Arixib-60 pulse drugs treat symptoms of rheumatoid arthritis, rheumatitis (10 blisters x 10 tablets)

Pharmacological effect group. Anti -inflammatory drugs and rheumatism, non -steroids, Coxib

Code ATC: M01AH05

Etoricoxib is an nonsteroidal anti-inflammatory drug (NSAID), belonging to the Celecoxib group, selectively inhibit the COX-2 (Cyclo-Oxygenase-2) for oral. In clinical pharmaceutical studies, Etoricoxib inhibits COX-2 depending on the dose but does not inhibit COX-1 when using the dose of 150mg/day. Etoricoxib does not inhibit the synthesis of prostaglandin stomach and does not affect platelet function.

Cyclogenase plays a role in the formation of prostaglandin, there are two types of COX enzymes that have been identified, including COX-1 and COX-2. COX-2 is created by pre-inflammatory agents and is said to play a major role in the synthesis of painful intermediaries, inflammation and prostanoid fever.

COX-2 also participates in ovulation, transplanting and closing arterioscleros, adjusting the kidney function and the functions of the central nervous system (such as fever, pain and cognitive function), and is likely to play a role in healing ulcers. Cox-2 has been found in tissues around the stomach ulcer in humans but has not determined the relationship of this substance has not been determined on the healing process.

The mechanism of action of Celecoxib is considered to inhibit the synthesis of prostaglandin, mainly through the effect of inhibiting isenzyme COX-2, resulting in a decrease in the formation of prostaglandin. Unlike the majority of previous nonsteroidal anti-inflammatory drugs, Celecoxib does not inhibit the ISOENZYM COX-1 with human treatment concentrations. Cox-1 is an enzyme available in most tissues, large single and platelet leukocytes. Cox-1 participates in the process of creating blood clots (such as thrombocytopenia to stop training), maintain the fence of the stomach mucosa and kidney function (such as maintaining kidney perfusion). Due to not inhibiting COX-1, Celecoxib is less likely to cause side effects such as bleeding, stomach ulcers, prolonging bleeding time, ... but can cause side effects in the kidneys similar to other nonsteroidal anti-inflammatory drugs.

Celecoxib may increase the risk of blood vessel thrombosis in some patients because of the prostaglandin synthesis inhibitors (a thrombotic anti -thrombotic) and does not affect the thromboxan A2 (a thrombus -prone substance).In addition, Celecoxib can also prevent colon cancer cell proliferation and reduce colorectal polyps.

Pharmacokinetics

absorption

Etoricoxib absorbs well when taken orally. The absolute bioavailability of the drug is approximately 100%. After taking the dose of 120 mg x 1 time/day, in a stable state, the peak concentration of the drug in plasma (the average value of cmax = 3.6 ng/ml) is achieved after about 1 hour (TMAX) after taking the drug in adults. The area below the average curve (AUC0-24 hours) is about 37.8 kg/ml. Mobile pharmacokinetics of linear Etoricoxib in clinical treatment dose.

Use the drug along with food (fat -rich meals) does not affect Etoricoxib's absorption level at 120 mg, but reducing CMAX 36% and increasing TMAX to 2 hours, these changes are not clinically significant. In clinical trials, Etoricoxib can be used with meals or not.

Distribution

about 92% Etoricoxib binds to plasma proteins, within the concentration range from 0.05 to 5 kg/ml. The distribution volume in a stable state (VDSS) is approximately 120 l in humans.

Etoricoxib passes through the mouse and rabbit placenta, and the blood-flabby barrier in the mouse.

Metabolism

Most Etoricoxib is metabolized, less than 1% of the dose found in urine in constant form.

The main metabolic path of the drug is to form 6’-hydroxymethyl, catalyzed by CYP enzymes. CYP3A4 participates in Etoricoxib's metabolism in Vivo studies. In vitro studies show that CYP2D6, CYP2C9, CYPIA2 and CYP2C19 can also catalyze this transformation path, but their real role in the body has not been studied.

has identified 5 metabolites of Etoricoxib in humans. The main metabolic substance is Etoricoxib's 6’-carboxylic acid derivatives formed by continuing oxidation of 6’hydroxymethyl substance. These main metabolites are not active or only inhibited inhibitors. No metabolites inhibit COX-1

Elimination

After intravenous injection, an Etoricoxib dose marks a 25 mg radioactive for healthy volunteers, 70% of the marked dose is found in the urine and 20% is found in feces, mainly in the form of metabolites.

less than 2% of the dose is found in a constant form.

Etoricoxib is metabolized and eliminated through the kidneys. Etoricoxib's stable concentration is reached within 7 days after taking the dose of 120 mg x 1 time/day, with the accumulation rate of about 2, and the sale time is about 22 hours. Plasma clearance after intravenous injection 25 mg is estimated at 50 ml/min.

