Arcoxia 120mg Organon treatment acute and chronic osteoarthritis and rheumatoid arthritis (3 blisters x 10 tablets)

Pharmacokology

Pharmacological group: Steroid anti -inflammatory drugs and Coxib arthritis treatment.

ATC code: m01 AH05.

Arcoxia (Etoricoxib) belongs to the group of Coxib drugs that relieve pain/treatment of arthritis. ARCOXIA is a very selective inhibitor cyclooxygenase-2 (COX-2).

Arcoxia is an non -steroid anti -inflammatory (NSAID) anti -inflammatory drugs that have anti -inflammatory, analgesic, and fever in animal models. Arcoxia is a strong, very selective Cycloxygenase-2 (COX-2) inhibitor, which is active when taken within the scope and is higher than the clinical dose range. Cycloxygenase has been identified: Cycloxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cox-1 is responsible for normal physiological functions through prostaglandin intermediaries such as protecting the gastric mucosa and platelet aggregation. The inhibition caused by COX-1 due to the use of non-selective NSAIDs often follows the stomach lesions and platelet inhibits. The COX-2 has been shown in the synthesis of the intermediate substances of prostanoic acid that causes pain, inflammation and fever. The selective inhibition of COX-2 due to the use of Etoricoxib has reduced these clinical signs and symptoms, along with reducing toxicity in the digestive tract without having the effect of platelet function.

In all clinical pharmaceutical studies, Arcoxia has the effect of inhibiting COX-2 depending on the dose of use without inhibiting COX-1 when using the dose up to 150 mg daily.

The effect of protecting the gastric mucosa of COX-1 is also assessed in a clinical study with gastric biopsy samples collected from the object used or Arcoxia 120 mg daily, or Naproxen 500 mg twice a day, or Placebo to assess the aggregate prostaglandin. Compared to Placebo, Arcoxia does not inhibit prostaglandin synthesis in the stomach. In contrast, Naproxen inhibits the synthesis of prostaglandin in the stomach up to nearly 80% when compared to Placebo. These data proves the selection of Arcoxia's COX-2.

Platelet function

Bleeding time is not affected when using Arcoxia multiple doses of up to 150 mg daily for 9 days compared to Placebo. Similarly, bleeding time is not changed in a single dose study with Arcoxia 250 or 500 mg. In experiments performed on culture cells (EX Vivo), there is no inhibition of arachidonic acid or platelet aggregation due to collagen in a sustainable state with ARCOXIA doses up to 150 mg. These findings are suitable for Etoricoxib's selection for COX-2.

Dynamic pharmacokinetics

Etoricoxib is well absorbed by oral. The oral average is nearly 100%oral. After taking the dose of 120 mg once a day until it reaches a stable state, the peak concentration in plasma (average cmax nucleus = 3.6 mcg/ml) is recorded nearly 1 hour (TMAX) after the adult object takes the medication when hungry. The average AUC0-24 hours is 37.8 mcg*hour/ml. Mobile pharmacokinetics of linear Etoricoxib with clinical dose range.

Normal meals have no clinical significance to the level or absorption rate of 1 dose of Etoricoxib 120 mg. In clinical trials, Etoricoxib is used not related to food.

Etoricoxib's pharmacokinetics in 12 healthy subjects are the same (equivalent to AUC, CMAX within a difference of 20%) when taking solitary drugs, when used with antacids containing magnesi/aluminum hydroxide, or antacids containing Carbonate containing carbonate (the ability to neutralize acid approximately 50 MEQ).

distribution

About 92% of the dose of Etoricoxib attached to protein in human plasma when used within the concentration of 0.05 - 5 mcg/ml. The distribution is in a sustainable state (VDSS) about 120 liters in humans.

Etoricoxib passes through the placenta in the rats and rabbits, and passes through the blood -brain barrier in the rat.

transformation

Etoricoxib is strongly metabolized with There have been 5 metabolites identified in humans. The main metabolic substance is Etoricoxib's 6'-carboxylic acid. These main metabolites manifest or have no active measurable or only active as COX-2 inhibitors. These metabolites do not inhibit COX-1.

excretion

After an intravenous injection of a single -dose of 25 mg Etoricoxib has radioactive attachment to healthy objects, 70% of radioactive active ingredients are found in urine and 20% in feces, mostly in the form of metabolites. Under 2% of radioactive active ingredients are found in non -metabolic drugs.

