reached after 7 days at a dose of 120 mg once daily with an accumulation index of approximately 2, corresponding to a half-life of approximately 22 hours. Blood plasma clearance after intravenous administration of 25 mg of the medication is approximately 50 mL/min.

Separate patient groups

Elderly patients. Pharmacokinetics in elderly patients (over 65 years of age) is similar to pharmacokinetics in younger patients.

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

Liver function impairment. In patients with mild hepatic impairment (Child-Pugh score 5-6) using etoricoxib at a dose of 60 mg once a day, the mean area under the pharmacokinetic curve concentration-time (AUC) was approximately 16% greater than in healthy volunteers at the same dosage of the medication. In patients with moderate liver dysfunction (7-9 score on the Child-Pugh scale) using etoricoxib at a dose of 60 mg every other day, the mean AUC was similar to that of healthy volunteers who took the medication at a dose of 60 mg once daily every day; the use of etoricoxib at a dose of 30 mg once daily has not been studied in this group of patients. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (≥ 10 score on the Child-Pugh scale).

Impaired kidney function. The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease undergoing haemodialysis, does not differ significantly from the pharmacokinetics in healthy volunteers. During haemodialysis, the medication is almost not removed (dialysis clearance is approximately 50 ml/min).

Children. The pharmacokinetics of etoricoxib in children (age up to 12 years) has not been studied.

In the course of pharmacokinetic studies (n=16), conducted with the participation of adolescents (aged 12 to 17 years), pharmacokinetics in patients with a body weight of 40‒60 kg, who were prescribed etoricoxib at a dose of 60 mg once a day, and in patients with a body weight of more than 60 kg, who were prescribed the medication at a dose of 90 mg once a day, was similar to the pharmacokinetics in adults who used etoricoxib at a dose of 90 mg once a day. The safety and efficacy of etoricoxib in children have not been determined.

Clinical characteristics.

Indications.

Symptomatic therapy for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and 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 risks in the patient.

Contraindications.

Eksib medication is contraindicated:

in case of hypersensitivity to the active substance or to any auxiliary substance of the medication
with active peptic ulcer or active gastrointestinal bleeding
to patients who experienced bronchospasm, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic reactions after using acetylsalicylic acid or NSAIDs, including COX-2 inhibitors
during pregnancy and breastfeeding
with severe liver dysfunction (serum albumin < 25 g/l or ≥ 10 score on the Child-Pugh scale)
if the calculated renal clearance of creatinine is < 30 ml/min
to children aged under 16
with inflammatory bowel diseases
with congestive heart failure (NYHA II‒IV)
to patients with arterial hypertension, whose blood pressure indicators are constantly higher than 140/90 mm Hg and are controlled insufficiently
with diagnosed ischemic heart disease, peripheral artery disease and/or cerebrovascular disease.

Interaction with other medicinal products and other types of interactions

Pharmacodynamical interactions

Peroral anticoagulants. Etoricoxib at a dose of 120 mg per day in patients whose condition is stabilized on constant warfarin use is accompanied by an increase of approximately 13% in prothrombin time of international normalized ratio (INR). Therefore, in patients using peroral anticoagulants, prothrombin time should be frequently checked, especially in the first days of taking etoricoxib or when changing its dosage.

Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. NSAIDs can deteriorate the effect of diuretics and other antihypertensive medications. Simultaneous use of an ACE inhibitor or an angiotensin II receptor antagonist and medications that inhibit cyclooxygenase can lead in some patients with impaired renal function (for example, in dehydrated patients or in elderly patients with impaired renal function) to further impairment of renal function, including acute renal failure, which is usually reversible. The possibility of such interactions should be kept in mind in patients who use etoricoxib simultaneously with ACE inhibitors or angiotensin II receptor antagonists. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Adequate hydration should be carried out and monitoring of renal function should be considered at the start of combined treatment and periodically thereafter.

