Etorelex^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

M01AH05 (Etoricoxib)

Active Substance

Etoricoxib (Rec.INN registered by WHO)

Dosage Forms

	Etorelex®	Film-coated tablets, 30 mg: from 2 to 100 pcs.
		Film-coated tablets, 60 mg: from 2 to 100 pcs.
		Film-coated tablets, 90 mg: from 2 to 100 pcs.
		Film-coated tablets, 120 mg: from 2 to 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex; the core in cross-section is from almost white to light yellow.

Excipients: hypromellose E15 – 1 mg, calcium hydrogen phosphate dihydrate – 30 mg, croscarmellose sodium – 2 mg, colloidal silicon dioxide – 0.5 mg, sodium stearyl fumarate – 1.5 mg, microcrystalline cellulose 200 – 35 mg.

Film coating composition: hypromellose E15 – 2.4 mg, copovidone (Kollidon VA64) – 0.32 mg, macrogol 6000 – 0.48 mg, talc – 0.16 mg, titanium dioxide – 0.64 mg.

From 2 to 14 pcs. – contour cell packaging (from 1 to 10 pcs.) – cardboard packs.
From 14 to 100 pcs. – jars with first opening control (1) – cardboard packs.

Film-coated tablets yellow, round, biconvex; the core in cross-section is from almost white to light yellow.

Excipients: hypromellose E15 – 2 mg, calcium hydrogen phosphate dihydrate – 60 mg, croscarmellose sodium – 4 mg, colloidal silicon dioxide – 1 mg, sodium stearyl fumarate – 3 mg, microcrystalline cellulose 200 – 70 mg.

Film coating composition: hypromellose E15 – 4.8 mg, copovidone (Kollidon VA64) – 0.64 mg, macrogol 6000 – 0.96 mg, yellow iron oxide dye – 0.16 mg, talc – 0.16 mg, titanium dioxide – 1.28 mg.

From 2 to 14 pcs. – contour cell packaging (from 1 to 10 pcs.) – cardboard packs.
From 14 to 100 pcs. – jars with first opening control (1) – cardboard packs.

Film-coated tablets white, round, biconvex; the core in cross-section is from almost white to light yellow.

Excipients: hypromellose E15 – 3 mg, calcium hydrogen phosphate dihydrate – 90 mg, croscarmellose sodium – 6 mg, colloidal silicon dioxide – 1.5 mg, sodium stearyl fumarate – 4.5 mg, microcrystalline cellulose 200 – 105 mg.

Film coating composition: hypromellose E15 – 7.2 mg, copovidone (Kollidon VA64) – 0.96 mg, macrogol 6000 – 1.44 mg, talc – 0.48 mg, titanium dioxide – 1.92 mg.

From 2 to 14 pcs. – contour cell packaging (from 1 to 10 pcs.) – cardboard packs.
From 14 to 100 pcs. – jars with first opening control (1) – cardboard packs.

Film-coated tablets red-pink, oval, biconvex; the core in cross-section is from almost white to light yellow.

Excipients: hypromellose E15 – 4 mg, calcium hydrogen phosphate dihydrate – 120 mg, croscarmellose sodium – 8 mg, colloidal silicon dioxide – 2 mg, sodium stearyl fumarate – 6 mg, microcrystalline cellulose 200 – 140 mg.

Film coating composition: hypromellose E15 – 9.6 mg, copovidone (Kollidon VA64) – 1.28 mg, macrogol 6000 – 1.92 mg, red iron oxide dye – 0.32 mg, talc – 0.32 mg, titanium dioxide – 2.56 mg.

From 2 to 14 pcs. – contour cell packaging (from 1 to 10 pcs.) – cardboard packs.
From 14 to 100 pcs. – jars with first opening control (1) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Highly selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID. Selective COX-2 inhibitor, at therapeutic concentrations blocks the formation of prostaglandins and has anti-inflammatory, analgesic and antipyretic effects. Selective inhibition of COX-2 is accompanied by a reduction in the severity of clinical symptoms associated with the inflammatory process, while there is no effect on platelet function and the gastrointestinal mucosa.

Etoricoxib has a dose-dependent effect of inhibiting COX-2, without affecting COX-1 when used at a daily dose of up to 150 mg. It does not affect the production of prostaglandins in the gastric mucosa and bleeding time. In conducted studies, no decrease in arachidonic acid levels and collagen-induced platelet aggregation was observed.

Pharmacokinetics

After oral administration, it is rapidly absorbed from the gastrointestinal tract. Oral bioavailability is about 100%. After a single 120 mg dose taken by adults on an empty stomach, C_max is 3.6 µg/ml, T_max is 1 hour after administration. Food intake does not significantly affect the extent and rate of absorption of etoricoxib when taken at a dose of 120 mg. However, C_max values decrease by 36% and T_max increases by 2 hours. The mean geometric AUC_0-24 was 37.8 µg × h/ml. The pharmacokinetics of etoricoxib within therapeutic doses are linear.