Most Etoricoxib is excreted mainly through metabolism, then through the excretion in the kidneys. Etoricoxib's concentration in a sustainable state is achieved within 7 days of treatment when taking a dose of 120 mg once a day, with an accumulated ratio of nearly 2, corresponding to the accumulated waste time of about 22 hours. It is estimated that the removal of drugs in plasma is approximately 50 ml/min.

The characteristics of patients (special population)

SexEtoricoxib's

pharmacokinetics in men and women are the same.

Elderly Pharmacokinetics in the elderly (≥ 65 years old) is similar to young people. No dose adjustment in elderly patients.

Race

The race does not create an important effect on the pharmacokinetics of Etoricoxib.

Liver failure

In patients with mild liver failure (Child-Pugh 5-6 score), Etoricoxib dose 60 mg once a day with an average AUC higher than 16% higher than healthy objects used in the same dose mode. Patients with average liver failure (Child-Pugh 7-9 score) using Etoricoxib dose of 60 mg once a day, the average AUC is similar to that in healthy subjects used in this population. There is no clinical document or pharmacokinetics when taking drugs in patients with severe liver failure (Child-Pugh score> 9).

kidney failureEtoricoxib's dynamic pharmacokinetics 120 mg in patients with medium - severe renal impairment and patients with end -stage renal disease being treated with hemolysis are not significant difference compared to pharmacokinetics in healthy subjects. Hemolysis does not contribute significantly to the elimination of drugs (the clearance of drugs through the appraisal of about 50 ml/minute).

Child patients Etoricoxib pharmacokinetics in children ( In a pharmacokinetic study (n = 16) conducted on teenagers (12-17 years old), pharmacokinetic pharmacokinetics in teenagers weighing 40 - 60 kg using Etoricoxib 60 mg once a day and in adolescents weighing> 60 kg of Etoricoxib 90 mg once a day, they are like pharmacokinetics in adults using Etoricoxib 90 mg once daily. Etoricoxib's safety and effectiveness has not been established in children's patients.

Interaction with additional pharmacokinetics data

Etoricoxib is biological transformation mainly through oxidation depends on the cytochrom enzyme system to form 6'-Hydroxymethyl Etoricoxib, which can be converted into carboxylic acid corresponding or O-glucuronide. In vitro data shows that CYP3A4 plays a major role (about 60%) in the reaction of Hydroxylation Etoricoxib and CYP2C9, 1A2, 2C19 and 2D6 in charge of the remaining hydroxylation (about 40%). Using strong CYP3A4 (Ketoconazole) drugs does not increase the Etoricoxib level in plasma to clinical significance level (an increase of AUC approximately 43%). Using drugs that strongly touch the enzymes CYP (Rifampin) reduces 65% of Etoricoxib's AUC in plasma.

The ability of Etoricoxib to inhibit or active induction of CYP3A4 has been studied in experiments in people through breathing tests after Erythromycin intravenous intravenous injection. Compared to Placbo, Etoricoxib (120 mg used daily, in 11 days) does not have any significant impact on the N-methylation reduction reaction of Erythromycin, which proves that the drug has no effect on the activity of CYP3A4 in the liver. Based on In vitro studies, erythromycin does not have the effect of inhibiting cytochrome P450 1A2, 2C9, 2C19, 2D6, or 2E1.

Do not use Arcoxia as a combined therapy with nonsteroidal anti -inflammatory drugs (NSAID) because there is no evidence to prove the benefits of synergies and the ability to cause additional adverse reactions.

Be cautious when using

need to be very careful when taking the drug for patients in the following cases:

Non -steroid anti -inflammatory drugs (NSAIDs), not aspirin, use systemic sugar, may increase the risk of cardiovascular events, 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, Arcoxia is needed at the lowest daily doses in the shortest possible time as possible. Clinical trials suggest that the group of COX-2 inhibitors can be jointly increased with the risk of thrombotic events (especially myocardial and stroke infarction), compared to Placebo and some nonsteroidal anti-inflammatory drugs (Naproxen). Because cardiovascular risks may increase according to the dose and time of using COX-2 selective inhibitors, the drug should be used in the shortest possible time and the lowest daily dose is effective. It is advisable to re -evaluate the patient's needs periodically for symptoms and response to treatment.

should only use Etoricoxib after careful consideration in patients with significant risk factors for cardiovascular events (such as hypertension, hyperlipidemia, diabetes, smoking).