Acetylsalicylic acid. In a study involving healthy volunteers under steady-state conditions, the use of etoricoxib at a dose of 120 mg once daily did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be prescribed simultaneously with acetylsalicylic acid in doses used for the prevention of cardiovascular diseases (the use of acetylsalicylic acid in low doses). However, the simultaneous use of low doses of acetylsalicylic acid and etoricoxib may increase the incidence of gastrointestinal ulceration and other complications compared to monotherapy with etoricoxib. The simultaneous use of etoricoxib is not recommended with acetylsalicylic acid, if the doses of the latter being higher than prophylactic, as well as with other NSAIDs.

Cyclosporine and tacrolimus. Although the interaction of etoricoxib with these medications has not been studied, the simultaneous use of any NSAID with cyclosporine or tacrolimus can increase the nephrotoxic effect of the latter. Renal function should be monitored when etoricoxib is co-administered with any of these medications.

Pharmacokinetic interactions

Effect of etoricoxib on the pharmacokinetics of other medications

Lithium. NSAIDs deteriorate excretion of lithium by the kidneys, thereby increasing its level in the blood plasma. If necessary, carefully monitor the level of lithium in the blood and adjust the dose of lithium during simultaneous use of these medications, as well as when the use of NSAIDs shall be stopped.

Methotrexate. In the course of two studies, the effects of etoricoxib when used in doses of 60 mg, 90 mg or 120 mg once daily for 7 days were studied in patients who administered methotrexate in a dose of 7.5 to 20 mg once weekly for rheumatoid arthritis. Etoricoxib at a dose of 60 mg and 90 mg did not affect the concentration in the blood plasma or the renal clearance of methotrexate. In one study, etoricoxib 120 mg had no effect on the plasma concentration and renal clearance of methotrexate, whereas in another study, etoricoxib 120 mg increased the plasma concentration of methotrexate by 28% and decreased the renal clearance of methotrexate by 13%. With the simultaneous prescription of etoricoxib and methotrexate, appropriate monitoring should be carried out for the appearance of toxic effects of methotrexate.

Peroral contraceptives. Etoricoxib at a dose of 60 mg, when used simultaneously with peroral contraceptives containing 35 mg of ethinyl estradiol and 0.5-1 mg of norethindrone for 21 days, caused an increase in the steady-state AUC0-24h for ethinyl estradiol by 37%. Etoricoxib at a dose of 120 mg increased the AUC0-24h value of ethinyl estradiol by 50–60% in the steady state when used with the specified oral contraceptives simultaneously or after 12 hours. Such an increase in the concentration of ethinyl estradiol should be kept in mind when choosing an oral contraceptive with a different content of ethinyl estradiol, which will be used simultaneously with etoricoxib. Increased exposure to ethinyl estradiol may increase the incidence of oral contraceptive-related adverse reactions (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy. Administration of 120 mg of etoricoxib with hormone replacement medications that include conjugated oestrogens (0.625 mg Premarin™) for 28 days increases the average AUC0-24h in the steady state of unconjugated estrone (by 41%), equilin (by 76%) and 17-β-estradiol (by 22%). The effect of etoricoxib doses recommended for long-term use (60 mg and 90 mg) has not been studied. If compared with an increase in dosage from 0.625 mg to 1.25 mg with Premarin™ monotherapy, the effect of etoricoxib in doses of 120 mg on the AUC0-24h of the estrogenic components of Premarin™ was less than a half. The clinical significance of such an increase is unknown, and high doses of Premarin™ concomitantly with etoricoxib have not been studied. Such an increase in oestrogen concentration should be taken into account when choosing a hormonal medication for use in the postmenopausal period when used simultaneously with etoricoxib, since the increase in oestrogen exposure increases the risk of adverse reactions during hormone replacement therapy.

Prednisone/prednisolone. In interaction studies, etoricoxib did not have a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. When using etoricoxib at a dose of 120 mg once daily for 10 days in healthy volunteers, there was no effect on the AUC0-24h indicator in the steady state and on the excretion of digoxin by the kidneys. An increase in Cmax of digoxin was observed (by approximately 33%). This increase is usually not significant in most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are administered simultaneously.

Effect of etoricoxib on medications metabolized by sulfotransferases

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and may also increase serum ethinyl estradiol concentration in blood plasma. Because the data on the effect of numerous sulfotransferases are still insufficient, and the clinical effects of many medications are still being studied, it is advisable to use caution when prescribing etoricoxib simultaneously with other medications that are metabolized mainly by human sulfotransferases (e.g., peroral salbutamol and minoxidil).