Plasma protein binding exceeds 92%. V_d at steady state is about 120 L. Etoricoxib crosses the placental and blood-brain barriers.

It is extensively metabolized in the liver, with the participation of cytochrome P450 isoenzymes and the formation of 6-hydroxymethyl-etoricoxib. Five metabolites of etoricoxib have been identified, the main ones being 6-hydroxymethyl-etoricoxib and its derivative, 6-carboxy-acetyl-etoricoxib. The main metabolites do not affect COX-1 and are either completely inactive or have low activity against COX-2.

It is excreted by the kidneys as metabolites. Less than 1% is excreted unchanged in the urine.

After a single intravenous administration, 70% is excreted by the kidneys, 20% through the intestines, mainly as metabolites. Less than 2% was found unchanged.

Steady state is reached after 7 days with daily administration of 120 mg, with an accumulation factor of about 2, which corresponds to a T_1/2 of about 22 hours. Plasma clearance is approximately 50 ml/min.

In patients with mild hepatic impairment (5-6 points on the Child-Pugh scale), a single dose of etoricoxib 60 mg/day was accompanied by a 16% increase in AUC compared to healthy subjects.

In patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale) taking the drug at a dose of 60 mg every other day, the AUC value was the same as in healthy subjects taking the drug daily at the same dose.

Hemodialysis had little effect on excretion (dialysis clearance about 50 ml/min).

Indications

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis; pain and inflammatory symptoms associated with acute gouty arthritis; short-term treatment of pain associated with dental surgery.

ICD codes

Dosage Regimen

Take the drug orally once daily. The recommended dose for osteoarthritis is 60 mg once daily. The recommended dose for rheumatoid arthritis is 90 mg once daily. The recommended dose for ankylosing spondylitis is 90 mg once daily.

For acute gouty arthritis, take 120 mg once daily. Use this dose only for the acute symptomatic period, with a maximum treatment duration of 8 days. For postoperative dental pain, take 90 mg once daily. Use for a maximum of 3 days.

Do not exceed the maximum daily dose of 120 mg. Use the lowest effective dose for the shortest duration necessary to control symptoms. Swallow tablets whole with water, with or without food.

For patients with moderate hepatic impairment (Child-Pugh score 7-9), do not exceed 60 mg once daily. For patients with mild hepatic impairment (Child-Pugh score 5-6), a starting dose of 60 mg is recommended. The drug is contraindicated in severe hepatic impairment (Child-Pugh score >9).

In elderly patients and those with mild to moderate renal impairment (creatinine clearance ≥30 mL/min), no dosage adjustment is initially required. Monitor renal function during therapy. The drug is contraindicated in severe renal impairment (creatinine clearance <30 mL/min).

Adverse Reactions

From the digestive system frequently – epigastric pain, nausea, diarrhea, dyspepsia, flatulence; sometimes – abdominal distension, belching, increased peristalsis, constipation, dryness of the oral mucosa, gastritis, ulcer of the gastric or duodenal mucosa, irritable bowel syndrome, esophagitis, oral mucosa ulcers, vomiting; very rarely – gastrointestinal ulcers (with bleeding or perforation), hepatitis.

From the nervous system frequently – headache, dizziness, weakness; sometimes – taste disturbance, drowsiness, sleep disorders, sensory disturbances, including paresthesia/hyperesthesia, anxiety, depression, concentration disorders; very rarely – hallucinations, confusion.

From the sensory organs sometimes – blurred vision, conjunctivitis, tinnitus, vertigo.

From the urinary system sometimes – proteinuria; very rarely – renal failure, usually reversible upon drug withdrawal.

Allergic reactions very rarely – anaphylactic/anaphylactoid reactions, including severe decrease in blood pressure and shock.

From the cardiovascular system frequently – palpitations, increased blood pressure; sometimes – hot flashes, cerebrovascular accident, atrial fibrillation, congestive heart failure, nonspecific ECG changes, myocardial infarction; very rarely – hypertensive crisis.

From the respiratory system sometimes – cough, shortness of breath, nosebleed; very rarely – bronchospasm.

Dermatological reactions frequently – ecchymoses; sometimes – facial swelling, skin itching, rash; very rarely – urticaria, Stevens-Johnson syndrome, Lyell’s syndrome.

Infectious complications sometimes – gastroenteritis, upper respiratory tract infections, urinary tract infections.

From the musculoskeletal system sometimes – muscle cramps, arthralgia, myalgia.

From metabolism frequently – edema, fluid retention; sometimes – changes in appetite, weight gain.

From laboratory tests: frequently – increased activity of liver transaminases; sometimes – increased blood and urine nitrogen, increased CPK activity, decreased hematocrit, decreased hemoglobin, hyperkalemia, leukopenia, thrombocytopenia, increased serum creatinine, increased uric acid; rarely – increased serum sodium.

Other frequently – flu-like syndrome; sometimes – chest pain.

