Roticox 60mg Krka medicine reduces osteoarthritis (3 blisters x 10 tablets)

Mechanism of action

Etoricoxib is taken orally, which is a selective inhibitor of cyclo-oxygenase-2 (COX-2) within clinical dosage.

In clinical pharmacological studies, Etoricoxib inhibits COX-2 without inhibiting COX-1 with a dose of up to 150 mg daily. Etoricoxib does not inhibit the synthesis of stomach prostaglandin and does not affect platelet function.

Cycloxygenase is responsible for creating prostaglandin. Cycloxygenase has been identified: Cycloxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-2 is the isotopes of the enzyme that it is considered to be the main responsibility in the synthesis of prostanoid intermediaries related to pain, inflammation and fever. COX-2 is also involved in ovulation, egg nesting process and arteriosclerary closure, renal function and functions of the central nervous system (fever, pain and cognitive function). It can also play a role in healing the ulcer. Cox-2 has been found in tissues around the stomach ulcers in humans but its associated with the healing of unknown ulcers.

Clinical and safety effect:

Effective:

For patients with osteoarthritis, Etoricoxib dose 60 mg once daily brings a significant improvement in pain and assessment of patients' disease status. These beneficial effects were observed immediately on the second day of the treatment process and maintained up to 52 weeks. Studies with Etoricoxib dose 30 mg once a day shows higher efficiency than placebo in 12 weeks of treatment (using the same evaluation method as the above studies). In a dose study, Etoricoxib 60 mg proves a significant improvement of a 30 mg dose for all 3 Primary Endpoints in 6 weeks of treatment. The 30 mg dose is not studied in osteoarthritis.

In patients with rheumatoid arthritis, both Etoricoxib 60 mg and 90 mg once daily have significant improvements in pain, inflammation and movement. In studies assessing the dose of 60 mg and 90 mg, these beneficial effects are maintained during 12 weeks of treatment. In a day -by -dose of 60 mg compared to the dose of 90 mg, both doses are more effective than placebo.

The dose of 90 mg is stronger than the dose of 60 mg according to the patient's whole pain assessment (collected by visual method with an awareness of 0 to 100 mm), with an average improvement of 2.71 mm (95% CL: -4.98 mm, -0.45 mm). For patients with acute gout, Etoricoxib 120 mg per day during the 8 -day treatment period, alleviating joint pain and inflammation at an average to very severe to very severe, compared to Indomethacin 50 mg three times daily. Pain relief is clearly seen after only 4 hours after the beginning of treatment.

For patients with joint spondylitis, Etoricoxib 90 mg once daily brings a significant improvement in spinal pain, inflammation, stiffness and spinal function. The clinical effect of Etoricoxib is observed from the date of the second treatment after the beginning of treatment and maintained during 52 weeks of treatment. In a second study with the dose of Etoricoxib 60 mg compared to the doses of Etoricoxib 90 mg, both doses of Etoricoxib are similar to Naproxen 1000mg per day. In patients who do not respond well to Etoricoxib doses within 6 weeks, increasing the daily dose to 90 mg has improved the intensity of back pain (performed by visual method with an awareness of 0 to 100 mm) with an average value of -2.70 mm (95% CL: -4.88 mm, 0.52 mm), compared to the next treatment with a dose of 60 mg.

In a clinical study assessing toothache after surgery, Etoricoxib 90 mg is used once a day for three days. In the group of patients with average pain at the beginning of the study, Etoricoxib 90 mg has the same analgesic effect as Ibuprofen 600 mg (16.11 compared to 16.39; p = 0.722), and higher than the dose of paracetamol/codeine 600 mg/60 mg (11,00; p

Safety

Multinational long -term trial program on arthritis uses Etoricoxib and Diclofenac (Medal): Refer to the information instruction sheet information.

Data Supplies for cardiovascular health safety

In clinical studies except for the Medal research program, approximately 3100 patients are treated with Etoricoxib> 60 mg per day about 12 weeks or longer. There is no difference in the serious rate of cardiovascular thrombosis between patients using Etoricoxib> 60 mg, placebo or Non - Naproxen NSAIDS. However, the rate of these side effects is higher in patients using Etoricoxib compared to patients using Naproxen 500 mg twice a day. The difference in anti-platelet gathering between some NSAIDs inhibits COX-1 and selective COX-2 inhibitors may have clinical significance in patients at risk of vasoconstriction-thrombosis. Selective COX-2 inhibitors reduce the formation of systemicclin (and therefore can also be endothelial prostacyclin) without affecting platasal thromboxane. The clinical relevance of these observations has not been determined.