Effects of etoricoxib on medications metabolized by CYP isozymes

According to in vitro studies, suppression of cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4 is not expected. In studies involving healthy volunteers, daily use of etoricoxib at a dose of 120 mg did not affect the activity of hepatic CYP3A4, as determined by the erythromycin breath test.

The influence of other medications on the pharmacokinetics of etoricoxib

The main route of metabolism of etoricoxib depends on CYP enzymes. CYP3A4 contributes to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 may also catalyse 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 in doses of 400 mg once daily for 11 days, ketoconazole did not have a clinically significant effect on the pharmacokinetics of etoricoxib in a single dose of 60 mg (increase in AUC by 43%).

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

Rifampicin. The simultaneous use of etoricoxib and rifampicin (a strong inducer of CYP enzymes) led to a decrease in the concentration of etoricoxib in blood plasma by 65%. This may be accompanied by a recurrence of symptoms when used simultaneously with etoricoxib. While such data may require for a dose increase, the use of etoricoxib at doses higher than those prescribed for each indication is not recommended, as the combined use of rifampicin and etoricoxib at these doses has not been studied.

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

Special warning and precautions for use

Effect on the gastrointestinal tract

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

Caution should be exercised in prescribing NSAIDs to patients at increased risk of gastrointestinal complications, elderly patients, patients using any other NSAIDs or acetylsalicylic acid at the same time, or patients with a history of gastrointestinal disease, such as ulcers and gastrointestinal bleeding in the anamnesis.

There is an additional risk of developing adverse reactions from the gastrointestinal tract (gastrointestinal ulcer or other complications from the gastrointestinal tract) when etoricoxib and acetylsalicylic acid (even in low doses) are administered simultaneously. In the course of long-term clinical studies, there was no significant difference in the safety of the gastrointestinal tract when using a selective COX-2 inhibitor + acetylsalicylic acid and NSAIDs + acetylsalicylic acid.

Effect on the cardiovascular system

Clinical studies indicate that the use of medications of the selective COX-2 inhibitors class may be associated with an increased risk of thrombotic complications (especially myocardial infarction and stroke) as compared with placebo and some NSAIDs. Since the risk of cardiovascular complications increases with increasing dose and duration of etoricoxib use, the medication should be prescribed for the shortest possible period of time and at the lowest effective daily dose. Patients' need for symptomatic pain relief and response to treatment should be periodically reviewed, particularly patients with osteoarthritis.

Etoricoxib should be prescribed to patients with pronounced risk factors for the development of cardiovascular complications (for example, arterial hypertension, hyperlipidaemia, diabetes, smoking) only after a careful assessment of the risk of developing a complication.

Selective COX-2 inhibitors do not replace the use of acetylsalicylic acid for the prevention of thromboembolic cardiovascular diseases, as they do not have an antiplatelet effect. Therefore, antiplatelet medications should not be discontinued.

Effect on kidneys

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, in conditions accompanied by impaired renal perfusion, the use of etoricoxib can lead to a decrease in the production of prostaglandins and, as a result, to renal blood flow, thereby worsening kidney function. A high risk of developing such a reaction is observed in patients with already existing pronounced disorders of kidney function, uncompensated heart failure or cirrhosis. Renal function should be monitored in such patients.

Fluid retention, oedema and hypertension

As with other medications inhibiting prostaglandin synthesis, fluid retention, oedema, and hypertension have been observed in patients treated with etoricoxib. All NSAIDs, including etoricoxib, can lead to the development or recurrence of congestive heart failure. For dose-response information, see in the section Pharmacological properties. Pharmacodynamics. The medication should be prescribed with caution to patients with heart failure, left ventricular dysfunction, or hypertension in the anamnesis, as well as to patients with oedema caused by any other reasons. Appropriate measures should be taken, including withdrawal of etoricoxib, if clinical signs of deterioration in such patients occur.

Etoricoxib, especially at high doses, may lead to more frequent and severe hypertension compared with some other NSAIDs and selective COX-2 inhibitors. Therefore, arterial hypertension should be controlled before starting etoricoxib, and special attention should be paid to blood pressure control during treatment with etoricoxib. Blood pressure should be monitored for 2 weeks after starting treatment and periodically thereafter. If blood pressure rises significantly, alternative treatment should be considered.