Cox-2 selective inhibitors are not aspirin replacement substitutes in cardiovascular disease because it does not work on platelets. Because Etoricoxib is a member of this drug group, has no effect on inhibiting platelet aggregation, so it is not allowed to stop platelets.

The risk of adverse effects in the gastrointestinal tract (gastrointestinal ulcers or other complications in the gastrointestinal tract) increases when using Etoricoxib, other COX-2 selective inhibitors and other nonsteroidal anti-inflammatory drugs (NSAIDs) are used at the same time as acetylsalicylic acid (even at low doses). The relatively different difference in the gastrointestinal tract between the Utility regimen of the Cox-2 filtering inhibitors + Acetylsalicylic acid compared to NSAID + Acetylsalicylic acid has not been fully evaluated in long-term clinical trials.

It is not recommended to use Arcoxia treatment for patients with severe renal disease. Clinical experience in patients with creatinine clearance ratio is estimated

Long -term use NSAID causes kidney necrosis and other kidney damage. Prostaglandin produced in the kidneys may have a role in compensating for the maintenance of kidney perfusion. Therefore, under the conditions of reducing kidney perfusion, the use of Arcoxia can reduce the establishment of prostaglandin and reduce blood flow to secondary kidneys and thus reduce kidney function. Patients with the highest risk of this reaction are those who have reduced kidney function, people with loss of heart failure, or people with cirrhosis significantly. It is advisable to consider monitoring kidney function in these patients. As with other drugs that inhibit prostaglandin synthesis, Arcoxia treatment will lead to recovery before treatment.

Be careful when starting Arcoxia therapy in patients with significant dehydration. Should rehydration for patients before starting Arcoxia.

As other drugs have the effect of inhibiting prostaglandin synthesis, water retention, edema and hypertension are also recorded in several patients using Arcoxia. It is advisable to take into account the ability to retain water, edema or hypertension when using Arcoxia for patients with edema, hypertension or heart failure. All nonsteroidal anti -inflammatory drugs (NSAID) including Etoricoxib may be related to a new onset or congestive heart failure relapse. Etoricoxib may be associated with more frequent and worse hypertension, compared to some other NSAIDs and other COX-2 inhibitors, especially when taking high doses. Therefore, special attention comes to check blood pressure during treatment with Etoricoxib. If blood pressure increases significantly, other treatments must be considered.

Doctors should know that each patient can develop the above ulcerative and ulcerative complications, not affected by treatment. Despite not excluding the risk of toxicity for the digestive tract when using Arcoxia, the results of the Medal program have shown in patients using Arcoxia therapy, the risk of toxicity for the digestive tract when using Arcoxia 60 mg or 90 mg once a day is noticeable than using Diclofenac 150 mg daily. In clinical studies with Ibuprofen and Naproxen, the risk of gastrointestinal ulcers detected by endoscopy in patients with Arcoxia 120 mg once a day is lower than patients using these unstable NSAIDs. While the risk of gastrointestinal ulcers detected by low endoscopy in patients with Arcoxia 120 mg, this risk is higher in patients using Placebo. The above ulcerative and ulcerative complications are recorded in patients using Arcoxia. These events can occur at any time during treatment and have no warning symptoms. Patients with a history of perforation, ulcers and gastrointestinal bleeding and patients over 65 years old are known to have a higher risk of these events, regardless of treatment.

About 1% of patients in clinical trials are treated for up to 1 year with Arcoxia 30, 60 and 90 mg daily increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately ≥ 3 times the upper limit of normal level). In clinical testing groups using other active ingredients, the rate of AST and/or ALT increases in patients using Arcoxia 60 and 90 mg daily is similar to the group of patients using Naproxen 1,000 mg daily, but noticeable lower than the Diclofenac 150 mg daily. The increase in these enzymes has completely cured in patients with Arcoxia therapy, with about ½ patients with increased liver enzymes while still taking the drug. In clinical trials with an ARCOXIA control 30 mg daily with ibuprofen 2,400 mg daily or Celecoxib 200 mg per day, the rate of ALT or AST increases is the same in groups.