Contraindications

Complete or incomplete combination of bronchial asthma, recurrent nasal polyposis or sinusitis and intolerance to acetylsalicylic acid and other NSAIDs (including in history).

Erosive and ulcerative changes in the gastric or duodenal mucosa, active gastrointestinal bleeding, cerebrovascular or other bleeding.

Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) in the acute phase.

Hemophilia and other bleeding disorders.

Severe heart failure (NYHA functional class II-IV).

Severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) or active liver disease.

Severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney disease, confirmed hyperkalemia.

Period after coronary artery bypass surgery; peripheral arterial disease, cerebrovascular disease, clinically significant coronary artery disease.

Persistent arterial hypertension with blood pressure values above 140/90 mm Hg.

Pregnancy, lactation (breastfeeding).

Children and adolescents under 16 years of age.

Hypersensitivity to etoricoxib.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation. Etoricoxib may adversely affect female fertility and is not recommended for women planning pregnancy.

Use in Hepatic Impairment

Contraindicated in severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) or active liver disease. In patients with moderate hepatic insufficiency (5-9 points on the Child-Pugh scale), it is recommended not to exceed the daily dose of 60 mg.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min), progressive kidney diseases.

Pediatric Use

Contraindicated in children and adolescents under 16 years of age.

Geriatric Use

Use with caution in elderly persons.

Special Precautions

Use with caution in cases with a history of gastrointestinal ulcers, Helicobacter pylori infection, in elderly persons, in patients receiving NSAIDs for a long time, in severe somatic diseases, dyslipidemia/hyperlipidemia, in diabetes mellitus, arterial hypertension, edema and fluid retention, smoking, in patients with creatinine clearance less than 60 ml/min, during concomitant therapy with the following drugs: anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid, clopidogrel), corticosteroids (e.g., prednisolone), selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine, sertraline), in chronic alcoholism.

During treatment, careful blood pressure monitoring is required during the first 2 weeks and periodically thereafter.

During treatment, liver and kidney function parameters should be regularly monitored. If liver transaminase activity increases by 3 times or more relative to the upper limit of normal, treatment should be discontinued.

Given the increased risk of adverse effects with increasing duration of use, it is necessary to periodically assess the need to continue treatment and the possibility of dose reduction.

Should not be used concomitantly with other NSAIDs.

Effect on ability to drive vehicles and operate machinery

During treatment, caution must be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. Patients who have experienced episodes of dizziness, drowsiness or weakness should refrain from activities requiring concentration.

Drug Interactions

In patients receiving warfarin, administration of etoricoxib at a dose of 120 mg/day was accompanied by an increase in INR and prothrombin time by approximately 13%. In patients receiving warfarin or similar drugs, INR should be monitored during the initiation of therapy or changes in the etoricoxib dosing regimen, especially in the first few days.

There are reports that non-selective NSAIDs and selective COX-2 inhibitors can weaken the hypotensive effect of ACE inhibitors. This interaction should be taken into account when treating patients taking Etoricoxib concomitantly with ACE inhibitors. In patients with impaired renal function (e.g., dehydration or elderly), such a combination may worsen functional renal failure.

Etoricoxib can be used concomitantly with low-dose acetylsalicylic acid intended for the prevention of cardiovascular diseases. However, concomitant administration of low-dose acetylsalicylic acid and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared with taking etoricoxib alone. After reaching steady state, administration of etoricoxib 120 mg once daily does not affect the antiplatelet activity of low-dose acetylsalicylic acid (81 mg/day). The drug does not replace the preventive effect of acetylsalicylic acid in cardiovascular diseases. Cyclosporine and tacrolimus increase the risk of nephrotoxicity during etoricoxib administration.

There is evidence that non-selective NSAIDs and selective COX-2 inhibitors can increase plasma lithium concentrations. This interaction should be taken into account when treating patients taking Etoricoxib concomitantly with lithium.

There is evidence of a 28% increase in plasma methotrexate concentration (by AUC) and a 13% decrease in its renal clearance under the influence of etoricoxib.

Administration of etoricoxib 120 mg with oral contraceptives containing 35 µg ethinyl estradiol and 0.5 to 1 mg norethindrone for 21 days, either simultaneously or 12 hours apart, increases the steady-state AUC_0-24 of ethinyl estradiol by 50-60%. However, norethisterone concentrations are generally not increased to a clinically significant extent. This increase in ethinyl estradiol concentration should be taken into account when selecting an appropriate oral contraceptive for concomitant use with etoricoxib. This fact may lead to an increased incidence of thromboembolism due to increased exposure to ethinyl estradiol.

Etoricoxib does not affect the steady-state AUC_0-24 or elimination of digoxin. However, Etoricoxib increases C_max (on average by 33%), which may be important in cases of digoxin overdose.

Concomitant administration of etoricoxib and rifampicin (a potent inducer of hepatic metabolism) leads to a 65% decrease in the plasma AUC of etoricoxib. This interaction should be taken into account when prescribing etoricoxib concomitantly with rifampicin.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.