Effect on the liver

Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately 3 or more times the upper limit of normal (ULN)) were observed in approximately 1% of patients from clinical trials receiving etoricoxib 30 mg, 60 mg and 90 mg per day for up to 1 year.

The condition should be monitored of all patients with symptoms of impaired liver function, as well as the condition of patients with pathological indicators of liver function. With signs of impaired liver function and persistent pathological changes in liver function indicators (3 times higher than the ULN), administration of etoricoxib should be discontinued.

General instructions

If, during treatment, the patient experiences a deterioration in the function of any of the above-mentioned organ systems, appropriate measures should be taken and the issue of withdrawal of etoricoxib should be considered. Appropriate medical supervision should be provided when using etoricoxib in elderly patients and patients with impaired renal, hepatic or cardiac function.

Etoricoxib should be started with caution in dehydrated patients. It is recommended to carry out rehydration before starting the use of etoricoxib.

The development of serious skin reactions, in some cases with a fatal outcome (including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis) has been very rarely reported with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance (see the section Adverse reactions section). The highest risk of developing such reactions in patients is at the beginning of therapy, and the onset of their manifestations in most cases is during 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 reaction to any medication. Etoricoxib should be discontinued at the first appearance of skin rashes, mucosal lesions, or other signs of hypersensitivity.

When using etoricoxib, manifestations of fever and other signs of the inflammatory process may be masked.

Etoricoxib and warfarin or other peroral anticoagulants should be used with caution.

The use of etoricoxib, like other medications that inhibit cyclooxygenase/prostaglandin synthesis, is not recommended for women planning pregnancy.

Important information about excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium/dose, 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 shown reproductive toxicity. The potential risk for pregnant women is unknown. The use of etoricoxib during the last trimester of pregnancy, like other medications that inhibit the synthesis of prostaglandins, can lead to the absence of uterine contractions and premature closure of the fallopian tube. The use of etoricoxib is contraindicated during pregnancy. If a woman becomes pregnant during treatment, etoricoxib should be discontinued.

Breastfeeding period

It is not known whether etoricoxib passes into breast milk. Etoricoxib is excreted in milk in rats. Women using etoricoxib should not breast-feed.

Fertility

The use of etoricoxib, like other medications that inhibit COX-2, is not recommended for women who are planning pregnancy.

The ability to influence the speed of reaction when driving vehicles or other mechanisms.

Patients who experience dizziness, vertigo, or drowsiness while taking etoricoxib should not drive or operate machinery.

Method of administration and dosage.

Eksib medication should be used orally. The medicine may be taken regardless of meals. The onset of the effect of the medication occurs faster when taken before a meal. This should be taken into account if there is a need for rapid relief of symptoms.

Since the risk of cardiovascular disorders when using etoricoxib increases with increasing dose and duration of exposure, the shortest courses of treatment should be carried out with the use of the lowest effective daily doses. 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 a day. In some patients, with insufficient relief of symptoms, increasing the dose to 60 mg once a day can increase effectiveness. In the absence of effect, other possible methods of treatment should be considered.

Rheumatoid arthritis

The recommended dose is 60 mg once a day. In some patients, with insufficient relief of symptoms, increasing the dose to 90 mg once a day can improve the therapeutic effect. When the clinical stabilisation of the patient is achieved, it is advisable to reduce the dose to 60 mg once a day. In the absence of improvement of the effect, other possible methods of treatment should be considered.

Ankylosing spondylitis

The recommended dose is 60 mg once a day. In some patients, with insufficient relief of symptoms, increasing the dose to 90 mg once a day can improve the therapeutic effect. When the clinical stabilization of the patient is achieved, it is advisable to reduce the dose to 60 mg once a day. In the absence of improvement of the effect, other possible methods of treatment should be considered.

Acute pain

In case of acute pain, etoricoxib is used only during the acute symptomatic period.

Acute gouty arthritis

The recommended dose is 120 mg once a day. In acute gouty arthritis clinical studies, etoricoxib was administered for 8 days.