Additional data on gastrointestinal safety

In two 12 -week blind studies on endoscopy, the rate of gastric ulcerative accumulation is significantly lower in patients treated with Etoricoxib 120 mg once daily than patients treated with Naproxen 500 mg twice daily or Ibuprofen 800 mg three times daily. Etoricoxib has higher ulcer ratio than placebo.

Research on kidney function in the elderly

A random study, double blindness, placebo -use group research and control groups to evaluate the effectiveness of 15 days of treatment with Etoricoxib (90 mg), Celecoxib (200 mg, 2 times/day), Naproxen (500 mg, 2 times/day) and placebo on the excretion of sodium urinary, blood pressure, and other kidney function parameters in patients from 60 to 85 MEG/day of 200 MEG/day. Etoricoxib, Celecoxib, and Naproxen have similar effects on sodium excretion in two weeks of treatment. All parameters used for comparisons indicate that there is an increase in systolic blood pressure compared to placebo; However, Etoricoxib is involved in statistical increases on the 14th when compared to Celecoxib and Naproxen (the average change compared to the beginning on Tam Thu blood pressure is: Etoricoxib 7.7 mmHg, Celecoxib 2.4 mmHg, Naproxen 3.6 mmHg).

Dynamic pharmacokinetics

absorption

Etoricoxib is well absorbed by oral. Absolute oral bioavailability is nearly 100%. 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. AUC0-24 hours is 37.8 mcg hours/ml.

Mobile pharmacokinetics of linear Etoricoxib with clinical dose range. Meals (high in fat) have clinical significance to the level of absorption of 1 dose of Etoricoxib 120 mg. The absorption rate is affected, resulting in a 36% decrease in CMAX and increasing TMAX to 2 hours. These data are not considered clinical significance. In clinical trials, Etoricoxib is used without caring for meals.

distribution

About 92% of Etoricoxib dose attached to protein in human plasma within the concentration of 0.05 - 5 μg/ml. The distribution volume in sustainable state (Vmax is approximately 120 l in humans.

Etoricoxib through the placenta in mice and rabbits, and blood - brain barriers in mice.

transformation

Etoricoxib is strongly metabolized with There have been 5 metabolites identified in humans. The main metabolite is the carboxylic acid of etoricoxib formed by oxidation of oxidation of 6’-hydroxymethyl derivative. These main metabolites do not show measurable activity or just the weakened COX-2 inhibitors. These metabolisms do not inhibit COX-1.

Elimination

After an intravenous injection of a single -dose of 25 mg Etoricoxib has radioactive attachment to healthy subjects, 70% of radioactive activity is found in urine and 20% in feces, mainly in the form of metabolites. Under 2% of radioactive activities are found in non -metabolic drugs. The majority of Etoricoxib is excreted mainly through the process of chemistry, 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 sale time of about 22 hours. It is estimated that the removal of drugs in plasma is approximately 50 ml/min after an intravenous injection of 25 mg.

Special patient groups

Older patients: Pharmacokinetics in the elderly (aged 65 and older) similar to young people.

Sex: Etoricoxib's pharmacokinetics in men and women are the same.

Patients with liver failure: In patients with mild hepatic impairment (Child-Pugh 5-6), Etoricoxib dose 60 mg once a day has an average AUC average about 16% higher than healthy patients using the same dose mode. Patients with average hepatic impairment (Child-Pugh 7-9) use Etoricoxib 60 mg every two days, the average AUC is similar to that in healthy objects using Etoricoxib 60 mg once a day; Etoricoxib 30 mg once daily has not been studied for this group of patients. There is no clinical or pharmacokinetic document for patients with severe liver failure (Child-Pugh> 10).

Patients with kidney failure: The pharmacokinetics of the Etoricoxib 120 mg for patients with average to severe renal impairment and patients with end -stage kidney disease are treating with hemolysis, it is not significant compared to pharmacokinetics in healthy subjects. Hemolysis does not contribute significantly to the elimination of drugs (the removal of the segment is about 50 ml/minute).

Children: Etoricoxib's pharmacokinetics in children ( 60 kg designed to use Etoricoxib 90 mg once a day, it is like pharmacokinetics in adults using Etoricoxib 90 mg once a day. Etoricoxib's safety and effectiveness has not been established in children's patients.

Older patients: No need to adjust the dose with older patients; Like other drugs, should be cautious for these patients.

Patients with liver failure: Maximum use for patients with mild liver dysfunction for all indications of 60mg once a day (Child-Pugh 5-6). Patients with average liver dysfunction (Child-Pugh 7-9) not exceeding 30mg once a day.