Tests should be tested for abnormal liver function in patients with symptoms and/or signs of suggesting liver dysfunction, or in people who have abnormal liver function tests. Arcoxia therapy must be discontinued if the liver function test is constantly abnormal (3 times the upper limit of the normal level).

Should use Arcoxia carefully in patients who have had acute asthma attacks, urticaria, or previous rhinitis due to allergies to salicylate drugs or non -selective cyclooxygenase inhibitors. Because the pathophysiology of these reactions is not well known, the doctor needs to consider the potential benefits of Arcoxia therapy compared to the risks.

When using Etoricoxib in the elderly and in patients with kidney, liver or heart dysfunction, it is necessary to maintain appropriate medical care regime. If these patients have worsened the disease gradually during treatment, they must take appropriate measures, including therapeutic discontinuation.

In after-sales surveillance, it is very rare for serious skin reactions, which some reactions can be fatal, including flaky dermatitis, Stevens-Johnson syndrome and poisoned epidermal necrosis when using NSAID and some COX-2 inhibitors. These serious effects can occur without notice. Patients with the highest risk of these reactions early during treatment: Most cases of betrayal onset in the first month of treatment. There have been reports of severe sensitive reactions (such as anaphylactic reactions) in patients using Etoricoxib. A few selective inhibitors of COX-2 have been associated with increasing the risk of multiple reactions in patients with a history of allergies. Etoricoxib therapy should be discontinued at the beginning of the skin rash, mucosal lesions or any other signs of hypersensitivity reactions.

Arcoxia can cover symptoms of fever, which is a sign of infection. Doctors should know this problem when taking Arcoxia for patients who are treating infections.

Use in children

Not yet established the safety and effectiveness of Etoricoxib in children's patients.

Used in older people

The pharmacokinetics of the drug in the elderly (≥ 65 years) similar to young people. In clinical trials, the adverse effect rate is higher in elderly patients when compared to younger patients; The relative differences between the Etoricoxib group and the evidence group are the same in the elderly and young people. It is impossible to eliminate more sensitivity in some older people.

The effect of the drug on driving and operating machinery

There is no information that suggests Arcoxia affects the ability to drive or operate the machine when the patient is taking the drug. Patients with dizziness, dizziness, drowsiness when using Etoricoxib should limit driving and operating machinery.

Use drugs for women during pregnancy and lactation

Pregnant women

As other drugs have a prostaglandin synthesis effect, should avoid Arcoxia in the last months of pregnancy because it can cause early closing of the ductus arterioscleria.

Research to toxicity on fertility is conducted in rats has proved that there is no evidence of abnormalities in the development of embryos when taking the drug up to 15 mg/kg/day (approximately 1.5 times the dose in humans [90 mg] is based on systemic contact). At the doses of approximately twice the contact dose in adults (90 mg) based on the whole body contact, it is recorded in a low rate of cardiovascular deformities and increased abortion in rabbits treated with etoricoxib. No effect on embryo development when the body contact dose is nearly or inferior to daily doses in humans (90 mg). However, animal fertility studies do not always be predicted in humans. There are no appropriate studies and good control in pregnant women. Arcoxia should only be used in the first two quarters of pregnancy when the potential benefits are more potential than the risk that may occur for the fetus.

Reproduction

Etoricoxib, as well as other COX-2 inhibitors, avoids women who are pregnant.

breastfeeding women

Etoricoxib is excreted in mother mouse milk. It is not known whether this drug is excreted in human milk or not. Because there are many drugs excreted in human milk and because of the adverse effects of prostaglandin synthetic inhibitors may occur in breastfeeding, depending on the importance of the mother for the mother, decide or stop breastfeeding or stop taking the drug.

Drug interaction

warfarin: In stable objects with chronic Warfarin therapy, the 120 mg Arcoxia regimen per day is often associated with an increase of about 13% of the international standard chemical ratio of prothrombin time (International Normalized Ratio - INR). The regular test should be checked for Inr values ​​when starting or changing treatment with Arcoxia, especially in the first few days in patients using warfarin or similar drugs.