Postoperative pain associated with dental surgery. The recommended dose is 90 mg once a day for a maximum of 3 days. Some patients may require additional postoperative analgesia.

Doses above those recommended for each indication have no additional efficacy or have not been studied, therefore:

the dose for osteoarthritis should not exceed 60 mg per day;
the dose for rheumatoid arthritis and ankylosing spondylitis should not exceed 90 mg per day;
the dose for acute gout should not exceed 120 mg per day during the maximum treatment period of 8 days;
the dose for acute pain after dental surgery should not exceed 90 mg per day for a maximum period of 3 days.

Elderly patients

There is no need to adjust the dosage for elderly patients. As with the use of other medications, the medication should be prescribed with caution to elderly patients.

Liver dysfunction

Regardless of the indication, patients with mild liver dysfunction (5-6 score on the Child-Pugh scale) should not exceed a dose of 60 mg once a day. Patients with liver function disorders of moderate severity (7‒9 score on the Child-Pugh scale), regardless of the indication, should not exceed a dose of 30 mg once a day.

Clinical experience is limited, especially in patients with moderate liver dysfunction, so the medication should be prescribed with caution. There is no clinical experience of using the medication in patients with severe liver dysfunction (≥ 10 score on the Child-Pugh scale), so the medication is contraindicated in such patients.

Kidney dysfunction

Dose adjustment is not required in patients with creatinine clearance ≥ 30 ml/min. The use of etoricoxib in patients with creatinine clearance < 30 ml/min is contraindicated.

Children

The medication Eksib is contraindicated for children under 16 years of age.

Overdose

In the course of clinical studies, no significant toxic effects were observed after the use of a single dose of etoricoxib up to 500 mg or multiple doses of up to 150 mg a day for 21 days. Acute overdose with etoricoxib has been reported, although in most cases no adverse reactions were reported. The most frequently observed adverse reactions corresponded to the safety profile of etoricoxib (gastrointestinal, cardiac and renal reactions).

In the event of an overdose, it is advisable to take the usual supportive measures, for example, removing the unabsorbed medication from the gastrointestinal tract, conducting clinical observation, if necessary - conducting supportive treatment.

Etoricoxib is not removed by haemodialysis; it is not known whether the medication is removed during peritoneal dialysis.

Adverse reactions

The safety of etoricoxib administration was evaluated in clinical trials involving 9,295 patients, including 6,757 patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis (approximately 600 patients with osteoarthritis or rheumatoid arthritis were treated for 1 year or longer).

In clinical trials, the adverse event profile was similar in patients with osteoarthritis or rheumatoid arthritis who received etoricoxib for 1 year or longer.

In a clinical trial involving patients with acute gouty arthritis, etoricoxib was prescribed at a dose of 120 mg once a day for 8 days. The adverse event profile in this study was generally similar to studies in patients with osteoarthritis, rheumatoid arthritis and chronic low back pain.

In the Cardiovascular Safety Evaluation Programme based on data from three controlled studies with an active comparator, 17,412 patients with osteoarthritis or rheumatoid arthritis received etoricoxib (60 mg or 90 mg) for an average of approximately 18 months. Safety data and more detailed information about this programme are presented in the Pharmacological Properties section.

In clinical trials involving patients with acute postoperative pain after dental, abdominal and gynaecological surgery, including 1,222 patients who received etoricoxib (at doses of 90 mg or 120 mg), the profile of adverse events was generally the same as in studies of involving patients with osteoarthritis, rheumatoid arthritis and chronic lower back pain.

The following adverse reactions were reported more frequently with etoricoxib than with placebo in clinical trials in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis who received etoricoxib 30 mg, 60 mg, or 90 mg for 12 weeks (study according to the MEDAL programme, short-term studies regarding acute pain and post-marketing experience).

