Description of the drug KOSTAROKS
In patients receiving warfarin, administration of etoricoxib at a dose of 120 mg/day was accompanied by an increase of approximately 13% in MHO and prothrombin time. In patients receiving warfarin or similar drugs, MHO levels should be monitored when initiating therapy or changing the dosage regimen of etoricoxib, 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 (for example, dehydration or old age), this combination may worsen renal failure.
Etoricoxib can be used concomitantly with acetylsalicylic acid in low doses intended for the prevention of cardiovascular diseases. However, simultaneous administration of acetylsalicylic acid in low doses and etoricoxib may lead to an increased incidence of gastrointestinal ulcers and other complications compared to taking etoricoxib alone. After reaching a steady state, taking etoricoxib at a dose of 120 mg 1 time / day does not affect the antiplatelet activity of acetylsalicylic acid in low doses (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 while taking etoricoxib.
There is evidence that non-selective NSAIDs and selective COX-2 inhibitors may increase plasma lithium concentrations. This interaction should be taken into account when treating patients taking etoricoxib concomitantly with lithium.
There is evidence of an increase in the concentration of methotrexate in plasma by 28% (according to AUC) and a decrease in its renal clearance by 13% under the influence of etoricoxib.
Taking etoricoxib 120 mg with oral contraceptives containing 35 mcg ethinyl estradiol and 0.5 to 1 mg norethindrone for 21 days, either simultaneously or 12 hours apart, increased the steady-state AUC0-24 of ethinyl estradiol by 50-60%. However, norethisterone concentrations usually do not increase to a clinically significant extent. This increase in ethinyl estradiol concentrations should be taken into account when selecting the 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 AUC0-24 at steady state or digoxin elimination. However, etoricoxib increases Cmax (by an average of 33%), which may be important in the development of digoxin overdose.
Concomitant use of etoricoxib and rifampicin (a potent inducer of hepatic metabolism) leads to a 65% decrease in plasma etoricoxib AUC. This interaction should be considered when etoricoxib is coadministered with rifampicin.
Kostarox, 28 pcs., 90 mg, film-coated tablets
Pharmacodynamic interactions
Oral anticoagulants (warfarin). In patients chronically taking warfarin, etoricoxib 120 mg daily was associated with an approximately 13% increase in international normalized ratio (INR)/prothrombin time. Therefore, in patients receiving oral anticoagulants, the INR/prothrombin time should be monitored when starting treatment or when changing the dose of etoricoxib, especially in the first few days.
Diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (eg, dehydrated patients or elderly patients with compromised renal function), concomitant use of an ACE inhibitor or angiotensin II receptor antagonist and drugs that inhibit COX may lead to further deterioration of renal function, including the possible development of acute renal failure, which is usually reversible. This should be taken into account in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Such combinations should be prescribed with caution, especially in elderly patients. Patients should be adequately hydrated and renal function monitored when initiating combination therapy and periodically thereafter.
Acetylsalicylic acid. In a study in healthy volunteers, etoricoxib 120 mg once daily at steady state did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used simultaneously with acetylsalicylic acid in low doses intended for the prevention of cardiovascular diseases. However, concomitant use of low doses of acetylsalicylic acid and etoricoxib may result in an increased incidence of gastrointestinal ulceration or other complications compared with etoricoxib alone. The simultaneous use of etoricoxib with acetylsalicylic acid in doses exceeding those recommended for the prevention of cardiovascular complications, as well as with other NSAIDs, is not recommended.
Cyclosporine and tacrolimus. The interaction of etoricoxib with these drugs has not been studied, however, simultaneous use of cyclosporine or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporine or tacrolimus. Monitor renal function when taking etoricoxib in combination with any of these drugs.
Pharmacokinetic interactions
Effect of other drugs on the pharmacokinetics of etoricoxib
The main route of metabolism of etoricoxib is dependent on CYP enzymes. The CYP3A4 isoenzyme promotes the metabolism of etoricoxib in vivo. In vitro studies indicate that the isoenzymes CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyze the major metabolic pathway, but their quantitative characteristics in vivo have not been studied.
Ketoconazole. Ketoconazole, a potent CYP3A4 inhibitor, when administered to healthy volunteers at a dose of 400 mg once daily for 11 days, did not have a clinically significant effect on the pharmacokinetics of a single dose of etoricoxib 60 mg (43% increase in AUC).
Voriconazole and miconazole. Co-administration of strong CYP3A4 inhibitors (oral voriconazole or topical miconazole oral gel) and etoricoxib resulted in a small increase in etoricoxib exposure, which was not considered clinically significant based on published data.
Rifampicin. The simultaneous use of etoricoxib and rifampicin (a powerful inducer of the cytochrome system) led to a decrease in the concentration of etoricoxib in the blood plasma by 65%. This interaction may result in relapse of symptoms when etoricoxib is coadministered with rifampicin. This information suggests a need for dose escalation, but use of etoricoxib in doses exceeding those recommended for each indication is not recommended as the combination of rifampicin and etoricoxib at such doses has not been studied.
Antacids. Antacids do not have a clinically significant effect on the pharmacokinetics of etoricoxib.
Effect of etoricoxib on other drugs
Lithium. NSAIDs reduce the excretion of lithium by the kidneys, therefore increasing the concentration of lithium in the blood plasma. If necessary, frequently monitor the concentration of lithium in the blood and adjust the dose of lithium during concomitant use with NSAIDs, as well as when NSAIDs are discontinued.