Special subject group

Elderly: Pharmacokinetics in people over 65 are similar to normal people.

Sex: The pharmacokinetics of the drug are similar in men and women.

Hepatic failure: Patients with mild liver failure (according to the Child-Pugh scale from 5-6) are indicated for Etoricoxib 60 mg 1 time/day with an average AUC value higher than 16% when compared to normal healthy people. Patients with medium liver failure (according to the Child-Pugh scale from 7-9) using Etoricoxib 60 mg x 1 time/day with an average AUC value equivalent to normal healthy people using the same dose level; There is no evaluation research at a dose of 30mg x 1 time/day. There is no clinical research data on pharmacokinetics in patients with severe liver failure (according to the scale of Child-Pugh≥ 10).

Kidney failure: Pharmacokinetics when using single dose of Etoricoxib 120 mg for patients with medium to severe renal failure and patients with end -stage renal impairment need dialysis do not show significant differences, when compared to healthy objects. Dialysis does not significantly affect the elimination of drugs.

Children: Etoricoxib's pharmacokinetics in children (under 12 years old) has not been established.

Be cautious when using

influence on the gastrointestinal tract

The above digestive tract complications (perforation, ulcers or bleeding - pubs), some may lead to deaths that occur in patients treated with Etoricoxib.

Be careful when treating patients at risk of gastric stomach complications with NSAIDs such as the elderly, patients with a history of gastrointestinal diseases such as ulcers and gastrointestinal bleeding before or after using any other NSAIDs or acetylsalicylic acid.

Side effects on the gastrointestinal tract (digestive ulcers or other complications) are at risk of increasing when using copper

Etoricoxib period with acetylsalicylic acid, even when used only at low doses. The significant difference in terms of safety with the bleeding time between use simultaneously selects COX-2 inhibitors with acetylsalicylic acid and NSAID with acetylsalicylic acid has not been proven in long-term clinical trials.

Cardiovascular thrombosis

Non -steroid anti -inflammatory drugs (NSAIDs), non -aspirin, body sugar, may increase the risk of cardiovascular thrombosis, including myocardial and stroke, which can lead to death.

This risk can appear early in the first few weeks of taking the drug and can increase over time.

The risk of cardiovascular thrombosis is recorded mainly at high doses.

Doctors need to periodically evaluate the appearance of cardiovascular events, even if the patient has no previous cardiovascular symptoms. Patients should be warned of symptoms of serious cardiovascular events and need to visit the doctor as soon as they appear.

To minimize the risk of adverse events, Etoricoxib is needed in the lowest daily daily doses in the shortest time.

Only indicate Etoricoxib for patients with high cardiovascular risks such as hypertension, blood fat, diabetes, smoking after careful consideration.

Selective Cox-2 inhibitors cannot be used instead of acetylsalicylic acid to prevent coronary artery disease due to lack of platelet inhibitors. Therefore, anti -platelets should not be stopped during medication.

The impact on the kidneys

Prostaglandin on the kidneys can play a role in maintaining blood flow through the kidneys. Therefore, in case the blood flow through the kidneys is not stable, using Etoricoxib may reduce the formation of prostaglandin, then reduce kidney perfusion, leading to impaired renal function. Patients with the highest risk include patients with impaired renal function, heart failure or loss of cirrhosis. Need to consider monitoring kidney function in these patients.

water retention, edema and hypertension

Like other Prostaglandin synthesis inhibitors, water retention, edema and hypertension have been observed in patients using Etoricoxib. All nonsteroidal anti -inflammatory drugs (NSAIDs), including Etoricoxib, can lead to the onset or relapse of congestive heart failure. Be careful when prescribing the drug in patients with a history of congestive heart failure, left ventricular dysfunction, high blood pressure or patients with edema for any reason. If there is a clinical evidence of a worse condition of the patient, it is necessary to apply appropriate measures, including stopping Etoricoxib.

Etoricoxib can lead to more frequent and more energetic hypertension than some NSAIDs and other COX-2 selective inhibitors, especially when used in high doses. Therefore, the patient's blood pressure is required to be treated with Etoricoxib before treatment, as well as paying special attention to monitoring blood pressure during Etoricoxib treatment. Blood pressure monitoring within two weeks should be monitored after starting treatment and then periodically checking. If hypertension is significantly, should consider other alternative treatment options.

influence on the liver

The increase in transaminase Alt and/or AST is about 3 times higher or more than the upper limit has been reported at about 1% of patients in clinical trials, treated up to 1 year with the dose of Etoricoxib 30 mg, 60 mg and 90 mg x 1 time/day.