Table 2

Organ system class

Adverse reactions

Incidence category*

Infections and invasions

alveolar osteitis

common

gastroenteritis, upper respiratory tract infections, urinary tract infections

uncommon

On the part of the blood and lymphatic system

anaemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia

uncommon

On the part of the immune system

hypersensitivity‡ ß

uncommon

angioedema, anaphylactic/anaphylactoid reactions, including shock‡

rare

Metabolic and nutritional disorders

oedema/ fluid retention

common

decrease or increase in appetite, weight gain

uncommon

Mental disorders

anxiety, depression, mental impairment, hallucinations‡

uncommon

confusion‡, restlessness‡

rare

On the part of the nervous system

dizziness, headache

common

dysgeusia, insomnia, paraesthesia/hypesthesia, drowsiness

uncommon

On the part of the vision organs

blurred vision, conjunctivitis

uncommon

On the part of the hearing organs and the vestibular apparatus

tinnitus, dizziness

uncommon

On the part of heart

Heart palpitations, arrhythmia‡

common

atrial fibrillation, tachycardia‡, congestive heart failure, nonspecific ECG changes, angina‡, myocardial infarction§

uncommon

On the part of the vascular system

hypertension

common

rush of blood, impaired cerebral circulation§, transient ischemic attack, hypertensive crisis‡, vasculitis‡

uncommon

On the part of the respiratory system, organs of the chest and mediastinum

bronchospasm‡

common

cough, dyspnoea, epistaxis

uncommon

On the part of gastrointestinal tract

Abdominal pain

very common

constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, mouth ulcers

common

abdominal distension, change in the character of intestinal peristalsis, dry mouth, gastroduodenal ulcers, peptic ulcers, including perforation and bleeding of the gastrointestinal tract, irritable bowel syndrome, pancreatitis‡

uncommon

On the part of the hepatobiliary system

an increase in ALT, an increase in AST

common

hepatitis‡

rare

hepatic failure‡, jaundice‡

rare†

On the part of the skin and subcutaneous tissue

ecchymosis

common

facial swelling, pruritus, rash, erythema‡, urticaria‡

uncommon

Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, medication resistant erythema‡

rare†

On the part of the musculoskeletal system and connective tissue

muscle spasms/convulsions, musculoskeletal pain/stiffness

uncommon

On the part of the kidneys and urinary system

proteinuria, increased serum creatinine, renal insufficiency/dysfunction‡ (see Special warnings and precautions for use section)

uncommon

General disorders and administration-related disorders

asthenia/fatigue, flu-like symptoms

common

chest pain

uncommon

Laboratory studies

increased levels of blood urea nitrogen, increased levels of creatine phosphokinase, hyperkalaemia, increased levels of uric acid

uncommon

decrease in the level of sodium in the blood

rare

* The frequency category is determined for each adverse effect by the frequency in the database of clinical studies: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10000).

‡ Adverse reaction identified during post-marketing surveillance. The frequency was determined by the maximum frequency in clinical studies (data collected according to the approved indications and doses).

† The frequency category rare was defined according to the Guideline on summary of product characteristics (SmPC) (2nd revision, September 2009) based on the calculated upper limit of the 95% CI for 0 events, taking into account the number of participants taking etoricoxib in the data analysis Phase III, combined by dose and indication (n=15470).

ß Hypersensitivity includes the concepts: allergy, drug allergy, drug hypersensitivity, hypersensitivity, unspecified hypersensitivity, hypersensitivity reaction and unspecified allergy.

§ In an analysis of long-term placebo-controlled and active-controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of major arterial thrombotic events, including myocardial infarction and stroke. Based on the available data, it is unlikely that the increase in the absolute risk of such events will exceed 1% per year (uncommon).

With the use of NSAIDs, the following serious adverse reactions have been reported: nephrotoxicity, including interstitial nephritis and nephrotic syndrome, so their occurrence with etoricoxib cannot be excluded.

Reporting on suspected adverse reactions

The reporting on suspected adverse reactions after the registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Expiration date. 2 years.

Storage life.

The medication should be stored in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging.

60 mg each, 90 mg each, 10 tablets in a contour blister, 1 or 3 contour blisters in a cardboard pack;

120 mg each, 10 tablets in a contour blister, 1 contour blister in a cardboard pack.

Medicinal product dispensing. By prescription

Manufacturer: PrJSC Darnitsa Pharmaceutical Firm

The manufacturer place of business address and location

13 Boryspilska Street, 02093, Kyiv, Ukraine.

Last revision date 16.08.2022.