There is no clinical experience in patients with average liver dysfunction and recommended caution. There is no clinical experience for severe liver dysfunction (Child-Pugh> 10); So contraindicated for these patients.

Patients with renal impairment: No dose adjustment for patients with creatinine clearance ≥ 30 ml/min. Contraindicated for patients with creatinine clearance

Children: Contraindicated for children and teenagers under 16.

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.

What to do when overdose?

In clinical studies, using Etoricoxib doses up to 500 mg and multiple doses up to 150mg/day for 21 days without significantly toxic. There have been reports on overdose with Etoricoxib, although the reactions are not reported in most cases. The most common adverse reactions are in line with the information about the safety of Etoricoxib (for example, digestive complications, heart and kidney problems).

Management

In case of overdose, it is advisable to use common support measures, such as removing non -absorbing substances from the digestive tract, conducting clinical monitoring and supportive treatment when necessary. Etoricoxib cannot be separated by hemorrhage; It is unknown whether Etoricoxib can be separated by peritoneal fertilizer.

In an emergency, call the 115 emergency center immediately or go to the nearest local health station.

What to do when forgetting 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double dose to compensate for missed dose.

Precautions when using

affects digestion

Aerodic complications on the gastrointestinal tract [perforation of the gastric, ulcer or hemorrhage (PUBS)], some deaths occurred when the patient was treated with Etoricoxib.

Be careful when treating patients who are at risk of gastrointestinal complications with NSAIDs; Elderly people, patients simultaneously use other NSAIDs or acetylsalicylic acid or patients with a history of gastrointestinal tract such as ulcers or hemorrhage.

The risk of adverse adverse effects in the stomach (stomach ulcer or other complications in the stomach) increases when using Etoricoxib at the same time as acetylsalicylic acid (even at low doses). Long-term clinical trials do not give a clear difference of safety in the gastric system between the Utility regimen of the selective inhibitors of COX-2 + Acetylsalicylic acid compared to NSAIDS + Acetylsalicy acid.

Cardiovascular effects

Risk of thrombosis:

Clinical trials show that the drugs of the selective inhibitor in Cox-2 may be related to the risk of thrombosis, especially myocardial and stroke, and also related to placebo and some other NSAIDs. Cardiovascular risks caused by Etoricoxib can increase according to the dose and time of use. This risk can appear early in the first few weeks of taking the drug and can increase over time. The risk of thrombosis is recorded mainly in 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 these symptoms appear.

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

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 Etoncoxib is a drug in this group, does not have the effect of inhibiting platelet's convergence, it is not allowed to stop using plateletic inhibitors when treated with Etoricoxib.

affects the kidneys

Prostaglandin produced in the kidneys may have a role in compensating for the maintenance of kidney perfusion. Therefore, in cases of reducing renal perfusion, the use of Roticox may reduce the formation of prostaglandin and the result is to reduce blood flow to the kidneys, resulting in reducing 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 before. Should consider monitoring kidney function in these patients.

Keeping water, edema and increasing pressure

As well as prostaglandin synthesis inhibitors, patients who take Etoricoxib are observed to retain water, edema and hypertension. All NSAIDs drugs, including Etoricoxib, may be related to the new onset or the recurrence of congestive heart failure, need to be cautious when used in patients with a history of heart failure, left ventricular dysfunction, or high blood pressure and in patients who have been edema for any other reason. If there is clinical evidence of the worsening condition of the patient, it is necessary to apply appropriate measures including stopping Etoricoxib.

Etoricoxib can make blood pressure more often and worse than some other NSAIDs and selective COX-2 inhibitors, especially at high doses. Therefore, hypertension should be fully controlled before treatment with Etoricoxib and pay special attention to the monitoring of blood pressure during treatment with Etoricoxib. Blood pressure should be monitored for the first two weeks after the beginning of treatment and periodically. If the blood pressure increases significantly, it is advisable to consider the replacement therapy.

influence the liver

The level of alanine aminotransferase (ALT) and/or Aspartate Aminotransferase (AST) (about three times or more than the upper limit) has been reported in about 1% of patients in clinical trials treated for up to a year with Etoricoxib 30.60 and 90 mg per day

Any patient shows signs of liver dysfunction, or in people whose results of liver function tests have abnormalities, need to be monitored. If signs of liver failure, or if there is an abnormal liver function test (three times higher liver enzymes), should stop using Etoricoxib.

The overall influence

During the treatment process, if the patient has impaired function of the system described by the system, it is necessary to take appropriate measures and stop using Etoricoxib. Maintenance of Etoricoxib should be maintained in elderly patients and patients with kidney, liver or heart dysfunction.