Any patient with symptoms and/or signs that have liver dysfunction, or abnormal liver function tests need to be monitored. If there are signs of liver failure or abnormal liver function test (3 times higher than the above limit), it should stop using Etoricoxib.

body

During treatment, the patient detects the symptoms described above, which should be treated appropriately and need to consider stopping Etoricoxib. Need to maintain medical monitoring when using drugs in the elderly, or

Patients with liver, kidney or heart dysfunction.

Be careful when starting with Etoricoxib in patients with dehydration. Promotions recommend for patients before starting with Etoricoxib.

Serious skin reactions, some may cause death, including flaking dermatitis, Stevens-Johnson syndrome and epidermal poisoning have been reported rare when using NSAID and some COX-2 selective inhibitors. Patients are at the highest risk of these reactions during the beginning of treatment, most cases occurred during the first month of treatment. Serious hypersensitivity reactions such as hypersensitivity and angioedema have been reported in patients using Etoricoxib. Some selective inhibitors of COX-2 may increase skin risk in patients with a history of allergies to some drugs. Etoricoxib should be discontinued when starting to detect skin rashes, mucosal lesions, or any signs of hypersensitivity.

Etoricoxib can hide fever and signs of inflammation.

Be cautious when used simultaneously Etoricoxib with warfarin or other oral anticoagulants.

Do not use Etoricoxib or any COX inhibitor or Prostaglandin synthesis in women who are trying to conceive.

The effect of the drug on the ability to drive and operate machinery

People with a history of dizziness, drowsiness after using Etoricoxib should not drive or operate machinery during medication.

Use drugs for women during pregnancy and lactation

Pregnant women

There is no clinical data available for using Etoricoxib for pregnant women. Animal studies have shown toxic drugs on reproduction. Human risks have not been identified during pregnancy.

Etoricoxib, as well as prostaglandin inhibitors, can cause uterine contractions and early closing artery in the last three months of pregnancy. Do not use Etoricoxib for pregnant women. If a woman is pregnant during treatment, it is necessary to stop using Etoricoxib.

breastfeeding women

It is not known whether Etoricoxib will excrete in breast milk, but Etoricoxib is present in mouse milk being raised with milk. Do not use Etoricoxib for breastfeeding women.

Reproduction

It is not recommended to use Etoricoxib, as well as other COX-2 inhibitors for women who are trying to conceive.

Drug interaction

Pharmacological interaction

Oral anticoagulant: When taking Etoricoxib for chronic patients taking warfarin, the dose of Etoricoxib 120 mg x 1 time/day shows prothrombin time (international normalization time - INR).

Therefore, it is necessary to closely monitor Prothrombin Inr for patients using oral anti -dynamic drugs, especially for a few days after starting treatment with Etoricoxib or changing the Etoricoxib dose.

diuretic, ACE inhibitors and Angiotensin II antagonists: NSAIDs can reduce the effectiveness of diuretics or other hypertension medications. In some patients with renal function damage such as dehydrated patients, elderly patients or renal function impairment, simultaneous use of ACE -ACE inhibitors or Angiotensin II antagonists and COX inhibitors can lead to impaired renal function, including acute renal failure, but can recover. These interactions should be considered in patients using Etoricoxib along with ACE inhibitors or Angiotension II antagonists. Therefore, be careful when combining these drugs, especially in elderly patients. Patients should be fully provided with water and need to consider monitoring kidney function after starting treatment, and need to consider periodic monitoring later.

Acetylsalicylic acid: In a study on a healthy volunteer, in a stable state, the dose of Etoricoxib 120 mg x 1 time/day does not affect the anti -platelet activity of acetylsalicylic acid (81 mg x 1 time/day). Etoricoxib can be used simultaneously with acetylsalicylic acid at cardiovascular prophylaxis (low dose). However, simultaneous use of these two drugs may increase the rate of digestive ulcers or other complications, compared to the case of only Etoricoxib alone. It is not recommended to simultaneously use Etoricoxib with acetylsalicylic acid at higher doses than cardiovascular prophylaxis.

Cyclosporin and Tacrolimus: Although this interaction has not been studied, the use of cyclosporine or tacrolimus with any NSAID can increase the toxicity of the kidneys of cyclosporine or tacrolimus. Need to control kidney function when combining Etoricoxib along with one of these two drugs.

Pharmacokinetic interaction

Etoricoxib's effect on the dynamics of some other drugs

Lithi: NSAID reduces lithium excretion, thus increasing lithium blood levels. If necessary, closely check the lithium concentration and adjust the lithium dose when combined with NSAID, or do not use NSAID during the use of this drug.