Methotrexate. Two studies examined the effects of etoricoxib 60, 90, or 120 mg once daily for seven days in patients receiving 7.5 to 20 mg of methotrexate once weekly for the treatment of RA. Etoricoxib at doses of 60 and 90 mg had no effect on plasma methotrexate concentrations or renal clearance of methotrexate. In one study, etoricoxib 120 mg had no pharmacokinetic effect on methotrexate, but in another study, plasma methotrexate concentrations were increased by 28% and methotrexate renal clearance was decreased by 13%. When taking etoricoxib and methotrexate concomitantly, it is recommended to monitor for possible toxic effects of methotrexate.
Oral contraceptives. Etoricoxib 60 mg, when coadministered for 21 days with oral contraceptives containing 35 mcg ethinyl estradiol (EE) and 0.5 mg to 1 mg norethindrone, increased the AUC0-24h of EE by 37% at steady state. Taking etoricoxib at a dose of 120 mg in combination with the above oral contraceptives (simultaneously or with an interval of 12 hours) increased AUC0-24h EE by 50-60% at steady state. This increase in EE concentrations should be taken into account when selecting an oral contraceptive for concomitant use with etoricoxib. Such an interaction may lead to an increased incidence of adverse events associated with the use of oral contraceptives (for example, venous thromboembolism in women at risk).
Hormone replacement therapy (HRT). The administration of etoricoxib at a dose of 120 mg simultaneously with drugs for HRT containing conjugated estrogens at a dose of 0.625 mg for 28 days increased the average value of the steady-state AUC0-24h of unconjugated estrone (41%), equilin (76%) and 17-β-estradiol (22 %). The effects of etoricoxib doses recommended for long-term use (30, 60 and 90 mg) have not been studied. Etoricoxib at a dose of 120 mg changed the exposure (AUC0-24h) of these estrogenic components to less than half compared with conjugated estrogens monotherapy when the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and the use of higher doses of conjugated estrogens in combination with etoricoxib has not been studied. Increased estrogen concentrations should be taken into account when choosing postmenopausal hormone therapy when coadministered with etoricoxib, as increased estrogen exposure may increase the risk of HRT-related adverse events.
Prednisone/prednisolone. In drug interaction studies, etoricoxib did not have a clinically significant effect on the pharmacokinetics of prednisone/prednisolone.
Digoxin. When etoricoxib was administered at a dose of 120 mg once daily for 10 days in healthy volunteers, there was no change in the steady-state AUC0-24h of digoxin in the blood plasma or an effect on its renal excretion. At the same time, an increase in Cmax of digoxin by approximately 33% was observed. This increase is usually not significant for most patients. However, when etoricoxib and digoxin are used concomitantly, patients at high risk for digoxin toxicity should be monitored.
Effect of etoricoxib on drugs metabolized by sulfotransferases. Etoricoxib is an inhibitor of human sulfotransferases (specifically SULT1E1) and may increase serum EE concentrations. Because there is currently limited data on the effects of various sulfotransferases, and their clinical relevance for the use of many drugs is still being studied, it is advisable to use caution when administering etoricoxib concomitantly with other drugs metabolized by human sulfotransferases (for example, oral salbutamol and minoxidil ).
Effect of etoricoxib on drugs metabolized by isoenzymes of the cytochrome system. Based on the results of in vitro studies, etoricoxib is not expected to inhibit cytochrome P450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in healthy volunteers, daily administration of etoricoxib 120 mg had no effect on hepatic CYP3A4 activity as assessed by the erythromycin breath test.
Kostarox
Allergic reactions: very rarely - anaphylactic/anaphylactoid reactions, including a pronounced decrease in blood pressure and shock.
From laboratory tests: often - increased activity of liver transaminases; sometimes - increased nitrogen in the blood and urine, increased activity of creatine phosphokinase, decreased hematocrit, decreased hemoglobin, hyperkalemia, leukopenia, thrombocytopenia, increased serum creatinine, increased uric acid; rarely - increased sodium in the blood serum.
Metabolism: often - swelling, fluid retention; sometimes - changes in appetite, weight gain.
From the musculoskeletal system: sometimes - muscle cramps, arthralgia, myalgia.
Dermatological reactions: often - ecchymosis; sometimes - swelling of the face, itching, rash; very rarely - urticaria, Stevens-Johnson syndrome, Lyell's syndrome.
From the respiratory system: sometimes - cough, shortness of breath, nosebleeds; very rarely - bronchospasm.
From the cardiovascular system: often - 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 urinary system: sometimes - proteinuria; very rarely - renal failure, usually reversible when the drug is discontinued.
From the senses: sometimes - blurred vision, conjunctivitis, tinnitus, vertigo.
From the nervous system: often - headache, dizziness, weakness; sometimes - taste disturbance, drowsiness, sleep disturbances, sensory disturbances, including paresthesia/hyperesthesia, anxiety, depression, concentration problems; very rarely - hallucinations, confusion.
From the digestive system: often - epigastric pain, nausea, diarrhea, dyspepsia, flatulence; sometimes - bloating, belching, increased peristalsis, constipation, dry oral mucosa, gastritis, ulcer of the gastric or duodenal mucosa, irritable bowel syndrome, esophagitis, ulcers of the oral mucosa, vomiting; very rarely - gastrointestinal ulcers (with bleeding or perforation), hepatitis.
Infectious complications: sometimes - gastroenteritis, infections of the upper respiratory tract, urinary tract.
Other: often - flu-like syndrome; sometimes - chest pain.