Be careful when starting to treat Etoricoxib for dehydration patients, need to rehydration for this patient before starting treatment with Etoricoxib.

In the report of drug monitoring after circulation shows a serious skin reaction, some of which are fatal, including skin peeling dermatitis, Stevens-Johnson syndrome and poisoned epidermal necrosis are rarely related to NSAIDs and but COX-2 inhibitors.

Patients with the highest risk of these effects in the first phase of the first month of treatment.

Serious hypersensitivity reactions (anaphylaxis and angioedema) have been reported to patients using Etoricoxib. Some selective COX-2 inhibitors related to an increase in the risk of reactions occurring in the skin in patients with a history of drug allergies. Etoricoxib should be discontinued as soon as the skin rash appears, mucosal damage or any other hypersensitivity signs.

Etoricoxib can hide fever and other inflammatory signs.

Be careful when using Etoricoxib with warfarin or other oral anticoagulants.

Use Etoricoxib as well as any product that inhibits the synthesis of cyclooxygenase/ prostaglandin that is not recommended for women to prepare for pregnancy.

The effect of drugs for driving and operating machinery

Patients who have been dizzy, dizzy or drowsiness while using Etoricoxib not to drive and operate machinery.

Pregnant or lactating women

Pregnancy

There is no clinical data on the impact of pregnancy when using Etoricoxib. Animal studies show that drugs are toxic to reproduction. The risk of toxicity for pregnant women is not known. Etoricoxib as well as other prostaglandin synthesis inhibitors, which can cause uterus and cause early arteriosclerate during the third quarter of pregnancy. Contraindicated Etoricoxib for pregnant women. If women are pregnant during treatment, Etoricoxib must be discontinued.

Breastfeeding period

There is no evidence of Etoricoxib whether or not to excrete in breast milk. Etoricoxib is excreted into milk in mice. Breastfeeding women must not use Etoricoxib.

fertility

Women who are preparing to get pregnant should not use Etoricoxib as well as COX-2 inhibitors.

Drug interaction

Pharmacological interaction

Anticoagulant drugs for oral oral:

For patients stabilizing with long-term warfarin therapy, the dosage of Etoricoxib 120 mg per day is usually related to an increase of about 13% of the international standard chemical ratio in prothrombin time (International Normalized Ratio-inr). For patients taking oral anticoagulants, regular Inr should check prothrombin at the beginning of treatment (especially the first few days) or when changing the dose of Etoricoxib.

Diuretics, enzyme inhibitors and Angiotensin II:

ns daids may reduce the treatment of hypertension of diuretics, ACE inhibitors and Angiotensin II antagonists. In some patients with impaired renal function (such as elderly patients or patients who have lost their cycles, including patients using diuretic therapy) taking nonsteroidal anti-inflammatory drugs, including COX-2 selective inhibitors, simultaneous use of Etoricoxib with ACE inhibitors or Angiotensin II antagonists can cause bad kidney function, including acute renal impairment and usual.

These interactions should be considered in patients who use Etoricoxib simultaneously with transferred or angiotensin II transfusion or antagonists. Therefore, be careful when combining the above drugs, especially in the elderly. Patients need to be fully compensated and need to consider monitoring the kidney function as soon as they start treating these medications at the same time and periodically monitoring later.

acetylsalicylic acid:

In a study in healthy people, in a stable state, Etoricoxib 120 mg once daily does not affect the anti -platelet adhesion of acetylsalicylic acid (81 mg once a day). Etoricoxib can be used simultaneously with acetylsalicylic acid at the dosage to prevent cardiovascular disease (low -dose acetylsalicylic acid).

However, simultaneously taking low -dose acetylsalicylic acetylsalicylic acid with Etoricoxib increases the rate of gastrointestinal ulcer or other complications compared to the case of only Etoricoxib. Etoricoxib should not be used simultaneously with acetylsalicylic acid higher than the cardiovascular prophylactic dose or with other NSAIDs.

ciclosporin and tacrolimus:

Although this interaction with Etoricoxib has not been studied, simultaneously used Ciclosporin or Tacrolimus with any NSAID can increase the toxicity of Ciclosporin or Tacrolimus's kidneys. Kidney function should be monitored when shared Etoricoxib with one of these drugs.

pharmacokinetic interaction

Effect of Etoricoxib on the pharmacokinetics of other drugs

lithium:

NSAIDS reduces lithium excretion through the kidneys and thus increases lithium concentration in plasma. If necessary, closely monitor the blood lithium and adjust the lithium dose while coordinating with Etoricoxib and when stopping NSAID.

methotrexate:

Two studies have surveyed the effects of Etoricoxib 60.90 or 120 mg once a day for seven days for patients who are taking methotrexate once a dose from 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib dose 60 and 90 mg does not affect methotrexate levels in plasma or kidney clearance. In another study, Etoricoxib 120 mg increases methotrexate levels in plasma by 28% and reduces the renal clearance of the renal of methotrexate 13%. Recommendations to fully monitor the toxicity of methotrexate when used simultaneously Etoricoxib and Methotrexate.