Rifampin: Use Arcoxia at the same time as rifampin, a strong induction substance that metabolism through the liver has reduced 65% of the area under the curve (AUC) to represent Etoricoxib concentration in plasma. This interaction should be taken into account when using Arcoxia at the same time as Rifampin.

Methotrexate: There are 2 research tests for the action of Arcoxia 60, 90 or 120 mg once a day in 7 days in patients using methotrexate dose 7.5 - 20 mg once a week to treat rheumatoid arthritis. Arcoxia dose 60 and 90 mg does not affect the concentration of methotrexate in plasma (rated by AUC) or the removal of drugs through the kidneys. In a test, Arcoxia 120 mg does not affect the concentration of methotrexate in plasma (rated by AUC) or the removal of drugs through the kidney. In the remaining test, Arcoxia 120 mg increased methotrexate levels, in plasma to 28% (rated by AUC) and reducing the methotrexate bar through the kidney by up to 13%. The monitoring of toxicity is related to methotrexate when using Arcoxia higher than 90 mg daily and using methotrexate therapy at the same time.

Diuretics, Angiotensin (ACE) and Angiotensin II (AIIA): The NSAID suggested reports include COX-2 selective inhibitors that can be aper-treatment effect on hypertension of diuretics, angiotensin transferring enamel and antagonistic Angiotensin II. Should pay attention to this interaction when using Arcoxia at the same time as these drugs.

In some patients with renal function (such as elderly patients or patients with the volume of circulatory fluid, including patients using diuretic therapy) being treated with nonsteroidal anti-inflammatory drugs, including COX-2 inhibitors, simultaneous use of angiotensin transferring enzymes or angiotensin II antagonists can worse renal function, including acute renal impairment. These effects can often be recovered. Therefore, be careful when combining drugs, especially in the elderly.

Lithium: The high-selected NSAIDs suggestive and selected Cox-2 inhibitors may increase lithium concentration in plasma. This interaction should be taken into account for patients to use Arcoxia at the same time as Lithium.

Aspirin: Arcoxia can be used at the same time as low -dose aspirin to prevent cardiovascular disease. In sustainable state, Etoricoxib 120 mg once a day does not affect the activity of platelet resistance of low -dose aspirin (81 mg once a day). However, using low -dose aspirin simultaneously with Arcoxia increases the rate of gastrointestinal ulcers or other complications compared to the use of single -treatment Arcoxia.

contraceptive pill: Arcoxia 60 mg is used at the same time as a contraceptive pill containing 35 mcg ethinyl estradiol and 0.5 - 1 mg norethindrone in 21 days has increased the Aucoza of Ethinyl Estradiol in a sustainable state of up to 37%. AUC, Ziga of Ethinyl Estradiol in a sustainable state has increased by 50 - 60% when Arcoxia 120 mg is used at the same time or 12 hours from this type of contraceptive pill. It is necessary to take into account the increase in Ethinyl estradiol level when choosing a contraceptive pill with Etoricoxib. Increasing exposure to Ethinyl estradiol may increase the proportion of adverse effects that are often associated with using contraceptives (such as venous thrombotic events in risky women).

Hormone replacement therapy: Arcoxia 120 mg is used with hormone replacement therapy containing conjugated estrogen (0.625 mg premarintm) for 28 days, increasing AUC0-24 hours, on average in the sustainable state of non-combined ester (41%), Equilin (76%) and 17-B-Eltradiol (22%). The impact of the recommended doses of Arcoxia (60 and 90 mg) for prolonged use has not been studied. The impact of Arcoxia 120 mg on concentration (AUC0-24 hours) these estrogen components in premarin is half less than the observed effect when using a single premarin and when the dose increases from 0.625 to 1.25 mg. It is still unknown to the clinical significance of these increase and there is no research on the higher dosage premarintm coordination regimen with Arcoxia. It is advisable to increase the concentration of estrogen when choosing to replace postmenopausal hormones to use with Arcoxia.

Other drugs: In studies on drug interaction, Arcoxia does not have clinically important effects on pharmacokinetic pharmacokinetics of prednisone/prednisolone or digoxin.

antacids and ketoconazole (1 strong CYP3A4 inhibitor) does not have important effects on the clinical dynamics of Arcoxia.