Methotrexate: Two studies have shown that using Etoricoxib dose 60, 90 and 120 mg x 1 time/day for 7 days in patients treated weekly with methotrexate at a dose of 7.5 mg to 20 mg to treat rheumatoid arthritis.

Etoricoxib at the dose of 60 mg and 90 mg does not affect blood concentrations or the renal clearance of methotrexate. In a study, Etoricoxib 120 mg does not influence, but in another study, Etoricoxib dose 120 mg increases 28% of methotrexate concentration in the blood and reducing 13% of the kidney clearance of methotrexate. Adequate monitoring of toxicity related to methotrexate when used simultaneously with Etoricoxib.

Oral contraceptive: Etoricoxib simultaneously used 60 mg with oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindron in 21 days increases the area under the AUCO-24 curve of EE 37%. Etoricoxib dose of 120 mg for the same oral contraceptive pills, at the same time or 12 hours apart, increasing the AUC0-24 hours of EE from 50-60%. It is necessary to consider increasing this EE concentration when choosing to use oral contraceptives and Etoricoxib. EE's AUC increase may increase the frequency of unwanted effects of oral contraceptives (for example, venous thrombosis in risky women).

Hormone replacement therapies (HRT): Etoricoxib 120 mg treatment with hormone replacement therapy including conjugated estrogen (0.625 mg premarintm) in 28 days, increasing the AUC0-24 hours of non-conjugate 41%, Equilin 76%and 17-B-Eltradiol 22%. The effect of the recommended dose for chronic diseases of Etoricoxib (30, 60 and 90 mg) has not been studied. Escapes of Etoricoxib 120 mg on AUC0-24 hours on premarin estrogen components are half lower than the visual value when used for monopoly premarin and the dose increases from 0.625 to 1.25 mg. The clinical significance of this increase has not been determined, and there is no study of combining Etoricoxib with premarin at higher doses. So it is necessary to mention the increase in estrogen levels when using postmenopausal hormone replacement therapy simultaneously with Etoricoxib, because of this increase in estrogen levels can increase unwanted effects related to HRT

Prednison/Prednisolon: In drug interactive studies, Etoricoxib does not have a significant clinical impact on the pharmacokinetics of Prednison or Prednisolon.

Digoxin: Use Etoricoxib 120 mg 1 time/day for 10 days for healthy lover does not affect AUC0-24 hours or excreting the kidney digoxin. Digoxin's CMAX increases about 33%, but this increase does not make sense to the majority of patients. However, patients at risk of digoxin toxicity should be closely monitored when using this drug with Etoricoxib and Digoxin at the same time.

Effect of Etoricoxib on drugs metabolized by sulfotransferase

Etoricoxib is an inhibitor of sulfotransferase in humans, especially sultie1, and shows an increase in the concentration of ethinyl estradiol in serum. Although the data on the effects of many sulfotransferase is limited and clinically affected by many drugs is still being studied, it is necessary to be cautious when using Etoricoxib simultaneously and major metabolic drugs via sulfotransferase (such as Salbutamol and Minoxidil oral Minoxidil).

Effects of Etoricoxib on drugs metabolized by isenzyme CYP

In In vitro studies, Etoricoxib does not see the cytochrom P450 (CYP0 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study on a healthy volunteer, using Etoricoxib 120 mg x 1 time/day does not change the activity of CYP3A4 in the liver when evaluating by the breathing test of Erenthromycin.

Effects of other drugs on Etoricoxib's pharmacokinetics

Etoricoxib's main metabolic path depends on the CYP enzymes. CYP3A4 is involved in Etoricoxib metabolism in the body. In vitro studies show that CYP2D6, CYP2C9, CYP1A2 or CYP2C19 can also catalyze this transformation path, but their true role in the body has not been studied.

Ketoconazole: Ketoconazole- A CYP3A4 inhibitor, when taking a dose of 400 mg x 1 time/day for 11 days on a healthy volunteer, it does not show a significant clinical impact compared to when using only the single dose of Etoricoxib 60 mg (AUC increases 43%).

voriconazole and miconazole: simultaneously use oral voriconazole or miconazole gel gel topical - strong inhibitor CYP3A4 along with Etoricoxib increases the concentration of Etoricoxib, but is not clinically significant, based on the announced data.

Rifampicin: Simultaneously use Etoricoxib and Rifampicin - 1 agent inhibiting the enzyme system CYP, reducing 65% of Etoricoxib concentration in the blood, reducing the effect of Etoricoxib and recurrent symptoms. Although the proposal to increase the dose, the coordination of rifampicin with Etoricoxib at the dose is greater than the recommended dose for each indicator has not been studied, so it is not recommended to simultaneously use these two drugs.

Antacid: Antacid has no clinical effects on pharmacokinetics of etoricoxib.