Oral contraceptive pills:

Etoricoxib 60 mg simultaneously used with birth control pills containing 35 microgram ethinyl estradiol (EE) and 0.5 - 1 mg norethindrone in 21 days has increased AUC0 -24H in stable state of EE 37%. Etoricoxib 120 mg simultaneously used with oral contraceptives or 12 hours apart, increasing AUC0-24H in stable state of EE from 50% to 60%. The phenomenon of increasing EE concentration should be considered when choosing contraceptives simultaneously with Etoricoxib.

Increasing contact (AUC) Ethinyl estradiol can increase the adverse events associated with the use of contraceptives (such as venous thrombotic events in risky women).

Hormon replacement therapy (HRT):

Etoricoxib 120 mg treatment with hormonal replacement therapy contains conjugated estrogen (0.625 mg premarin ™) in 28 days, increasing the AUC0-24H in stable state of non-conjugate estrone (41%), Equilin (76%) and 17-β-Eltradiol (22%). The impact of the recommended doses of Etoricoxib (30.60, VA 90 mg) for prolonged use has not been studied.

The impact of Etoricoxib 120 mg on (AUC0-24H) of the estrogen components of premarin ™ shows that AUC0-24H is half less than the case of observation when using a single premarin ™ and when the dose increases from 0.625 to 1.25 mg. The clinical significance of this increase is unknown and the higher dose of premarin is not studied when combined with Etoricoxib. The increase in the concentration of estrogen when choosing postmenopausal hormonal replacement therapy and simultaneously with Etoricoxib because of the increase in exposure (AUC) of estrogen will increase the risk of events related to hormone replacement therapy.

Prednisone/Prednisolone: ​​

In drug interactive studies, Roticox has no clinical important effects on pharmacokinetics of Prednisone/Prednisolone.

digoxin:

Etoricoxib 120 mg is used once a day for 10 days for healthy volunteers not to change AUC0-24H in plasma in a stable state or eliminate digoxin through the kidney. There is an increase in CMAX Digoxin (approximately 33%). This increase is not important for most patients. However, patients at risk of digoxin toxicity should be monitored when used simultaneously Etoricoxib and Digoxin.

Effects of Etoricoxib on drugs metabolized by sulfotransferase:

Etoricoxib is an inhibitor of sulfotransferase in humans, especially sult1e1, and increases the concentration of ethinyl estradiol. Although the knowledge of the effects of many sulfotransferase on many drugs is still limited and clinical results for many drugs are still being considered, cautious when prescribing Etoricoxib with drugs mainly metabolized by sulfotransferase (e.g. salbutamol oral and minoxidil).

Effects of Etoricoxib on drugs metabolized by CYP Isoenzymes:

Based on In vitro, Etoricoxib studies do not affect the inhibition of Cytochromes P450 (CYP) 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study on healthy people, the daily dose of Etoricoxib 120 mg does not change the activity of CYP3A4 in the liver after being assessed by checking the breath of Erythromycin.

Effect of other drugs on Etoricoxib's pharmacokinetics:

Etoricoxib's main metabolic path depends on CYP enzymes. CYP3A4 seems to contribute to the metabolism of Etoricoxib in the body. In vitro studies show that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyze the main transformation path, but their quantitative role has not been studied in the human body.

ketoconazole:

Ketoconazole, a strong inhibitor of CYP3A4, a dose of 400 mg once a day, used about 11 days for healthy volunteers, without an important clinical impact on the pharmacokinetics of the only dose of 60 mg of etoricoxib (an increase of AUC 43%).

voriconazole and miconazole:

Simultaneously use Etoricoxib with voriconazole oral or miconazole gel tops - are strong CYP3A4 inhibitors, slightly increasing the AUC of Etoricoxib, but not clinically based on the announced data.

rifampicin:

Simultaneous use of Etoricoxib with rifampicin, is a strong stimulant of CYP enzymes, reducing 65% of the Etoricoxib concentration in plasma. This interaction can lead to recurrence of symptoms when sharing et vamricoxib with rifampicin. This information leads to the suggestion of increasing the dose but the dose is greater than the dose of each indicator above when combined with Rifampicin has not been studied.

Antacids:

Antacids do not affect the pharmacokinetics of the clinical Etoricoxib.